Next Article in Journal
Non-Coding RNAs in the Therapeutic Landscape of Pathological Cardiac Hypertrophy
Next Article in Special Issue
Immune Checkpoint Proteins, Metabolism and Adhesion Molecules: Overlooked Determinants of CAR T-Cell Migration?
Previous Article in Journal
Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells
Previous Article in Special Issue
How CAR T Cells Breathe
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 11
Issue 11
10.3390/cells11111804
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies

by
Katsiaryna Marhelava
1,
Marta Krawczyk
1,2,3,
Malgorzata Firczuk
1,2 and
Klaudyna Fidyt
1,*
1
Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland
2
Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
3
Doctoral School of Translational Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Cells 2022, 11(11), 1804; https://doi.org/10.3390/cells11111804
Submission received: 27 April 2022 / Accepted: 27 May 2022 / Published: 31 May 2022
(This article belongs to the Special Issue State of the Art in CAR-T Cell Therapy)
Browse Figure
Versions Notes

Abstract

:
Chimeric antigen receptor (CAR)-T cell therapy is undeniably a promising tool in combating various types of hematological malignancies. However, it is not yet optimal and a significant number of patients experience a lack of response or relapse after the treatment. Therapy improvement requires careful analysis of the occurring problems and a deeper understanding of the reasons that stand behind them. In this review, we summarize the recent knowledge about CAR-T products’ clinical performance and discuss diversified approaches taken to improve the major shortcomings of this therapy. Especially, we prioritize the challenges faced by CD19 CAR-T cell-based treatment of B cell-derived malignancies and revise the latest insights about mechanisms mediating therapy resistance. Since the loss of CD19 is one of the major obstacles to the success of CAR-T cell therapy, we present antigens that could be alternatively used for the treatment of various types of B cell-derived cancers.

1. Introduction

In the last decade, chimeric antigen receptor (CAR)-modified T cells have emerged as a breakthrough treatment for patients with relapsed/refractory (r/r) B cell-derived malignancies. Until now, B cell acute lymphoblastic leukemia (B-ALL) and B cell lymphoma patients have benefited most from this clinically-approved cellular therapy. The survival prognosis for r/r B-ALL and diffuse large B cell lymphoma (DLBCL) patients who receive conventional treatment is still not satisfactory. Before the approval of CD19 CAR-T cells, the 3-year survival rate after the first relapse for adult B-ALL was 11% [1], whereas for pediatric patients the event-free survival did not exceed 50% [2,3]. For relapsed DLBCL patients, 4-year progression-free survival varied between 20 and 40% [4]. Similar to r/r B cell cancers, plasma cell-derived malignancy—multiple myeloma (MM) is difficult to manage clinically, especially due to an increasing resistance to the available treatment regimens [5,6]. Therefore, very recently, CAR-T therapy targeting B cell maturation antigen (BCMA) was introduced for the treatment of r/r MM patients [7].
Unfortunately, despite the undeniable success of CAR-T cell therapy in hemato-oncology, there are still patients who progress after this therapy or develop resistance mechanisms that avert the eradication of malignant cells. Taking into consideration major CAR-T pitfalls, herein, we describe novel strategies aimed at boosting the antitumor effects of this highly personalized treatment. In particular, we present improvements in the area of CAR-T cells persistence and the management of effector cells exhaustion. Furthermore, we highlight the mechanisms exploited by malignant B cells to escape the CD19 CAR-T treatment. Indeed, we characterize various factors contributing to the development of resistance, both related and unrelated to the CD19 antigen loss. Lastly, we describe surface molecules that could be used as new promising targets for CAR-T adoptive therapy in B cell and plasma cell-derived blood cancers.

2. Clinically Available CAR-T Therapies

Currently, there are four different CD19-targeting, and one BCMA-targeting CAR-T products, approved by American and European Drug Agencies (Food and Drugs Administration and European Medicines Agency, respectively). All these products are used for the treatment of malignancies derived from abnormal B cells at different stages of their differentiation.
The general structure of a CAR construct includes four parts: (1) an extracellular antigen-binding domain, (2) a hinge, (3) a transmembrane helix, and (4) an intracellular signaling domain. Accordingly, decades of research in the area of CAR design have led to the development of five CAR-T cell generations, each of them differing in an intracellular signaling milieu composition. In fact, the first CAR-T generation contains only a single immunoreceptor tyrosine-based activation motif (ITAM) domain derived from a CD3ζ chain of the T cell receptor (TCR). Further approaches have involved adding one (second generation) or two (third generation) co-stimulatory domains (mostly CD28 and/or 4-1BB) that enhance CAR-T cells activation and persistence [8,9,10]; however, in order to additionally boost the CAR-T cells activation, proliferation, and killing potential, fourth and fifth CAR-T generations were designed [11]. Such CAR-T cells are armored with additional intracellular domains responsible for specific cytokines production (e.g., IL-12, IL-2). These CAR-T cells are currently being evaluated in the research phase.
CAR-T cells products used for therapy of hematological patients represent the second CAR-T cell generation, with either a CD28 or 4-1BB (CD137) co-stimulatory domain. Since 2017, four CAR-T cell products aimed to target CD19 were approved based on pivotal phase 1/2 clinical trials, all of which are still active. Initial clinical responses for each trial and appropriate follow-up studies results (with observations lasting longer than 2 years) are summarized in Table 1.
Out of these four products only tisagenlecleucel (Kymriah) is registered for children and young adults (up to 25 years old) with B-ALL, who are refractory to previous treatment regimens, or with more than two relapses. Considering that it was the first CAR-T cell therapy approved, there is the longest follow-up available for this product (median 4.8 years), showing complete response (CR) in more than 60% of the patients and overall survival (OS) equal to 10.5 months [13]. On the other hand, the access to CD19-targeted CAR-T therapy for adult r/r B-ALL patients was not granted until recently, when in October 2021 the FDA approved brexucabtagene autoleucel (Tecartus) for such indication. The registration was based on the multicenter ZUMA-3 trial [20,25]. The efficacy estimation group in the phase 2 ZUMA-3 trial included 55 adult previously treated patients, of which 27% represented a high-risk group, bearing BCR-ABL1 translocation [20]. CR was achieved in 56% of the patients, and more importantly, CR or complete remission with incomplete hematological recovery (CRi) was reached in 60% of the patients previously submitted to blinatumomab, another CD19-targeted immunotherapy. The side effects post CAR-T infusions were generally manageable. Taking into consideration the combined results of phases 1 and 2, the median duration of remission in this trial was estimated by the investigators at 13.4 months; however, a longer follow-up is needed to draw stronger conclusions regarding safety profiles and the durability of responses.
In addition to adult B-ALL, brexucabtagene autoleucel is also approved for the treatment of mantle cell lymphoma (MCL). The results gathered during ZUMA-2 trial showed encouraging responses in heavily pre-treated r/r MCL patients, with CR achieved in 67% after single CAR-T administration [19]. Common adverse events following CAR-T therapy occurred in the majority of treated patients, however, they were mostly manageable. A one-year follow-up of the ZUMA-2 trial presented at the 2020 ASH Annual Meeting showed that with a median of 17.5 month-long observations, the CR was maintained in 67% of the patients [26].
For the treatment of B cell lymphomas, several CAR-T products are available. Based on JULIET [14] and ZUMA-1 [16] trials, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), respectively, were first to be approved for the treatment of various types of B cell lymphoma, including adult r/r DLBCL, DLBCL arising from follicular lymphoma (FL), or primary mediastinal large B cell lymphoma (PMBCL), for the patients who failed after two or more lines of systemic therapy (see Table 1 for more details). Importantly, long-term follow-up of patients’ status within these trials (median follow-up exceeding 3 years) provided data showing a superior efficacy of Yescarta, with median OS reaching 25.8 months [17] as compared to 11.1 months for Kymriah [15]. This discrepancy, however, could arise from the fact that most of the patients in the JULIET study received a bridging therapy (e.g., rituximab, nucleoside analogues, corticosteroids), whereas in the ZUMA-1 trial bridging chemotherapy was not allowed, with the exception of corticosteroids administration. Thus, one can speculate that the JULIET trial included more patients with aggressive lymphomas; however, the direct impact of bridging therapies on CAR-T responses should not be excluded.
The year 2021 was extremely rich in FDA/EMA approvals for CAR-T therapies. In addition to the aforementioned Tecartus approval for r/r adult B-ALL, the additional registrations included axicabtagene ciloleucel (Yescarta) for r/r adult FL [18], and lisocabtagene maraleucel (Breyanzi) for adult r/r DLBCL, r/r PMBCL, grade 3B FL [21]. Moreover, in 2021, we witnessed the first approval of a BCMA-directed CAR-T therapy designated for adult r/r MM patients who had failed at least four previous lines of treatment [24]. Indeed, the efficacy of idecabtagene vicleucel (Abecma) was evaluated in the pivotal KarMMa clinical trial [23]. Stringent CR (sCR) was detected in only 28%, however, the CAR-T cells were administered to patients with a significant number of prior lines of treatment (median of 6 lines) [24]. Importantly, 65% of the patients who achieved sCR had a durable response for at least 12 months. All in all, CAR-T cells targeting BCMA seem to be an attractive treatment option for heavily pre-treated, relapsed MM patients. Certainly, a longer follow-up is still required to estimate the safety profiles and survival rates in a long run.

3. Managing Major Pitfalls of CAR-T Cell Therapy

Despite the phenomenal success of CD19 CAR-T therapy, it is not without limitations and side effects. The challenges faced by CAR-T cell therapy are related to both effector and target cells and include: (1) proliferation, persistence, and exhaustion of CAR-T cells, (2) side effects, (3) immunosuppressive tumor microenvironment, and (4) tumor intrinsic factors that account for the development of resistance.
The obstacles related to effector CAR-T cells are elegantly described by others [27,28,29,30,31]. Therefore, below we only shortly present currently investigated and implemented solutions to modulate insufficient CAR-T cells persistence in vivo, and exhaustion of the effector cells. Considering, however, that more and more data is now gathered on tumor related features contributing to immunotherapy resistance, in this review we will mostly focus on limitations and solutions concerning target cells. In particular, we portray the mechanisms responsible for resistance to CD19 CAR-T therapy, both CD19-dependent and independent (Section 4), and new antigens explored in hemato-oncology (Section 5).

3.1. Improvement of CAR-T Cells Persistence

The sufficient number of viable and functional CAR-T cells is one of the major contributors to the therapy’s success [16,32]. The poor persistence even after the achievement of complete remission is considered to be the main reason for the development of CD19-positive relapses [33,34]. One of the features affecting CAR-T cell persistence and proneness to exhaustion is the co-stimulatory domain incorporated in the CAR construct. CD28 and 4-1BB are the most frequently exploited co-stimulatory domains in pre-clinically tested and in clinically available CAR products (Table 1). Several studies have demonstrated a higher proliferative capacity and longer in vivo persistence of CAR-T cells bearing a 4-1BB domain as compared to CD28 [35,36]. This effect was at least partly attributed to the 4-1BB-mediated activation of non-canonical nuclear factor κB (ncNF-κB) signaling in CAR-T cells [37]; however, as CARs with a CD28 domain exhibit more rapid tumor elimination [38], attempts to improve their in vivo performance have led to a generation of mutant CD28 endodomain [39], or third generation CARs containing both CD28 and 4-1BB sequences [40]. The latter were demonstrated to retain the beneficial aspects of both domains, showing enhanced antitumor activity and concomitantly increased in vivo persistence.
In the clinical settings, in order to improve CAR-T cells persistence and thus the overall therapy efficacy, lymphodepleting chemotherapy is performed prior to CAR-T cells infusion. The pre-conditioning is most often based on fludarabine and/or cyclophosphamide administration. The reason standing behind this approach was demonstrated in several studies showing higher response rates in patients with r/r B-ALL [41,42], and non-Hodgkin lymphomas, including r/r DLBCL [43,44,45], who received lymphodepleting chemotherapy regimens prior to CD19 CAR-T cells. Primarily, lymphodepletion reduces the numbers of endogenous lymphocytes, which normally absorb the cytokines that stimulate T cells proliferation and thus limit their availability for infused CAR-T cells [44,46]. In addition, it partially eliminates T regulatory cells (Tregs) which exhibit immunosuppressive activity towards tumor-specific cytotoxic T cells [47]. The beneficial effect of lymphodepleting regimens was demonstrated for both CD8-positive and CD4-positive CAR-T cell populations [48].
However, the intensity of existing pre-conditioning therapy using fludarabine and cyclophosphamide was shown to be correlated with higher toxicity of the CAR-T cell-based therapy, thus it may exclude the application of this approach for numerous patients [49]. The approach of targeted lymphodepletion with a CD45-directed antibody radioconjugate, which was recently shown to eliminate several subsets of leukocytes while preserving progenitor hematopoietic cells in a murine model, could potentially be proposed as a safer alternative [50]. However, regardless of the lymphodepleting protocol used, the inevitable side effects of these regimens are lymphopenia and prolonged T cells dysfunction, which may lead not only to overall higher sensitivity to infections and autoimmunity development, but also to tumor relapse [51].
Some already existing approaches undermine the need for lymphodepletion. The most prominent is based on the construction of CAR-T cells that besides having the ability to recognize specific targets can also produce selected proteins, in particular cytokines [52]. These 4th generation CAR-T cells are called TRUCKs (T cells redirected for antigen-unrestricted cytokine-initiated killing). Cytokines are crucial for CAR-T cells’ survival, proliferation and persistence, both during in vitro culture and following the administration into the patient [53]. The additional modification of CD19 CAR-T cells to secrete IL-12 was shown to improve their in vivo cytotoxicity towards murine cells expressing human CD19 and alleviate their suppression by Tregs—the main two aims of pre-conditioning with chemotherapy [54]. Similar observations were made by Kueberuwa et al., who demonstrated that CD19 CAR-T cells expressing IL-12 effectively eliminated lymphoma cells in fully lymphorepleted mice [55]. Besides the killing of CD19-positive target cells directly, the TRUCKs also contributed to the induction of an anticancer response elicited by the host immune cells, primarily CD8-positive T cells.
Except for IL-12, other cytokines were also shown to improve the persistence and effector functions of transferred cytotoxic T cells. In particular, IL-2, IL-7, and IL-15 supplementation during the culture of CAR-T cells has beneficial effects [56,57]. Interestingly, CAR-T cells expanded with IL-15 exhibited a higher anticancer efficacy as compared to IL-2-supplemented CD19 CAR-T cells against a lymphoma cell line in vivo [58]. In addition, IL-15-expressing CAR-T cells appear to be less terminally differentiated and have an increased ability to expand in vitro, but also tend to be more toxic in vivo due to the simultaneously higher production of TNF-α and IL-2, as compared to CAR-T cells without IL-15 [59]. On the other hand, constitutive cytokine expression poses a risk for the uncontrolled growth of administered CAR-T cells which may lead to overt toxicity. Several research groups have demonstrated that novel CAR constructs may be engineered to induce cytokine signaling only after antigen stimulation (5th CAR-T generation) and preserve their superior antitumor effects while having minimal toxicity [60,61,62]. The additional incorporation of an inducible caspase-9-based suicide gene, which mediates the selective depletion of CAR-T cells in case of toxicity, may increase the safety while keeping all the advantages of the therapy based on using anti-CD19 TRUCKs [63,64,65].

3.2. Modulation of CAR-T Cells Exhaustion

The effectiveness of CAR-T cells is also impeded by their exhaustion, which is often caused by the enhanced expression of immune checkpoint molecules on cancer cells and CAR-T cells. In particular, PD-1/PD-L1 interaction activates downstream signaling pathways and inhibits T cell activation, which leads to tumor immune escape [66]. PD-L1 was reported to be overexpressed in classical Hodgkin lymphoma [67,68] and DLBCL [69]. Moreover, PD-1 expression was observed to be increased on T cells isolated from B-ALL patients’ bone marrow aspirates [70]. Similarly, CD19 CAR-T cells were also reported to have increased PD-1 expression following the infusion to the patients [71]. The solution for this issue can be achieved by combining a CAR-based therapy with anti-PD-1 antibodies [72,73], or their administration just after CAR-T failure [74]. The more advanced and safe approaches include the delivery of CAR-T cells secreting anti-PD-1 scFv [75], or the transformation of PD-1 in CAR-T cells into a co-stimulatory molecule using the switch-receptor technology [76].
Recent reports have also shown that CAR-T cells exhaustion occurs due to epigenetic reprogramming [77,78,79]. In a clinically-relevant setting, Zebley et al. observed the changes in DNA methylation patterns in CD8-positive CD19 CAR-T cells that were previously administered to B-ALL patients [79]. Importantly, a deletion of a gene coding DNA methyltransferase 3 alpha (DNMT3A) in T cells bearing CAR constructs augmented a long-term antitumor response and prevented them from developing an exhausted phenotype [77]. In addition, several other modifications show promise to limit CAR-T cells exhaustion. For instance, CAR-T cells engineered to overexpress a transcription factor c-Jun had an improved ability to resist exhaustion and maintain functionality despite prolonged activation [80].
There are also other factors contributing to the loss of CAR-T cells effector abilities, including those related to CAR tonic signaling [81]. One of the consequences of CAR tonic signaling is terminal differentiation to effector cells. The available literature indicates the involvement of sustained phosphoinositide 3-kinase (PI3K)/Akt pathway activation in this process [82,83]. Therefore, pharmacological approaches aimed at PI3K/Akt signaling inhibition have been implemented during the manufacturing phase to maintain CAR-T cells stemness, including the addition of tyrosine kinase inhibitors, e.g., idelalisib [84], ibrutinib [85], or duvelisib [86]. In addition, the modifications of CAR constructs may be performed to address the issue of CAR tonic signaling and involve several aspects, e.g., the substitution of co-stimulatory domains, alterations in the spacer and hinge domain, or the improvement of scFv stability [81]. An alternative approach is to reduce CAR surface expression and selectively switch-off CAR signaling. This could be achieved by incorporating the ligand-induced degradation/destabilizing domain into the C-terminus of the CAR construct [87,88]. In addition, Weber et al. modulated CAR-T cells exhaustion by the addition of dasatinib, a tyrosine kinase inhibitor that reversed the tonic signaling and led to downregulation of the immune checkpoint markers [88]. Importantly, dasatinib administration inhibits the secretion of cytokines by CAR-T cells and impairs their in vivo antitumor activity [89]. This effect, however, is reversible after the drug discontinuation, which implies that short-term dasatinib treatment could be used as a switch to control CAR-T cells’ performance.

4. Mechanisms of Resistance to the CD19 CAR-T Therapy in B Cell Malignancies

As already mentioned in Section 3, not only insufficient effector cells are to blame for CAR-T therapy failures. Intrinsic features of malignant B cells also significantly contribute to the development of resistance underlying a relapse in patients with B-ALL and high-grade lymphomas. Indeed, the relapse in B-ALL patients following CD19 CAR-T treatment can affect even half of them, but the cumulative incidence of relapse according to the meta-analysis of available clinical trials’ reports is estimated at 36% [90]. The most commonly reported causes of tumor resistance to CD19 CAR-T treatment and subsequent relapse concern various tumor cells aberrations, among which the loss of CD19 antigen is the most frequent [91]. The loss of CD19 is reported even in up to 25% of B-ALL cases [12,92,93,94,95]. The relapses after CD19 CAR-T therapy occur also in lymphomas, where about 30% of the patients demonstrate a loss of CD19 expression [16,96,97]. Moreover, in some patients the CD19 downregulation is accompanied by decreased expression of other surface antigens, such as CD20 and CD22 in B-ALL [98] and similarly CD20, CD22, and CD79a in lymphomas [99,100]. Below, we describe the currently known tumor-intrinsic mechanisms of CD19 CAR-T therapy resistance, highlighting the similarities and differences between various B cell malignancies, particularly B-ALL and B cell lymphomas (Figure 1).

4.1. Resistance Related to CD19 Antigen

One of the causes of the CD19 antigen loss is a mutation in the CD19 gene and alternative splicing of the CD19 transcript. The missense and frameshift mutations in exon 2 of the CD19 gene, as well as alternative splice variants lacking exon 2 or exons 5–6, were detected in samples from relapsed B-ALL patients after CD19 CAR-T therapy [101]. Sotillo et al. also highlighted that the deletion of exon 2 promotes arising of the N-terminal truncated CD19 isoform, which prevents killing by CD19 CAR-T cells, due to the loss of the epitope recognized by a particular anti-CD19 scFv used in this study [101]. Moreover, CD19 exon 2 retention was linked with a function of serine and arginine-rich splicing factor 3 (SRSF3). The reduced expression of SRSF3 and consequent N-terminally truncated CD19 was observed in samples from B-ALL patients who relapsed after CD19 CAR-T [101]. Similar results were obtained by Orlando et al. [102], where CD19 mutations were linked to the antigen loss. The analysis of primary material from 17 B-ALL pediatric and young-adult patients with relapses after CD19 CAR-T administration revealed that 12 of them were CD19-negative. All of these 12 patients had mutations in the CD19 gene that affected exons 2–5 and led to the expression of a truncated protein devoid of the transmembrane domain; however, some of the observed mutations could be subclonal, which is reflected by the ratio between the CD19 negative cells percentage and the rate of mutations observed in the patients’ sample [102]. Later studies showed that CD19 splice variants lacking exon 2 were also detected in B-ALL pediatric patients at diagnosis and could be the cause of initial leukemia resistance to CD19-targeting CAR-T treatment [103]. Similar observations were made for B cell lymphoma, where CD19 isoforms with exon 2 and exons 5–6 aberrations (that could affect FMC63 epitope) were detected in patients’ samples and were found to be more common after relapse. On the other hand, the full-length isoform of CD19 was co-expressed with spliced variants in relapsed samples, suggesting that the loss of the FMC63 epitope is not the only cause of relapse [100].
Another genetic-related factor that could account for the CD19 loss is the retention of intron 2 in CD19 mRNA. The presence of intron 2 in mature mRNA molecules can induce premature termination and decay of the CD19 transcript or the appearance of a truncated protein. The phenomenon of intron 2 retention was revealed using lymphoma and B-ALL cell lines models and confirmed in matched diagnosis-relapse B-ALL patients’ samples [104].
Recent studies also showed that the antigen loss following CD19 CAR-T therapy can be a result of hypermethylation of the CD19 promoter in tumor cells [105]. It was demonstrated in an in vivo chronic lymphocytic leukemia (CLL) relapse model after CD19 CAR-T treatment, as well as in vitro experiments using primary CLL cells and CLL and Burkitt lymphoma cell lines co-cultured with CD19 CAR-T cells. The correlation between CD19 promoter hypermethylation and decreased CD19 expression was found to be reversible by demethylating drugs, highlighting the reversible character of this epigenetic modification.
In addition to CD19 loss on the surface of malignant cells, CAR-T therapy failure may be caused by CD19 epitope masking. This mechanism was identified by Ruella et al. in a B-ALL patient with relapse that was discovered almost 9 months after CD19 CAR-T treatment [106]. Unexpectedly, the researchers observed CAR-expressing leukemic blasts in the patient’s bone marrow. It turned out to be a result of unintentional CAR transgene insertion into a single neoplastic B cell during the CD19 CAR-T cells manufacturing process. As a consequence, CAR expression on the cell surface of leukemic B cells masked the CD19 epitope in cis and hampered the binding of the antigen by CAR-T cells. This phenomenon was further confirmed using a CD19 CAR-modified Nalm-6 cell line and in a xenograft model in vivo. These experiments proved that leukemic B cells expressing CAR are resistant to CD19 CAR-T cell-mediated killing [106]. This discovery contributed to modifications of the CAR-T manufacturing protocols and the development of new strategies providing maximal T cell selection [107,108]. Importantly, the CD19 epitope masking may also be due to prior CD19-targeted therapy. Indeed, Fitzgerald et al. observed that tafasitimab, an anti-CD19 antibody approved for r/r DLBCL treatment, masked the CD19 epitope and caused a delay in CD19 CAR-T therapy responses [109].
Yet another way of resistance to CD19 CAR-T cell therapy is lineage switch, which results not only in CD19 loss but also in many other phenotypic changes. It was demonstrated that some B-ALL patients after CD19 CAR-T treatment relapsed with a myeloid type of leukemia expressing CD34, CD33, or CD64 markers [110]. Moreover, lineage reprogramming in these cases was found to be correlated with the aberration of genes encoding Pax5, EBF1, or FLT3. The phenomenon of lineage switch is one of the causes of resistance to CD19 CAR-T therapy, mainly in mixed lineage leukemia (MLL)-rearranged B-ALL [111,112,113], however, one case was also detected in a Philadelphia chromosome-positive B-ALL patient [114]. Recent studies showed that a similar situation can also occur in lymphomas. Zhang et al. described the case of MCL that transdifferentiated into sarcoma [115]. It was triggered by epigenetic reprogramming, including the silencing of mature B cell characteristic genes by promoter DNA methylation. The broad analysis of samples from patients with lymphomas (mainly DLBCL) before and after CD19 CAR-T therapy displayed a tremendous phenotypic shift in tumor cells after CAR-T infusion. These genomic changes included downregulated expression of B cell markers (CD19, CD20, CD22, CD79a), an increased methylation profile, and mutations affecting immune suppressive mechanisms, such as the PI3K pathway [116].

4.2. Resistance Not Related to CD19 Antigen

Currently, it is known that not only CD19 aberrations can influence the response to CD19 CAR-T immunotherapy. The circulating tumor DNA profiling of samples from r/r DLBCL patients who underwent CD19 CAR-T treatment determined the association of SOCS1, TNFAIP3, and XPO1 mutations with a poor prognosis after that therapy [117]. Additionally, the whole-genome sequencing analysis of CD19 CAR-T-treated large B cell lymphoma patients indicated some tumor intrinsic aberrations, such as RHOA or RB1 deletions, APOBEC mutational activity, and chromothripsis events as characteristics for relapsed patients [118,119]. The aforementioned defects were accompanied by preserved CD19 expression.
An inherent resistance of neoplastic B cells for CD19 CAR-T therapy has been also correlated with aberrant expression of genes from the death receptor apoptosis pathway such as BID, FADD, CASP8, TNFRSF10B, Fas, and TRAIL [91,120]. The crucial role of death receptor signaling in susceptibility to CD19 CAR-T cytotoxicity was demonstrated in a Nalm-6 B-ALL cell line in vitro model and CRISPR-based genome-wide loss-of-function screen [121,122]. It was observed that Nalm-6 cells with a deletion of apoptotic genes, such as BID or FADD, diminished the CAR-T cells’ expansion and their cytotoxic abilities. Moreover, analysis of primary samples from B-ALL pediatric patients after CD19 CAR-T therapy indicated a lower expression of death receptor signaling genes in a group of patients who did not respond to the treatment as compared to those who achieved complete remissions [122]. Using the same approach based on the CRISPR-based screen, the significant role of Fas-FasL in antigen-specific T cell killing was confirmed in B cell lymphoma cell lines [123].
In addition to the aforementioned resistance mechanisms, the lack of CD58 on the surface of malignant B cells, a co-stimulatory ligand for CD2 on T cells, was also demonstrated as one of the causes of poor prognosis and resistance to CD19 CAR-T therapy. Changes in CD58, including downregulation, mutation, or loss, were observed in up to 67% of DLBCL patients [124]. CD58 aberrations were found to be correlated with a faster progression of lymphoma disease and decreased durable, complete responses to CD19 CAR-T treatment. This observation was also confirmed in in vitro and in vivo models using a Nalm-6 CD58 KO B-ALL cell line. These pre-clinical studies showed that CD19 CAR-T cells had a reduced cytokine production and killing potential after contact with CD58 KO tumor cells. Similarly, mice with B-ALL tumors lacking CD58 expression only partially responded to CD19 CAR-T treatment [125].

5. New CAR-T Targets Explored in Hematological Malignancies

Considering that around half of the leukemia relapses that occur following CD19 CAR-T administration are manifested by the appearance of CD19-negative cells [12,93], the development of new approaches is crucial to managing such cases. One of the strategies to eliminate the risk of the disease recurrence is to perform allogeneic hematopoietic stem cell transplantation (allo-HSCT) [126]; however, many of the patients, who are usually heavily pre-treated, are not eligible for allo-HSCT due to its toxicity and potential side effects [127]. Hence, another strategy to avoid CD19-negative relapses is focused on targeting alternative molecules expressed on the surface of malignant cells. Searching for novel antigens is still ongoing, and several targets are already being evaluated in pre-clinical and/or clinical studies [128]. Herein, we present promising targets that are currently investigated for the treatment of B cell and plasma cell-derived malignancies.
These novel (other than CD19) targets are summarized in Table 2. For each targeted molecule, we highlight its physiological functions, the expression on normal cells, and the targeted disease. Further in this section, we also describe several antigens in more detail. Primarily, we elaborate on less-explored targets that are not widely discussed in CAR-T-oriented literature reviews, such as CD32B, CD70, and CD72. We also characterized promising, clinically explored targets that are tested in blood cancers derived from B cells at various stages of development and maturation, including BAFF-R (B-ALL), CD37 (CLL, B cell lymphoma), and GPRC5D (MM).

5.1. Novel Antigens under Investigation in Pre-Clinical Studies

CD32B (FcγRIIB) is the low-affinity inhibitory receptor for IgG, which contains an intracellular immune inhibitory motif (ITIM). CD32 is expressed in three isoforms: CD32A, B, and C. The isoform B occurs in normal and malignant B cells and some subpopulations of dendritic cells and granulocytes [138]. The expression of CD32B was also detected in non-hematopoietic tissues such as liver endothelial cells [140] and airway smooth muscle cells [139]. CD32B is the main FcγR present on B cells. Following co-ligation with activating receptors such as B cell receptor (BCR), CD32B recruits SH-2 containing inositol 5′ phosphatase 1 (SHIP-1), which attenuates activating signals and contributes to the regulation of B cell activation and homeostasis [138,180,181]. High and homogenous expression of CD32B was also demonstrated in B cell-related disorders [141,182]. Moreover, it was shown that the expression of CD32B negatively affects immunotherapy of CD20-expressing lymphomas with therapeutic monoclonal antibody (mAb) rituximab [183,184]. The mechanism results from the binding and internalization of rituximab by CD32B. Antagonistic mAbs specifically targeting the CD32B isoform improved rituximab efficacy in pre-clinical lymphoma models and were further tested in combination with rituximab in lymphoma patients [185]. Recently, CAR-T cells containing scFv derived from mAbs specifically recognizing the CD32B isoform were generated and presented to efficiently kill CD32B-expressing cell lines and primary CLL cells in vitro and in vivo [141]. However, considering the expression of CD32B in normal cells, CAR constructs with improved safety such as dual CARs with an “AND” logic gate should be developed due to the potential on-target off-tumor toxicity.
CD70, a type II transmembrane glycoprotein from the tumor necrosis factor (TNF) family, is a ligand for the CD27 receptor present on T cells [186,187]. The CD70/CD27 interaction was shown to serve as a co-stimulatory signal for T cell activation and to play a role in T cell-dependent B cell differentiation into plasma cells [188,189]. In healthy individuals, the expression of CD70 was found to be restricted to subsets of activated T cells, B cells, NK cells, mature DCs, and epithelial cells of the thymic medulla [142,143]. In contrast to normal cells, various types of malignant lymphoid cells exhibit aberrant CD70 expression. Increased CD70 levels were observed on various malignant B cells, for instance, isolated from patients with CLL, DLBCL, MCL, and MM [190,191]. Importantly, CD70 overexpression in MCL patients was recently reported to be associated with higher proliferation, a more aggressive clinical course of the disease, and with an increased number of Tregs infiltration in the tumor [192]. The possible role of CD70 in the generation of the immune-suppressive tumor microenvironment was also demonstrated by Yang et al. [193]. In this study, CD70-positive biopsy-derived primary lymphoma B cells more potently enhanced Foxp3 levels in CD4-positive CD25−negative T cells subpopulation than their CD70-negative counterparts.
Anti-CD70 antibodies inhibited tumor growth and prolonged mice survival in models of CD70-positive B cell malignancies [191,194], providing the rationale for targeting CD70 with CAR-T cells. In 2011, Shaffer et al. demonstrated that CD70-specific T cells caused in vivo lymphoma regression [144]. Importantly, the study also evaluated the toxicity of CD70 CAR-T cells towards activated T and B cells, which physiologically express CD70 upon activation. While activated T cells were not killed in cytotoxicity assays, B cells stimulated with the CD40 ligand were observed to be eliminated by CD70 CAR-T. However, the issue of potential B cell aplasia in vivo remains uncertain as CD70 expression on normal lymphoid cells occurs only transiently. Recently, Deng et al. also showed the effectiveness of CD70 CAR-T cells against CD19 KO Raji cells in vitro and in vivo [145]. The study shows the potential application of this approach in the treatment of CD19-negative B cell malignancies, thus addressing the issue of antigen escape following CD19 CAR-T cell therapy.
CD72 is a B cell-specific protein that recruits Src homology region 2 domain-containing phosphatase-1 (SHP-1) to intracellular ITIM motifs and is involved in the negative regulation of BCR signaling [195,196]. CD72 was shown to interact with CD5, CD100, and nuclear lupus self-antigens [197,198,199]. The interaction with CD100 turns off the negative signals of CD72 and enhances BCR signaling [198]. CD72 −/− mice develop lupus-like syndrome and CD72 is downregulated in humans diagnosed with lupus erythematosus, indicating the involvement of CD72 in the pathogenesis of autoimmune diseases [200,201]. CD72 is predominantly expressed in B cells. Its expression starts at the pro-B cell stage and continues throughout all stages of B cell development with the exception of plasma cells [146]. CD72 is also abundantly expressed in B cell-derived neoplasms, including B-ALL, CLL, and B cell lymphomas [146,147,202]. In contrast, CD72 is rarely expressed in other normal tissues including the human brain [146,147]; however, the presence of CD72 was reported on a subset of activated NK cells [203] and in mast cells [204]. Recently, Nix et al. analyzed the surfaceome of a MLL-rearranged B-ALL subtype, in which significant cell surface upregulation of CD72 was observed [147]. Using an in vitro yeast display library, the authors developed CD72-binding nanobodies and generated CD72 CAR-T cells effective against CD72-positive B-ALL and B cell lymphoma cell lines. Importantly, CD72 expression was maintained in CD19-negative cells and CD72 CAR-T cells effectively eliminated CD19-negative leukemia cells in vitro and in vivo. In contrast, CD72 CAR-T cells were not toxic against normal cells including peripheral blood mononuclear cells, immortalized vascular endothelial cells, mesenchymal stem cells, and induced pluripotent stem cells [147]. Overall, CD72 CAR-T cells are very promising candidates to be tested in clinical trials, in particular as a second-line treatment in patients relapsing after CD19-targeted immunotherapy.

5.2. Promising Antigens Tested in Clinical Trials

B cell activating factor receptor (BAFF-R, also known as BR3, CD268 or TNFRSF17) is a type III membrane protein belonging to the tumor necrosis factor receptors (TNFR) family [205]. The BAFF-R interaction with its specific ligand BAFF was shown to be crucial for the generation of mature B cells in both mice and humans [206,207,208]. In humans, the receptor can be detected on most B cells. The evaluation of BAFF-R expression on different B cell subsets revealed that cells with pre–B phenotype as well as plasma cells lack the receptor, while most circulating B cells, a subset of B cells within germinal centers, and B cells colonizing the mantle zones of reactive lymphoid tissues and a splenic marginal zone are BAFF-R-positive. Importantly, the BAFF-R expression pattern was found to be preserved on mature neoplastic B cells [159]. BAFF-R protein is present on several lymphomas, including MCL, FL and DLBCL [209,210,211,212,213], and on most CLL cells [214]. Surprisingly, malignant pre-B cells also exhibit high BAFF-R expression in contrast to their normal counterparts [215,216]. Moreover, BAFF-R-positive blasts were found to persist in previously treated relapsed pediatric B-ALL [217]. High tissue specificity and the low possibility of BAFF-R antigen escape related to its importance for B cell survival make this receptor an attractive target for immunotherapies in both lymphomas and leukemias.
Antibodies targeting BAFF-R were demonstrated to promote NK cell-mediated killing of B-ALL, CLL and MCL cells in pre-clinical studies [213,218,219], and currently, anti-BAFF-R antibody ianalumab (VAY736) is being evaluated in the treatment of CLL patients in combination with ibrutinib (NCT03400176). In 2019, the results with BAFF-R-specific CAR-T cells were firstly published [220]. In this study, BAFF-R-targeting CAR-T cells caused tumor regression and prolonged the survival of mice with various human lymphomas and B-ALL. Moreover, BAFF-R CAR-T cells efficiently eradicated CD19-negative malignant cells, which were either generated using CRISPR-Cas9 technology, or obtained from the patients relapsing after CD19-targeted therapy. In 2020, a first-in-human trial evaluating BAFF-R-targeting CAR-T cells for patients with r/r B-ALL was initiated (NCT04690595).
CD37 belongs to the transmembrane 4 superfamily (TM4SF) of tetraspanin proteins, which have four potential membrane-spanning domains. Unlike most tetraspanin proteins, which are not tissue-specific, CD37 can be detected only in several subsets of immune cells [221] and plays a role in both cellular and humoral immune responses [222,223]. B cells show the highest expression of CD37 among leukocytes in human blood and in primary and secondary lymphoid organs [166]. Low or medium CD37 expression was also observed on T cells, NK cells, monocytes and dendritic cells. Importantly, the level of CD37 on B cells changes during their development, with low expression in B cell precursors, a peak in mature/peripheral B lymphocytes and a decrease at the stage of plasma cells [224]. A similar pattern of expression is observed on malignant B cells, as B-ALL and MM cells were found to be CD37-low or CD37-negative, whereas mature/peripheral B cell leukemias and lymphomas highly express this antigen [224]. Therefore, CD37 is considered to be a promising immunotherapeutic target in non-Hodgkin lymphoma (NHL) and CLL [225]. Several anti-CD37 molecules were investigated in clinical trials, including monoclonal antibody otlertuzumab [226] (NCT00614042, NCT01188681), Fc-engineered monoclonal antibody BI 836826 [227] (NCT01403948), antibody-drug conjugates AGS67E [228] (NCT02175433), IMGN529 [229] (NCT01534715), and radio-immunoconjugate betalutin [230] (NCT02658968). The first CD37-specific CAR was presented in 2018 and its efficacy in the eradication of MCL tumors was demonstrated in murine models, which were established using a Jeko-1 cell line and a patient-derived xenograft [231]. Importantly, although CD37 may also have been present on T cells, no significant T cell fratricide occurred during the in vitro expansion of CD37-CAR T cells. These results were also confirmed by Köksal et al., along with the additional observation that CD19 and CD37 are not always mutually expressed on the cell surface, and that CD37 CAR-T cells are able to kill both CD19-positive and CD19-negative cells [232]. Since the pre-clinical studies showed no evidence of the off-tumor activity, the approach was advanced to a clinical trial, where CD37 CAR-T cells were evaluated in patients with relapsed or refractory CD37-positive hematologic malignancies (NCT04136275). According to the recent report, three out of four enrolled patients with relapsed B cell or T cell malignancies eventually achieved CR; however, one patient with refractory double-hit high-grade B cell lymphoma (HGBCL), who relapsed after CD19 CAR-T, experienced disease progression post CD37 CAR-T administration with a CD19-negative and CD37-negative phenotype. Additionally, two patients experienced unexpected bone marrow aplasia, but it was rescued with allogeneic HSCT [233].
GPRC5D is a seven-pass membrane protein belonging to the family of orphan G-protein coupled receptors, all of which lack identified ligands [234]. In normal tissues, elevated levels of GPRC5D mRNA were observed in differentiating cells that produce hard keratin [235], in lymph nodes, and the spleen. Minimal GPRC5D mRNA levels were also detected in lung, skin, and testis [236]. However, GPRC5D protein was found on the surface of the cells from hair follicles [173], and among hematopoietic compartment only on CD19-positive B cells and plasma cells [174,175]. In 2012, GPRC5D mRNA was for the first time reported to be expressed in the bone marrow of patients with MM [237]. Moreover, it was later demonstrated that MM cells express significantly higher levels of GPRC5D mRNA and protein as compared to normal plasma cells, and, importantly, MM patients’ plasma cells continue to express GPRC5D after therapy with immunomodulatory drugs, proteasome inhibitors, or CD38-targeting antibodies [175]. The GPRC5D surface protein level was also confirmed in several MM cancer cell lines [236]. Pre-clinical studies of talquetamab (JNJ-64407564), a humanized bispecific antibody binding CD3 and GPRC5D, demonstrated its ability to effectively induce MM cell death and inhibit tumor growth in murine models [236]. Moreover, an ex vivo analysis showed that MM cells isolated from newly diagnosed or heavily pretreated refractory patients were equally susceptible to talquetamab-mediated lysis [175]. The initial results of an ongoing clinical study of talquetamab (NCT03399799) enrolling 137 patients presented an overall response rate (ORR) at 78% in patients who received the drug intravenously [238]. GPRC5D was also recognized as an attractive molecule for CAR-based therapy, and in 2018, GPRC5D-specific CAR was shown to effectively target MM cells in vitro and eradicate MM xenografts in a murine model [239]. Moreover, the ability of GPRC5D CAR-T cells to eliminate BCMA KO MM cells in vivo was observed by Smith et al. along with an independent BCMA and GPRC5D protein expression in MM patients’ CD138-positive plasma cells [173]. Altogether, these results suggest that treatment with anti-GPRC5D CAR-T cells may rescue relapses caused by an antigen escape after BCMA CAR-T therapy. The GPRC5D-targeted CAR construct MCARH109 is currently being evaluated in a clinical trial (NCT04555551), and the first results were shown in 2021. So far, 18 r/r MM patients were enrolled in the study. From 12 patients who had already received the treatment, 83% of them had at least a minimal response and 75% remained progression-free (13 weeks median follow-up). No dose-limiting toxicities were observed during the treatment. Additionally, six patients who experienced relapse following BCMA CAR-T therapy responded to MCARH109, and two of them achieved stringent CR [240].

5.3. New Directions for Alternative CAR-T Targets Development

In the light of lessons learned from the experience with single-aimed CAR-T regimens, the field of adoptive therapies is now focused on developing multiple-targeting CAR-T cells. Currently, the safety and efficacy of the approach is being evaluated in a clinical study (NCT03455972), where patients with MM receive both CD19 and BCMA CAR-T cells [241]. The more advanced approach involves utilizing CAR constructs able to recognize multiple targets simultaneously. The treatment with dual CAR-T targeting both CD19 and BCMA resulted in CR in 9/16 MM patients (56.3%) with the median follow-up time being 7.3 months (NCT04236011) [242]. In addition, CD38 and BCMA bispecific CAR-T cells application led to stringent CR in 13 out of 16 patients, 76.9% of whom did not relapse or progress during a follow-up of 11.5 months (ChiCTR1900026286) [243]. In non-Hodgkin lymphoma or CLL, bispecific CARs targeting simultaneously CD19 and CD20 were also successful, with 92% of the patients having CR (NCT03019055). Importantly, the relapse in some of the patients was not associated with CD19 antigen loss [244]. In the case of B-ALL, CD19 and CD22 dual CAR-T cells were evaluated in clinical trials (NCT03233854, NCT03289455). Despite the promising results from in vitro and in vivo studies [245], relapses were observed in approximately 50% of the patients [246,247].
Moreover, it was recently reported that CD20 and CD22 are not only heterogeneously expressed in B-ALL samples but can also be downregulated in CD19-negative relapsed cancer cells [98]. The solution to prevent cancer cell escape via such a mechanism could be the induction of the antigen expression pharmacologically. For instance, bryostatin 1 potently upregulated CD22 expression and improved CD22 CAR-T activity in a pre-clinical B-ALL model [248]. In addition, histone deacetylase inhibitors are known to upregulate CD20 expression on several types of malignant B cells [249,250], though not on CLL cells in vivo [251].
The limitation for a traditional CAR construct in terms of specificity is its ability to recognize molecules expressed only on the cell surface; however, recent advances in the construct design may overcome this limitation by generating TCR-like CARs. TCRs can detect particular tumor antigens as peptides presented by MHC molecules. Since most of the mutated proteins are presented in this mechanism, TCR-based CARs can be more tumor-specific and thus less toxic to non-malignant cells [252]. The examples are novel TCR-like CAR-T cells targeting an HLA*0201-restricted SSX2 epitope, which were shown to be effective against acute myeloid leukemia cells in vitro [253]. In addition, TÜ165 CAR-T is able to recognize an Epstein–Barr nuclear antigen (EBNA)−3C-derived peptide in HLA-B*35 context and specifically target EBV-infected B cells [254].

6. Conclusions

Adoptive CAR-T cell therapy has emerged as a breakthrough treatment for relapsed and refractory B cell malignancies. Despite initial success and an induction of remissions, long-term observations have provided data showing a significant number of patients with disease progression and relapse. Hence, understanding the major difficulties at all phases of CAR-T treatment is of crucial importance.
Clinical trials evaluating CD19 CAR-T and their follow-ups have already shed more light on the treatment-related obstacles and the approaches that could be undertaken to avoid them. Therefore, the current research focuses on improving various aspects, including CAR-T cells proliferation and persistence, their killing potential in an immunosuppressive tumor environment, and target antigen expression. Importantly, relapses associated with the loss of target antigen following CAR-T cells administration have led to an interest in finding alternative targets. One of the most important characteristics of a potent target is its tumor-specificity. Unfortunately, such targets are not broadly available as many of them are also expressed on normal hematopoietic cells or other tissues. Hence, many studies develop strategies to address off-tumor effects, for instance by modulating scFv affinity, incorporating on/off switches or suicide genes to the CAR constructs, or the generation of TCR-based CARs. In addition, high-throughput approaches are currently being implemented to study the surfaceome of malignant cells. Such a large-scale approach generating extensive data can yield positive results and help to identify yet unexplored surface antigens for CAR-T cell therapy. In this review, we described several antigens that were selected either by standard or large-scale approaches and that are currently under investigation in pre-clinical or clinical trials. However, targeting only one antigen on cancer cells poses a risk, as the administration of single-targeting CD19 CAR-T cells was linked with unsatisfactory relapse rates. For this reason, the selection of an antigen that is involved in malignant cells’ survival, and that its loss is detrimental, would be of great advantage. Another alternative to solving the issue of target antigen downmodulation is to target multiple antigens with a single CAR-T cell, and such attempts are already being implemented in clinical trials.
Even though CAR-T cell therapy still requires improvement, it has already revolutionized the care of patients with blood cancers; however, further basic research, as well as clinical trials, are needed to find optimal therapeutic solutions and durable effects. Ideally, all those efforts would lead to a safe, effective, and financially available adoptive therapy for all patients with hematological malignancies.

Author Contributions

Conceptualization, K.F. and K.M.; writing—original draft preparation K.M., M.K., M.F. and K.F.; writing—review and editing, K.M., M.K., M.F. and K.F.; visualization, M.K. and K.F.; supervision, K.F. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Centre for Research and Development within POLNOR program NOR/POLNOR/ALTERCAR/0056/2019 (PI: Magdalena Winiarska) and by the Ministry of Education and Science within “Regional Initiative of Excellence” in years 2019–2022, program 013/RID/2018/19, project budget 12,000,000 PLN (PI: Jakub Golab).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to thank Magdalena Winiarska for constructive comments and feedback. Figure 1 was created with BioRender.com.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Gökbuget, N.; Dombret, H.; Ribera, J.M.; Fielding, A.K.; Advani, A.; Bassan, R.; Chia, V.; Doubek, M.; Giebel, S.; Hoelzer, D.; et al. International Reference Analysis of Outcomes in Adults with B-Precursor Ph-Negative Relapsed/Refractory Acute Lymphoblastic Leukemia. Haematologica 2016, 101, 1524–1533. [Google Scholar] [CrossRef] [Green Version]
  2. Sun, W.; Malvar, J.; Sposto, R.; Verma, A.; Wilkes, J.J.; Dennis, R.; Heym, K.; Laetsch, T.W.; Widener, M.; Rheingold, S.R.; et al. Outcome of Children with Multiply Relapsed B-Cell Acute Lymphoblastic Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma Study. Leukemia 2018, 32, 2316–2325. [Google Scholar] [CrossRef]
  3. Freyer, D.R.; Devidas, M.; La, M.; Carroll, W.L.; Gaynon, P.S.; Hunger, S.P.; Seibel, N.L. Postrelapse Survival in Childhood Acute Lymphoblastic Leukemia Is Independent of Initial Treatment Intensity: A Report from the Children’s Oncology Group. Blood 2011, 117, 3010–3015. [Google Scholar] [CrossRef] [Green Version]
  4. Modi, D.; Potugari, B.; Uberti, J. Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions. Cancers 2021, 13, 5827. [Google Scholar] [CrossRef]
  5. Bazarbachi, A.H.; Al Hamed, R.; Malard, F.; Harousseau, J.-L.; Mohty, M. Relapsed Refractory Multiple Myeloma: A Comprehensive Overview. Leukemia 2019, 33, 2343–2357. [Google Scholar] [CrossRef]
  6. Durer, C.; Durer, S.; Lee, S.; Chakraborty, R.; Malik, M.N.; Rafae, A.; Zar, M.A.; Kamal, A.; Rosko, N.; Samaras, C.; et al. Treatment of Relapsed Multiple Myeloma: Evidence-Based Recommendations. Blood Rev. 2020, 39, 100616. [Google Scholar] [CrossRef]
  7. Susanibar, A.S.; Stadtmauer, E.A.; Cohen, A.D. CAR T Cell Therapy for Multiple Myeloma: What Have We Learned? Leukemia 2022, 22, 39–47. [Google Scholar] [CrossRef]
  8. Brentjens, R.J.; Santos, E.; Nikhamin, Y.; Yeh, R.; Matsushita, M.; La Perle, K.; Quintás-Cardama, A.; Larson, S.M.; Sadelain, M. Genetically Targeted T Cells Eradicate Systemic Acute Lymphoblastic Leukemia Xenografts. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2007, 13, 5426–5435. [Google Scholar] [CrossRef] [Green Version]
  9. Milone, M.C.; Fish, J.D.; Carpenito, C.; Carroll, R.G.; Binder, G.K.; Teachey, D.; Samanta, M.; Lakhal, M.; Gloss, B.; Danet-Desnoyers, G.; et al. Chimeric Receptors Containing CD137 Signal Transduction Domains Mediate Enhanced Survival of T Cells and Increased Antileukemic Efficacy in vivo. Mol. Ther. J. Am. Soc. Gene Ther. 2009, 17, 1453–1464. [Google Scholar] [CrossRef]
  10. Zhong, X.S.; Matsushita, M.; Plotkin, J.; Riviere, I.; Sadelain, M. Chimeric Antigen Receptors Combining 4–1BB and CD28 Signaling Domains Augment PI3kinase/AKT/Bcl-XL Activation and CD8+ T Cell-Mediated Tumor Eradication. Mol. Ther. J. Am. Soc. Gene Ther. 2010, 18, 413–420. [Google Scholar] [CrossRef]
  11. Tokarew, N.; Ogonek, J.; Endres, S.; von Bergwelt-Baildon, M.; Kobold, S. Teaching an Old Dog New Tricks: Next-Generation CAR T Cells. Br. J. Cancer 2019, 120, 26–37. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H.; Bader, P.; Verneris, M.R.; Stefanski, H.E.; Myers, G.D.; et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 439–448. [Google Scholar] [CrossRef]
  13. Shah, N.N.; Lee, D.W.; Yates, B.; Yuan, C.M.; Shalabi, H.; Martin, S.; Wolters, P.L.; Steinberg, S.M.; Baker, E.H.; Delbrook, C.P.; et al. Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2021, 39, 1650–1659. [Google Scholar] [CrossRef] [PubMed]
  14. Schuster, S.J.; Bishop, M.R.; Tam, C.S.; Waller, E.K.; Borchmann, P.; McGuirk, J.P.; Jäger, U.; Jaglowski, S.; Andreadis, C.; Westin, J.R.; et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N. Engl. J. Med. 2019, 380, 45–56. [Google Scholar] [CrossRef]
  15. Schuster, S.J.; Tam, C.S.; Borchmann, P.; Worel, N.; McGuirk, J.P.; Holte, H.; Waller, E.K.; Jaglowski, S.; Bishop, M.R.; Damon, L.E.; et al. Long-Term Clinical Outcomes of Tisagenlecleucel in Patients with Relapsed or Refractory Aggressive B-Cell Lymphomas (JULIET): A Multicentre, Open-Label, Single-Arm, Phase 2 Study. Lancet. Oncol. 2021, 22, 1403–1415. [Google Scholar] [CrossRef]
  16. Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544. [Google Scholar] [CrossRef]
  17. Jacobson, C.; Locke, F.L.; Ghobadi, A.; Miklos, D.B.; Lekakis, L.J.; Oluwole, O.O.; Lin, Y.; Hill, B.T.; Timmerman, J.M.; Deol, A.; et al. Long-Term (≥4 Year and ≥5 Year) Overall Survival (OS) By 12- and 24-Month Event-Free Survival (EFS): An Updated Analysis of ZUMA-1, the Pivotal Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Refractory Large B-Cell Lymphoma (LBCL). Blood 2021, 138, 1764. [Google Scholar] [CrossRef]
  18. Jacobson, C.A.; Chavez, J.C.; Sehgal, A.R.; William, B.M.; Munoz, J.; Salles, G.; Munshi, P.N.; Casulo, C.; Maloney, D.G.; de Vos, S.; et al. Axicabtagene Ciloleucel in Relapsed or Refractory Indolent Non-Hodgkin Lymphoma (ZUMA-5): A Single-Arm, Multicentre, Phase 2 Trial. Lancet Oncol. 2022, 23, 91–103. [Google Scholar] [CrossRef]
  19. Wang, M.; Munoz, J.; Goy, A.; Locke, F.L.; Jacobson, C.A.; Hill, B.T.; Timmerman, J.M.; Holmes, H.; Jaglowski, S.; Flinn, I.W.; et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N. Engl. J. Med. 2020, 382, 1331–1342. [Google Scholar] [CrossRef]
  20. Shah, B.D.; Ghobadi, A.; Oluwole, O.O.; Logan, A.C.; Boissel, N.; Cassaday, R.D.; Leguay, T.; Bishop, M.R.; Topp, M.S.; Tzachanis, D.; et al. KTE-X19 for Relapsed or Refractory Adult B-Cell Acute Lymphoblastic Leukaemia: Phase 2 Results of the Single-Arm, Open-Label, Multicentre ZUMA-3 Study. Lancet 2021, 398, 491–502. [Google Scholar] [CrossRef]
  21. Abramson, J.S.; Palomba, M.L.; Gordon, L.I.; Lunning, M.A.; Wang, M.; Arnason, J.; Mehta, A.; Purev, E.; Maloney, D.G.; Andreadis, C.; et al. Lisocabtagene Maraleucel for Patients with Relapsed or Refractory Large B-Cell Lymphomas (TRANSCEND NHL 001): A Multicentre Seamless Design Study. Lancet 2020, 396, 839–852. [Google Scholar] [CrossRef]
  22. Abramson, J.S.; Palomba, M.L.; Gordon, L.I.; Lunning, M.A.; Wang, M.; Arnason, J.E.; Purev, E.; Maloney, D.G.; Andreadis, C.; Sehgal, A.R.; et al. Two-Year Follow-up of Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (Liso-Cel) in Relapsed or Refractory (R/R) Large B-Cell Lymphomas (LBCL). Blood 2021, 138, 2840. [Google Scholar] [CrossRef]
  23. Munshi, N.C.; Anderson, L.D.J.; Shah, N.; Madduri, D.; Berdeja, J.; Lonial, S.; Raje, N.; Lin, Y.; Siegel, D.; Oriol, A.; et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N. Engl. J. Med. 2021, 384, 705–716. [Google Scholar] [CrossRef] [PubMed]
  24. Sharma, P.; Kanapuru, B.; George, B.; Lin, X.; Xu, Z.; Bryan, W.W.; Pazdur, R.; Theoret, M.R. FDA Approval Summary: Idecabtagene Vicleucel for Relapsed or Refractory Multiple Myeloma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2022, 21, 3803. [Google Scholar] [CrossRef]
  25. Shah, B.D.; Bishop, M.R.; Oluwole, O.O.; Logan, A.C.; Baer, M.R.; Donnellan, W.B.; O’Dwyer, K.M.; Holmes, H.; Arellano, M.L.; Ghobadi, A.; et al. KTE-X19 Anti-CD19 CAR T-Cell Therapy in Adult Relapsed/Refractory Acute Lymphoblastic Leukemia: ZUMA-3 Phase 1 Results. Blood 2021, 138, 11–22. [Google Scholar] [CrossRef] [PubMed]
  26. Wang, M.; Munoz, J.; Goy, A.H.; Locke, F.L.; Jacobson, C.A.; Hill, B.T.; Timmerman, J.M.; Holmes, H.; Jaglowski, S.; Flinn, I.W.; et al. One-Year Follow-up of ZUMA-2, the Multicenter, Registrational Study of KTE-X19 in Patients with Relapsed/Refractory Mantle Cell Lymphoma. Blood 2020, 136, 20–22. [Google Scholar] [CrossRef]
  27. Shah, N.N.; Fry, T.J. Mechanisms of Resistance to CAR T Cell Therapy. Nature reviews. Clin. Oncol. 2019, 16, 372–385. [Google Scholar] [CrossRef]
  28. Brudno, J.N.; Kochenderfer, J.N. Recent Advances in CAR T-Cell Toxicity: Mechanisms, Manifestations and Management. Blood Rev. 2019, 34, 45–55. [Google Scholar] [CrossRef]
  29. Rodriguez-Garcia, A.; Palazon, A.; Noguera-Ortega, E.; Powell, D.J.J.; Guedan, S. CAR-T Cells Hit the Tumor Microenvironment: Strategies to Overcome Tumor Escape. Front. Immunol. 2020, 11, 1109. [Google Scholar] [CrossRef]
  30. Zhylko, A.; Winiarska, M.; Graczyk-Jarzynka, A. The Great War of Today: Modifications of CAR-T Cells to Effectively Combat Malignancies. Cancers 2020, 12, 2030. [Google Scholar] [CrossRef]
  31. Sterner, R.C.; Sterner, R.M. CAR-T Cell Therapy: Current Limitations and Potential Strategies. Blood Cancer J. 2021, 11, 69. [Google Scholar] [CrossRef] [PubMed]
  32. Mueller, K.T.; Maude, S.L.; Porter, D.L.; Frey, N.; Wood, P.; Han, X.; Waldron, E.; Chakraborty, A.; Awasthi, R.; Levine, B.L.; et al. Cellular Kinetics of CTL019 in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia. Blood 2017, 130, 2317–2325. [Google Scholar] [CrossRef] [PubMed]
  33. Nie, Y.; Lu, W.; Chen, D.; Tu, H.; Guo, Z.; Zhou, X.; Li, M.; Tu, S.; Li, Y. Mechanisms Underlying CD19-Positive ALL Relapse after Anti-CD19 CAR T Cell Therapy and Associated Strategies. Biomark. Res. 2020, 8, 18. [Google Scholar] [CrossRef] [PubMed]
  34. Gupta, A.; Gill, S. CAR-T Cell Persistence in the Treatment of Leukemia and Lymphoma. Leuk. Lymphoma 2021, 62, 2587–2599. [Google Scholar] [CrossRef]
  35. Kawalekar, O.U.; O’Connor, R.S.; Fraietta, J.A.; Guo, L.; McGettigan, S.E.; Posey, A.D.J.; Patel, P.R.; Guedan, S.; Scholler, J.; Keith, B.; et al. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity 2016, 44, 380–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Zhao, X.; Yang, J.; Zhang, X.; Lu, X.A.; Xiong, M.; Zhang, J.; Zhou, X.; Qi, F.; He, T.; Ding, Y.; et al. Efficacy and Safety of CD28- or 4-1BB-Based CD19 CAR-T Cells in B Cell Acute Lymphoblastic Leukemia. Mol. Ther. Oncol. 2020, 18, 272–281. [Google Scholar] [CrossRef] [PubMed]
  37. Philipson, B.I.; O’Connor, R.S.; May, M.J.; June, C.H.; Albelda, S.M.; Milone, M.C. 4–1BB Costimulation Promotes CAR T Cell Survival through Noncanonical NF-ΚB Signaling. Sci. Signal. 2020, 13, 8248. [Google Scholar] [CrossRef] [PubMed]
  38. Zhao, Z.; Condomines, M.; van der Stegen, S.J.C.; Perna, F.; Kloss, C.C.; Gunset, G.; Plotkin, J.; Sadelain, M. Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. Cancer Cell 2015, 28, 415–428. [Google Scholar] [CrossRef] [Green Version]
  39. Boucher, J.C.; Li, G.; Kotani, H.; Cabral, M.L.; Morrissey, D.; Lee, S.B.; Spitler, K.; Beatty, N.J.; Cervantes, E.V.; Shrestha, B.; et al. CD28 Costimulatory Domain-Targeted Mutations Enhance Chimeric Antigen Receptor T-Cell Function. Cancer Immunol. Res. 2021, 9, 62–74. [Google Scholar] [CrossRef]
  40. Roselli, E.; Boucher, J.C.; Li, G.; Kotani, H.; Spitler, K.; Reid, K.; Cervantes, E.V.; Bulliard, Y.; Tu, N.; Lee, S.B.; et al. 4-1BB and Optimized CD28 Co-Stimulation Enhances Function of Human Mono-Specific and Bi-Specific Third-Generation CAR T Cells. J. Immunother. Cancer 2021, 9, 3354. [Google Scholar] [CrossRef]
  41. Wang, J.; Mou, N.; Yang, Z.; Li, Q.; Jiang, Y.; Meng, J.; Liu, X.; Deng, Q. Efficacy and Safety of Humanized Anti-CD19-CAR-T Therapy Following Intensive Lymphodepleting Chemotherapy for Refractory/Relapsed B Acute Lymphoblastic Leukaemia. Br. J. Haematol. 2020, 191, 212–222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Fabrizio, V.A.; Boelens, J.J.; Mauguen, A.; Baggott, C.; Prabhu, S.; Egeler, E.; Mavroukakis, S.; Pacenta, H.; Phillips, C.L.; Rossoff, J.; et al. Optimal Fludarabine Lymphodepletion Is Associated with Improved Outcomes after CAR T-Cell Therapy. Blood Adv. 2022, 6, 1961–1968. [Google Scholar] [CrossRef] [PubMed]
  43. Turtle, C.J.; Hanafi, L.-A.; Berger, C.; Hudecek, M.; Pender, B.; Robinson, E.; Hawkins, R.; Chaney, C.; Cherian, S.; Chen, X.; et al. Immunotherapy of Non-Hodgkin’s Lymphoma with a Defined Ratio of CD8+ and CD4+ CD19-Specific Chimeric Antigen Receptor-Modified T Cells. Sci. Transl. Med. 2016, 8, 355ra116. [Google Scholar] [CrossRef] [Green Version]
  44. Hirayama, A.V.; Gauthier, J.; Hay, K.A.; Voutsinas, J.M.; Wu, Q.; Gooley, T.; Li, D.; Cherian, S.; Chen, X.; Pender, B.S.; et al. The Response to Lymphodepletion Impacts PFS in Patients with Aggressive Non-Hodgkin Lymphoma Treated with CD19 CAR T cells. Blood 2019, 133, 1876–1887. [Google Scholar] [CrossRef] [Green Version]
  45. Lyu, C.; Cui, R.; Wang, J.; Mou, N.; Jiang, Y.; Li, W.; Deng, Q. Intensive Debulking Chemotherapy Improves the Short-Term and Long-Term Efficacy of Anti-CD19-CAR-T in Refractory/Relapsed DLBCL with High Tumor Bulk. Front. Oncol. 2021, 11, 706087. [Google Scholar] [CrossRef]
  46. Neelapu, S.S. CAR-T Efficacy: Is Conditioning the Key? Blood 2019, 133, 1799–1800. [Google Scholar] [CrossRef]
  47. Chen, M.L.; Pittet, M.J.; Gorelik, L.; Flavell, R.A.; Weissleder, R.; von Boehmer, H.; Khazaie, K. Regulatory T Cells Suppress Tumor-Specific CD8 T Cell Cytotoxicity through TGF-Beta Signals in vivo. Proc. Natl. Acad. Sci. USA 2005, 102, 419–424. [Google Scholar] [CrossRef] [Green Version]
  48. Watanabe, S.; Arita, M.; Takahashi, M.; Saida, Y.; Koya, T.; Kikuchi, T. Effect of Lymphodepletion on Donor T Cells and the Role of Recipient Cells Persisting after Cytotoxic Treatments in Cancer Immunotherapies. Crit. Rev. Immunol. 2017, 37, 59–73. [Google Scholar] [CrossRef]
  49. Hay, K.A.; Hanafi, L.A.; Li, D.; Gust, J.; Liles, W.C.; Wurfel, M.M.; López, J.A.; Chen, J.; Chung, D.; Harju-Baker, S.; et al. Kinetics and Biomarkers of Severe Cytokine Release Syndrome after CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy. Blood 2017, 130, 2295–2306. [Google Scholar] [CrossRef] [Green Version]
  50. Dawicki, W.; Allen, K.J.H.; Garg, R.; Geoghegan, E.M.; Berger, M.S.; Ludwig, D.L.; Dadachova, E. Targeted Lymphodepletion with a CD45-Directed Antibody Radioconjugate as a Novel Conditioning Regimen Prior to Adoptive Cell Therapy. Oncotarget 2020, 11, 3571–3581. [Google Scholar] [CrossRef]
  51. Williams, K.M.; Hakim, F.T.; Gress, R.E. T Cell Immune Reconstitution Following Lymphodepletion. Semin. Immunol. 2007, 19, 318–330. [Google Scholar] [CrossRef] [Green Version]
  52. Chmielewski, M.; Abken, H. TRUCKS, the Fourth-Generation CAR T Cells: Current Developments and Clinical Translation. Adv. Cell Gene Ther. 2020, 3, e84. [Google Scholar] [CrossRef]
  53. Jin, J.; Cheng, J.; Huang, M.; Luo, H.; Zhou, J. Fueling Chimeric Antigen Receptor T Cells with Cytokines. Am. J. Cancer Res. 2020, 10, 4038–4055. [Google Scholar]
  54. Pegram, H.J.; Lee, J.C.; Hayman, E.G.; Imperato, G.H.; Tedder, T.F.; Sadelain, M.; Brentjens, R.J. Tumor-Targeted T Cells Modified to Secrete IL-12 Eradicate Systemic Tumors without Need for Prior Conditioning. Blood 2012, 119, 4133–4141. [Google Scholar] [CrossRef]
  55. Kueberuwa, G.; Kalaitsidou, M.; Cheadle, E.; Hawkins, R.E.; Gilham, D.E. CD19 CAR T Cells Expressing IL-12 Eradicate Lymphoma in Fully Lymphoreplete Mice through Induction of Host Immunity. Mol. Ther. Oncol. 2018, 8, 41–51. [Google Scholar] [CrossRef] [Green Version]
  56. Xu, Y.; Zhang, M.; Ramos, C.A.; Durett, A.; Liu, E.; Dakhova, O.; Liu, H.; Creighton, C.J.; Gee, A.P.; Heslop, H.E.; et al. Closely Related T-Memory Stem Cells Correlate with in Vivo Expansion of CAR.CD19-T Cells and Are Preserved by IL-7 and IL-15. Blood 2014, 123, 3750–3759. [Google Scholar] [CrossRef] [Green Version]
  57. Zhang, X.; Lv, X.; Song, Y. Short-Term Culture with IL-2 Is Beneficial for Potent Memory Chimeric Antigen Receptor T Cell Production. Biochem. Biophys. Res. Commun. 2018, 495, 1833–1838. [Google Scholar] [CrossRef]
  58. Alizadeh, D.; Wong, R.A.; Yang, X.; Wang, D.; Pecoraro, J.R.; Kuo, C.F.; Aguilar, B.; Qi, Y.; Ann, D.K.; Starr, R.; et al. IL15 Enhances CAR-T Cell Antitumor Activity by Reducing MTORC1 Activity and Preserving Their Stem Cell Memory Phenotype. Cancer Immunol. Res. 2019, 7, 759–772. [Google Scholar] [CrossRef]
  59. Ataca Atilla, P.; McKenna, M.K.; Tashiro, H.; Srinivasan, M.; Mo, F.; Watanabe, N.; Simons, B.W.; McLean Stevens, A.; Redell, M.S.; Heslop, H.E.; et al. Modulating TNFα Activity Allows Transgenic IL15-Expressing CLL-1 CAR T Cells to Safely Eliminate Acute Myeloid Leukemia. J. Immunother. Cancer 2020, 8, 1229. [Google Scholar] [CrossRef]
  60. Chmielewski, M.; Kopecky, C.; Hombach, A.A.; Abken, H. IL-12 Release by Engineered T Cells Expressing Chimeric Antigen Receptors Can Effectively Muster an Antigen-Independent Macrophage Response on Tumor Cells That Have Shut down Tumor Antigen Expression. Cancer Res. 2011, 71, 5697–5706. [Google Scholar] [CrossRef] [Green Version]
  61. Kagoya, Y.; Tanaka, S.; Guo, T.; Anczurowski, M.; Wang, C.H.; Saso, K.; Butler, M.O.; Minden, M.D.; Hirano, N. A Novel Chimeric Antigen Receptor Containing a JAK-STAT Signaling Domain Mediates Superior Antitumor Effects. Nat. Med. 2018, 24, 352–359. [Google Scholar] [CrossRef] [PubMed]
  62. Štach, M.; Ptáčková, P.; Mucha, M.; Musil, J.; Klener, P.; Otáhal, P. Inducible Secretion of IL-21 Augments Anti-Tumor Activity of PiggyBac-Manufactured Chimeric Antigen Receptor T Cells. Cytotherapy 2020, 22, 744–754. [Google Scholar] [CrossRef] [PubMed]
  63. Hoyos, V.; Savoldo, B.; Quintarelli, C.; Mahendravada, A.; Zhang, M.; Vera, J.; Heslop, H.E.; Rooney, C.M.; Brenner, M.K.; Dotti, G. Engineering CD19-Specific T Lymphocytes with Interleukin-15 and a Suicide Gene to Enhance Their Anti-Lymphoma/Leukemia Effects and Safety. Leukemia 2010, 24, 1160–1170. [Google Scholar] [CrossRef] [Green Version]
  64. Diaconu, I.; Ballard, B.; Zhang, M.; Chen, Y.; West, J.; Dotti, G.; Savoldo, B. Inducible Caspase-9 Selectively Modulates the Toxicities of CD19-Specific Chimeric Antigen Receptor-Modified T Cells. Mol. Ther. J. Am. Soc. Gene Ther. 2017, 25, 580–592. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Guercio, M.; Manni, S.; Boffa, I.; Caruso, S.; Di Cecca, S.; Sinibaldi, M.; Abbaszadeh, Z.; Camera, A.; Ciccone, R.; Polito, V.A.; et al. Inclusion of the Inducible Caspase 9 Suicide Gene in CAR Construct Increases Safety of CAR.CD19 T Cell Therapy in B-Cell Malignancies. Front. Immunol. 2021, 12, 755639. [Google Scholar] [CrossRef]
  66. Sharpe, A.H.; Pauken, K.E. The Diverse Functions of the PD1 Inhibitory Pathway. Nature reviews. Immunology 2018, 18, 153–167. [Google Scholar] [CrossRef]
  67. Roemer, M.G.M.; Advani, R.H.; Ligon, A.H.; Natkunam, Y.; Redd, R.A.; Homer, H.; Connelly, C.F.; Sun, H.H.; Daadi, S.E.; Freeman, G.J.; et al. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2016, 34, 2690–2697. [Google Scholar] [CrossRef] [Green Version]
  68. Cader, F.Z.; Schackmann, R.C.J.; Hu, X.; Wienand, K.; Redd, R.; Chapuy, B.; Ouyang, J.; Paul, N.; Gjini, E.; Lipschitz, M.; et al. Mass Cytometry of Hodgkin Lymphoma Reveals a CD4(+) Regulatory T-Cell-Rich and Exhausted T-Effector Microenvironment. Blood 2018, 132, 825–836. [Google Scholar] [CrossRef]
  69. Xie, W.; Medeiros, L.J.; Li, S.; Yin, C.C.; Khoury, J.D.; Xu, J. PD-1/PD-L1 Pathway and Its Blockade in Patients with Classic Hodgkin Lymphoma and Non-Hodgkin Large-Cell Lymphomas. Curr. Hematol. Malig. Rep. 2020, 15, 372–381. [Google Scholar] [CrossRef]
  70. Park, S.H.; You, E.; Park, C.-J.; Cho, Y.U.; Jang, S.; Im, H.J.; Seo, J.J.; Park, H.S.; Lee, J.H. Increased Expression of Immune Checkpoint Programmed Cell Death Protein-1 (PD-1) on T Cell Subsets of Bone Marrow Aspirates in Patients with B-Lymphoblastic Leukemia, Especially in Relapse and at Diagnosis. Cytometry. Part B Clin. Cytom. 2020, 98, 336–347. [Google Scholar] [CrossRef]
  71. Brudno, J.N.; Somerville, R.P.T.; Shi, V.; Rose, J.J.; Halverson, D.C.; Fowler, D.H.; Gea-Banacloche, J.C.; Pavletic, S.Z.; Hickstein, D.D.; Lu, T.L.; et al. Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease. J. Clin. Oncol. J. Am. Soc. Clin. Oncol. 2016, 34, 1112–1121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Li, A.M.; Hucks, G.E.; Dinofia, A.M.; Seif, A.E.; Teachey, D.T.; Baniewicz, D.; Callahan, C.; Fasano, C.; McBride, B.; Gonzalez, V.; et al. Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia. Blood 2018, 132, 556. [Google Scholar] [CrossRef]
  73. Cao, Y.; Lu, W.; Sun, R.; Jin, X.; Cheng, L.; He, X.; Wang, L.; Yuan, T.; Lyu, C.; Zhao, M. Anti-CD19 Chimeric Antigen Receptor T Cells in Combination with Nivolumab Are Safe and Effective Against Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. Front. Oncol. 2019, 9, 767. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Chong, E.A.; Alanio, C.; Svoboda, J.; Nasta, S.D.; Landsburg, D.J.; Lacey, S.F.; Ruella, M.; Bhattacharyya, S.; Wherry, E.J.; Schuster, S.J. Pembrolizumab for B-Cell Lymphomas Relapsing after or Refractory to CD19-Directed CAR T-Cell Therapy. Blood 2022, 139, 1026–1038. [Google Scholar] [CrossRef] [PubMed]
  75. Rafiq, S.; Yeku, O.O.; Jackson, H.J.; Purdon, T.J.; van Leeuwen, D.G.; Drakes, D.J.; Song, M.; Miele, M.M.; Li, Z.; Wang, P.; et al. Targeted Delivery of a PD-1-Blocking ScFv by CAR-T Cells Enhances Anti-Tumor Efficacy in vivo. Nat. Biotechnol. 2018, 36, 847–856. [Google Scholar] [CrossRef]
  76. Liu, H.; Lei, W.; Zhang, C.; Yang, C.; Wei, J.; Guo, Q.; Guo, X.; Chen, Z.; Lu, Y.; Young, K.H.; et al. CD19-Specific CAR T Cells That Express a PD-1/CD28 Chimeric Switch-Receptor Are Effective in Patients with PD-L1-Positive B-Cell Lymphoma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2021, 27, 473–484. [Google Scholar] [CrossRef]
  77. Prinzing, B.; Zebley, C.C.; Petersen, C.T.; Fan, Y.; Anido, A.A.; Yi, Z.; Nguyen, P.; Houke, H.; Bell, M.; Haydar, D.; et al. Deleting DNMT3A in CAR T Cells Prevents Exhaustion and Enhances Antitumor Activity. Sci. Transl. Med. 2021, 13, eabh0272. [Google Scholar] [CrossRef]
  78. Gennert, D.G.; Lynn, R.C.; Granja, J.M.; Weber, E.W.; Mumbach, M.R.; Zhao, Y.; Duren, Z.; Sotillo, E.; Greenleaf, W.J.; Wong, W.H.; et al. Dynamic Chromatin Regulatory Landscape of Human CAR T Cell Exhaustion. Proc. Natl. Acad. Sci. USA 2021, 118, 8118. [Google Scholar] [CrossRef]
  79. Zebley, C.C.; Brown, C.; Mi, T.; Fan, Y.; Alli, S.; Boi, S.; Galletti, G.; Lugli, E.; Langfitt, D.; Metais, J.-Y.; et al. CD19-CAR T Cells Undergo Exhaustion DNA Methylation Programming in Patients with Acute Lymphoblastic Leukemia. Cell Rep. 2021, 37, 110079. [Google Scholar] [CrossRef]
  80. Lynn, R.C.; Weber, E.W.; Sotillo, E.; Gennert, D.; Xu, P.; Good, Z.; Anbunathan, H.; Lattin, J.; Jones, R.; Tieu, V.; et al. C-Jun Overexpression in CAR T Cells Induces Exhaustion Resistance. Nature 2019, 576, 293–300. [Google Scholar] [CrossRef]
  81. Ajina, A.; Maher, J. Strategies to Address Chimeric Antigen Receptor Tonic Signaling. Mol. Cancer Ther. 2018, 17, 1795–1815. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Kim, E.H.; Suresh, M. Role of PI3K/Akt Signaling in Memory CD8 T Cell Differentiation. Front. Immunol. 2013, 4, 20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Caforio, M.; de Billy, E.; De Angelis, B.; Iacovelli, S.; Quintarelli, C.; Paganelli, V.; Folgiero, V. PI3K/Akt Pathway: The Indestructible Role of a Vintage Target as a Support to the Most Recent Immunotherapeutic Approaches. Cancers 2021, 13, 4040. [Google Scholar] [CrossRef] [PubMed]
  84. Stock, S.; Übelhart, R.; Schubert, M.L.; Fan, F.; He, B.; Hoffmann, J.M.; Wang, L.; Wang, S.; Gong, W.; Neuber, B.; et al. Idelalisib for Optimized CD19-Specific Chimeric Antigen Receptor T Cells in Chronic Lymphocytic Leukemia Patients. Int. J. Cancer 2019, 145, 1312–1324. [Google Scholar] [CrossRef] [PubMed]
  85. Fan, F.; Yoo, H.J.; Stock, S.; Wang, L.; Liu, Y.; Schubert, M.L.; Wang, S.; Neuber, B.; Hückelhoven-Krauss, A.; Gern, U.; et al. Ibrutinib for Improved Chimeric Antigen Receptor T-Cell Production for Chronic Lymphocytic Leukemia Patients. Int. J. Cancer 2021, 148, 419–428. [Google Scholar] [CrossRef]
  86. Funk, C.R.; Wang, S.; Chen, K.Z.; Waller, A.; Sharma, A.; Edgar, C.L.; Gupta, V.A.; Chandrakasan, S.; Zoine, J.T.; Fedanov, A.; et al. PI3Kδ/γ Inhibition Promotes Human CART Cell Epigenetic and Metabolic Reprogramming to Enhance Antitumor Cytotoxicity. Blood 2022, 139, 523–537. [Google Scholar] [CrossRef]
  87. Richman, S.A.; Wang, L.C.; Moon, E.K.; Khire, U.R.; Albelda, S.M.; Milone, M.C. Ligand-Induced Degradation of a CAR Permits Reversible Remote Control of CAR T Cell Activity In Vitro and In Vivo. Mol. Ther. J. Am. Soc. Gene Ther. 2020, 28, 1600–1613. [Google Scholar] [CrossRef]
  88. Weber, E.W.; Parker, K.R.; Sotillo, E.; Lynn, R.C.; Anbunathan, H.; Lattin, J.; Good, Z.; Belk, J.A.; Daniel, B.; Klysz, D.; et al. Transient Rest Restores Functionality in Exhausted CAR-T Cells through Epigenetic Remodeling. Science 2021, 372, 1786. [Google Scholar] [CrossRef]
  89. Mestermann, K.; Giavridis, T.; Weber, J.; Rydzek, J.; Frenz, S.; Nerreter, T.; Mades, A.; Sadelain, M.; Einsele, H.; Hudecek, M. The Tyrosine Kinase Inhibitor Dasatinib Acts as a Pharmacologic on/off Switch for CAR T Cells. Sci. Transl. Med. 2019, 11, 5907. [Google Scholar] [CrossRef]
  90. Aamir, S.; Anwar, M.Y.; Khalid, F.; Khan, S.I.; Ali, M.A.; Khattak, Z.E. Systematic Review and Meta-Analysis of CD19-Specific CAR-T Cell Therapy in Relapsed/Refractory Acute Lymphoblastic Leukemia in the Pediatric and Young Adult Population: Safety and Efficacy Outcomes. Clin. Lymphoma Myeloma Leuk. 2021, 21, e334–e347. [Google Scholar] [CrossRef]
  91. Lemoine, J.; Ruella, M.; Houot, R. Born to Survive: How Cancer Cells Resist CAR T Cell Therapy. J. Hematol. Oncol. 2021, 14, 199. [Google Scholar] [CrossRef]
  92. Park, J.H.; Rivière, I.; Gonen, M.; Wang, X.; Sénéchal, B.; Curran, K.J.; Sauter, C.; Wang, Y.; Santomasso, B.; Mead, E.; et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 449–459. [Google Scholar] [CrossRef] [PubMed]
  93. Gardner, R.A.; Finney, O.; Annesley, C.; Brakke, H.; Summers, C.; Leger, K.; Bleakley, M.; Brown, C.; Mgebroff, S.; Kelly-Spratt, K.S.; et al. Intent-to-Treat Leukemia Remission by CD19 CAR T Cells of Defined Formulation and Dose in Children and Young Adults. Blood 2017, 129, 3322–3331. [Google Scholar] [CrossRef] [PubMed]
  94. Turtle, C.J.; Hanafi, L.A.; Berger, C.; Gooley, T.A.; Cherian, S.; Hudecek, M.; Sommermeyer, D.; Melville, K.; Pender, B.; Budiarto, T.M.; et al. CD19 CAR-T Cells of Defined CD4+:CD8+ Composition in Adult B Cell ALL Patients. J. Clin. Investig. 2016, 126, 2123–2138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Maude, S.L.; Frey, N.; Shaw, P.A.; Aplenc, R.; Barrett, D.M.; Bunin, N.J.; Chew, A.; Gonzalez, V.E.; Zheng, Z.; Lacey, S.F.; et al. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. N. Engl. J. Med. 2014, 371, 1507–1517. [Google Scholar] [CrossRef] [Green Version]
  96. Schuster, S.J.; Svoboda, J.; Chong, E.A.; Nasta, S.D.; Mato, A.R.; Anak, Ö.; Brogdon, J.L.; Pruteanu-Malinici, I.; Bhoj, V.; Landsburg, D.; et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N. Engl. J. Med. 2017, 377, 2545–2554. [Google Scholar] [CrossRef]
  97. Spiegel, J.Y.; Dahiya, S.; Jain, M.D.; Tamaresis, J.; Nastoupil, L.J.; Jacobs, M.T.; Ghobadi, A.; Lin, Y.; Lunning, M.; Lekakis, L.; et al. Outcomes of Patients with Large B-Cell Lymphoma Progressing after Axicabtagene Ciloleucel Therapy. Blood 2021, 137, 1832–1835. [Google Scholar]
  98. Fousek, K.; Watanabe, J.; Joseph, S.K.; George, A.; An, X.; Byrd, T.T.; Morris, J.S.; Luong, A.; Martínez-Paniagua, M.A.; Sanber, K.; et al. CAR T-Cells That Target Acute B-Lineage Leukemia Irrespective of CD19 Expression. Leukemia 2021, 35, 75–89. [Google Scholar] [CrossRef] [Green Version]
  99. Shalabi, H.; Kraft, I.L.; Wang, H.-W.; Yuan, C.M.; Yates, B.; Delbrook, C.; Zimbelman, J.D.; Giller, R.; Stetler-Stevenson, M.; Jaffe, E.S.; et al. Sequential Loss of Tumor Surface Antigens Following Chimeric Antigen Receptor T-Cell Therapies in Diffuse Large B-Cell Lymphoma. Haematologica 2018, 103, e215–e218. [Google Scholar] [CrossRef]
  100. Plaks, V.; Rossi, J.M.; Chou, J.; Wang, L.; Poddar, S.; Han, G.; Wang, Z.; Kuang, S.Q.; Chu, F.; Davis, R.E.; et al. CD19 Target Evasion as a Mechanism of Relapse in Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel. Blood 2021, 138, 1081–1085. [Google Scholar] [CrossRef]
  101. Sotillo, E.; Barrett, D.M.; Black, K.L.; Bagashev, A.; Oldridge, D.; Wu, G.; Sussman, R.; Lanauze, C.; Ruella, M.; Gazzara, M.R.; et al. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov. 2015, 5, 1282–1295. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Orlando, E.J.; Han, X.; Tribouley, C.; Wood, P.A.; Leary, R.J.; Riester, M.; Levine, J.E.; Qayed, M.; Grupp, S.A.; Boyer, M.; et al. Genetic Mechanisms of Target Antigen Loss in CAR19 Therapy of Acute Lymphoblastic Leukemia. Nat. Med. 2018, 24, 1504–1506. [Google Scholar] [CrossRef] [PubMed]
  103. Fischer, J.; Paret, C.; El Malki, K.; Alt, F.; Wingerter, A.; Neu, M.A.; Kron, B.; Russo, A.; Lehmann, N.; Roth, L.; et al. CD19 Isoforms Enabling Resistance to CART-19 Immunotherapy Are Expressed in B-ALL Patients at Initial Diagnosis. J. Immunother. 2017, 40, 187–195. [Google Scholar] [CrossRef] [Green Version]
  104. Asnani, M.; Hayer, K.E.; Naqvi, A.S.; Zheng, S.; Yang, S.Y.; Oldridge, D.; Ibrahim, F.; Maragkakis, M.; Gazzara, M.R.; Black, K.L.; et al. Retention of CD19 Intron 2 Contributes to CART-19 Resistance in Leukemias with Subclonal Frameshift Mutations in CD19. Leukemia 2020, 34, 1202–1207. [Google Scholar] [CrossRef] [PubMed]
  105. Ledererova, A.; Dostalova, L.; Kozlova, V.; Peschelova, H.; Ladungova, A.; Culen, M.; Loja, T.; Verner, J.; Pospisilova, S.; Smida, M.; et al. Hypermethylation of CD19 Promoter Enables Antigen-Negative Escape to CART-19 in Vivo and in Vitro. J. Immunother. Cancer 2021, 9, 2352. [Google Scholar] [CrossRef] [PubMed]
  106. Ruella, M.; Xu, J.; Barrett, D.M.; Fraietta, J.A.; Reich, T.J.; Ambrose, D.E.; Klichinsky, M.; Shestova, O.; Patel, P.R.; Kulikovskaya, I.; et al. Induction of Resistance to Chimeric Antigen Receptor T Cell Therapy by Transduction of a Single Leukemic B Cell. Nat. Med. 2018, 24, 1499–1503. [Google Scholar] [CrossRef]
  107. Ruella, M.; Barrett, D.M.; Shestova, O.; Perazzelli, J.; Posey, A.D.; Hong, S.J.; Kozlowski, M.; Lacey, S.F.; Melenhorst, J.J.; June, C.H.; et al. A Cellular Antidote to Specifically Deplete Anti-CD19 Chimeric Antigen Receptor-Positive Cells. Blood 2020, 135, 505–509. [Google Scholar] [CrossRef]
  108. Quintarelli, C.; Guercio, M.; Manni, S.; Boffa, I.; Sinibaldi, M.; Di Cecca, S.; Caruso, S.; Abbaszadeh, Z.; Camera, A.; Cembrola, B.; et al. Strategy to Prevent Epitope Masking in CAR.CD19+ B-Cell Leukemia Blasts. J. Immunother. Cancer 2021, 9, 1514. [Google Scholar] [CrossRef]
  109. Fitzgerald, K.N.; Quesada, A.E.; von Keudell, G.; Raj, S.; Lewis, N.E.; Dogan, A.; Salles, G.; Palomba, M.L. CD19 Epitope Masking by Tafasitamab Leads to Delays in Subsequent Use of CD19 CAR T-Cell Therapy in Two Patients with Aggressive Mature B-Cell Lymphomas. Leuk. Lymphoma 2022, 63, 751–754. [Google Scholar] [CrossRef]
  110. Liao, W.; Kohler, M.E.; Fry, T.; Ernst, P. Does Lineage Plasticity Enable Escape from CAR-T Cell Therapy? Lessons from MLL-r Leukemia. Exp. Hematol. 2021, 100, 1–11. [Google Scholar] [CrossRef]
  111. Jacoby, E.; Nguyen, S.M.; Fountaine, T.J.; Welp, K.; Gryder, B.; Qin, H.; Yang, Y.; Chien, C.D.; Seif, A.E.; Lei, H.; et al. CD19 CAR Immune Pressure Induces B-Precursor Acute Lymphoblastic Leukaemia Lineage Switch Exposing Inherent Leukaemic Plasticity. Nat. Commun. 2016, 7, 12320. [Google Scholar] [CrossRef] [PubMed]
  112. Gardner, R.; Wu, D.; Cherian, S.; Fang, M.; Hanafi, L.-A.; Finney, O.; Smithers, H.; Jensen, M.C.; Riddell, S.R.; Maloney, D.G.; et al. Acquisition of a CD19-Negative Myeloid Phenotype Allows Immune Escape of MLL-Rearranged B-ALL from CD19 CAR-T-Cell Therapy. Blood 2016, 127, 2406–2410. [Google Scholar] [CrossRef] [Green Version]
  113. Lamble, A.J.; Myers, R.M.; Taraseviciute, A.; John, S.; Yates, B.; Steinberg, S.M.; Sheppard, J.; Kovach, A.E.; Wood, B.L.; Borowitz, M.; et al. KMT2A Rearrangements Are Associated with Lineage Switch Following CD19 Targeting CAR T-Cell Therapy. Blood 2021, 138, 256. [Google Scholar] [CrossRef]
  114. Li, L.Z.; Sun, Q.; Fang, Y.; Yang, L.J.; Xu, Z.Y.; Hu, J.H.; Cao, L.; Huang, J.Y.; Hong, M.; Li, J.Y.; et al. A Report on Lineage Switch at Relapse of CD19 CAR-T Therapy for Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia. Chin. Med. J. 2020, 133, 2001–2003. [Google Scholar] [CrossRef] [PubMed]
  115. Zhang, Q.; Orlando, E.J.; Wang, H.Y.; Bogusz, A.M.; Liu, X.; Lacey, S.F.; Strauser, H.T.; Nunez-Cruz, S.; Nejati, R.; Zhang, P.; et al. Transdifferentiation of Lymphoma into Sarcoma Associated with Profound Reprogramming of the Epigenome. Blood 2020, 136, 1980–1983. [Google Scholar] [CrossRef] [PubMed]
  116. Laurent, C.; Syrykh, C.; Hamon, M.; Adélaïde, J.; Guille, A.; Escudié, F.; Jalowicki, G.; Fina, F.; Bardet, A.; Mescam, L.; et al. Resistance of B-Cell Lymphomas to CAR T-Cell Therapy Is Associated with Genomic Tumor Changes Which Can Result in Transdifferentiation. Am. J. Surg. Pathol. 2021, 97, 1834. [Google Scholar] [CrossRef] [PubMed]
  117. Zhou, L.; Zhao, H.; Shao, Y.; Chen, X.; Hong, R.; Wang, L.; Ni, F.; Nagler, A.; Hu, Y.; Huang, H. Serial Surveillance by Circulating Tumor DNA Profiling after Chimeric Antigen Receptor T Therapy for the Guidance of r/r Diffuse Large B Cell Lymphoma Precise Treatment. J. Cancer 2021, 12, 5423–5431. [Google Scholar] [CrossRef]
  118. Jain, M.D.; Ziccheddu, B.; Coughlin, C.A.; Faramand, R.; Griswold, A.J.; Reid, K.M.; Landgren, O.; Locke, F.L.; Maura, F.; Davila, M.L.; et al. Genomic Drivers of Large B-Cell Lymphoma Resistance to CD19 CAR-T Therapy. Blood 2021, 138, 42. [Google Scholar] [CrossRef]
  119. Jain, M.D.; Ziccheddu, B.; Coughlin, C.A.; Faramand, R.; Griswold, A.J.; Reid, K.M.; Landgren, O.; Locke, F.L.; Maura, F.; Davila, M.L.; et al. Genomic Drivers of Large B-Cell Lymphoma Resistance to CD19 CAR-T Therapy. bioRxiv 2021, 25, 457649. [Google Scholar] [CrossRef]
  120. Lemoine, J.; Ruella, M.; Houot, R. Overcoming Intrinsic Resistance of Cancer Cells to CAR T-Cell Killing. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2021, 27, 6298–6306. [Google Scholar] [CrossRef]
  121. Dufva, O.; Koski, J.; Maliniemi, P.; Ianevski, A.; Klievink, J.; Leitner, J.; Pölönen, P.; Hohtari, H.; Saeed, K.; Hannunen, T.; et al. Integrated Drug Profiling and CRISPR Screening Identify Essential Pathways for CAR T-Cell Cytotoxicity. Blood 2020, 135, 597–609. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Singh, N.; Lee, Y.G.; Shestova, O.; Ravikumar, P.; Hayer, K.E.; Hong, S.J.; Lu, X.M.; Pajarillo, R.; Agarwal, S.; Kuramitsu, S.; et al. Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-Cell Dysfunction. Cancer Discov. 2020, 10, 552–567. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Upadhyay, R.; Boiarsky, J.A.; Pantsulaia, G.; Svensson-Arvelund, J.; Lin, M.J.; Wroblewska, A.; Bhalla, S.; Scholler, N.; Bot, A.; Rossi, J.M.; et al. A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-Cell Immunotherapy. Cancer Discov. 2021, 11, 599–613. [Google Scholar] [CrossRef] [PubMed]
  124. Challa-Malladi, M.; Lieu, Y.K.; Califano, O.; Holmes, A.B.; Bhagat, G.; Murty, V.V.; Dominguez-Sola, D.; Pasqualucci, L.; Dalla-Favera, R. Combined Genetic Inactivation of Β2-Microglobulin and CD58 Reveals Frequent Escape from Immune Recognition in Diffuse Large B Cell Lymphoma. Cancer Cell 2011, 20, 728–740. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Majzner, R.G.; Frank, M.J.; Mount, C.; Tousley, A.; Kurtz, D.M.; Sworder, B.; Murphy, K.A.; Manousopoulou, A.; Kohler, K.; Rotiroti, M.C.; et al. CD58 Aberrations Limit Durable Responses to CD19 CAR in Large B Cell Lymphoma Patients Treated with Axicabtagene Ciloleucel but Can Be Overcome through Novel CAR Engineering. Blood 2020, 136, 53–54. [Google Scholar] [CrossRef]
  126. Jiang, H.; Hu, Y.; Mei, H. Consolidative Allogeneic Hematopoietic Stem Cell Transplantation after Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia: Who? When? Why? Biomark. Res. 2020, 8, 66. [Google Scholar] [CrossRef]
  127. Henig, I.; Zuckerman, T. Hematopoietic Stem Cell Transplantation-50 Years of Evolution and Future Perspectives. Rambam Maimonides Med. J. 2014, 5, e0028. [Google Scholar] [CrossRef]
  128. Savani, M.; Oluwole, O.; Dholaria, B. New Targets for CAR T Therapy in Hematologic Malignancies. Best practice & research. Clin. Haematol. 2021, 34, 101277. [Google Scholar] [CrossRef]
  129. Vercelli, D.; Jabara, H.H.; Lee, B.W.; Woodland, N.; Geha, R.S.; Leung, D.Y. Human Recombinant Interleukin 4 Induces Fc Epsilon R2/CD23 on Normal Human Monocytes. J. Exp. Med. 1988, 167, 1406–1416. [Google Scholar] [CrossRef]
  130. Kumagai, S.; Ishida, H.; Iwai, K.; Tsubata, T.; Umehara, H.; Ozaki, S.; Suginoshita, T.; Araya, S.; Imura, H. Possible Different Mechanisms of B Cell Activation in Systemic Lupus Erythematosus and Rheumatoid Arthritis: Opposite Expression of Low-Affinity Receptors for IgE (CD23) on Their Peripheral B Cells. Clin. Exp. Immunol. 1989, 78, 348–353. [Google Scholar]
  131. Armitage, R.J.; Goff, L.K.; Beverley, P.C.L. Expression and Functional Role of CD23 on T Cells. Eur. J. Immunol. 1989, 19, 31–35. [Google Scholar] [CrossRef] [PubMed]
  132. Fourcade, C.; Arock, M.; Ktorza, S.; Ouaaz, F.; Merle-Béral, H.; Mentz, F.; Kilchherr, E.; Debré, P.; Mossalayi, M.D. Expression of CD23 by Human Bone Marrow Stromal Cells. Eur. Cytokine Netw. 1992, 3, 539–543. [Google Scholar]
  133. Capron, M.; Truong, M.J.; Aldebert, D.; Gruart, V.; Suemura, M.; Delespesse, G.; Tourvieille, B.; Capron, A. Eosinophil IgE Receptor and CD23. Immunol. Res. 1992, 11, 252–259. [Google Scholar] [CrossRef] [PubMed]
  134. Krauss, S.; Mayer, E.; Rank, G.; Rieber, E.P. Induction of the Low Affinity Receptor for IgE (Fc Epsilon RII/CD23) on Human Blood Dendritic Cells by Interleukin-4. Adv. Exp. Med. Biol. 1993, 329, 231–236. [Google Scholar] [CrossRef] [PubMed]
  135. Yamaoka, K.A.; Arock, M.; Issaly, F.; Dugas, N.; Le Goff, L.; Kolb, J.P. Granulocyte Macrophage Colony Stimulating Factor Induces Fc Epsilon RII/CD23 Expression on Normal Human Polymorphonuclear Neutrophils. Int. Immunol. 1996, 8, 479–490. [Google Scholar] [CrossRef] [Green Version]
  136. Giordano Attianese, G.M.P.; Marin, V.; Hoyos, V.; Savoldo, B.; Pizzitola, I.; Tettamanti, S.; Agostoni, V.; Parma, M.; Ponzoni, M.; Bertilaccio, M.T.S.; et al. In Vitro and in Vivo Model of a Novel Immunotherapy Approach for Chronic Lymphocytic Leukemia by Anti-CD23 Chimeric Antigen Receptor. Blood 2011, 117, 4736–4745. [Google Scholar] [CrossRef]
  137. Tettamanti, S.; Rotiroti, M.C.; Giordano Attianese, G.M.P.; Arcangeli, S.; Zhang, R.; Banerjee, P.; Galletti, G.; McManus, S.; Mazza, M.; Nicolini, F.; et al. Lenalidomide Enhances CD23.CAR T Cell Therapy in Chronic Lymphocytic Leukemia. Leuk. Lymphoma 2022, 94, 1–14. [Google Scholar] [CrossRef]
  138. Nimmerjahn, F.; Ravetch, J. V Fcgamma Receptors: Old Friends and New Family Members. Immunity 2006, 24, 19–28. [Google Scholar] [CrossRef] [Green Version]
  139. Xia, Y.C.; Schuliga, M.; Shepherd, M.; Powell, M.; Harris, T.; Langenbach, S.Y.; Tan, P.S.; Gerthoffer, W.T.; Hogarth, P.M.; Stewart, A.G.; et al. Functional Expression of IgG-Fc Receptors in Human Airway Smooth Muscle Cells. Am. J. Respir. Cell Mol. Biol. 2011, 44, 665–672. [Google Scholar] [CrossRef] [Green Version]
  140. Bruggeman, C.W.; Houtzager, J.; Dierdorp, B.; Kers, J.; Pals, S.T.; Lutter, R.; van Gulik, T.; den Haan, J.M.M.; van den Berg, T.K.; van Bruggen, R.; et al. Tissue-Specific Expression of IgG Receptors by Human Macrophages Ex Vivo. PLoS ONE 2019, 14, e0223264. [Google Scholar] [CrossRef]
  141. Wang, G.; Sun, X.; Zuo, S.; Li, C.; Niu, Q.; Xia, Y.; Meng, Y.; Liu, M.; Fang, Z.; Yang, X.; et al. Homogeneously High Expression of CD32b Makes It a Potential Target for CAR-T Therapy for Chronic Lymphocytic Leukemia. J. Hematol. Oncol. 2021, 14, 149. [Google Scholar] [CrossRef] [PubMed]
  142. Hintzen, R.Q.; Lens, S.M.; Koopman, G.; Pals, S.T.; Spits, H.; van Lier, R.A. CD70 Represents the Human Ligand for CD27. Int. Immunol. 1994, 6, 477–480. [Google Scholar] [CrossRef]
  143. Wajant, H. Therapeutic Targeting of CD70 and CD27. Expert Opin. Ther. Targets 2016, 20, 959–973. [Google Scholar] [CrossRef] [PubMed]
  144. Shaffer, D.R.; Savoldo, B.; Yi, Z.; Chow, K.K.H.; Kakarla, S.; Spencer, D.M.; Dotti, G.; Wu, M.F.; Liu, H.; Kenney, S.; et al. T Cells Redirected against CD70 for the Immunotherapy of CD70-Positive Malignancies. Blood 2011, 117, 4304–4314. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Deng, W.; Chen, P.; Lei, W.; Xu, Y.; Xu, N.; Pu, J.J.; Liang, A.; Qian, W. CD70-Targeting CAR-T Cells Have Potential Activity against CD19-Negative B-Cell Lymphoma. Cancer Commun. 2021, 41, 925–929. [Google Scholar] [CrossRef] [PubMed]
  146. Schwarting, R.; Castello, R.; Moldenhauer, G.; Pezzutto, A.; von Hoegen, I.; Ludwig, W.D.; Parnes, J.R.; Dörken, B. Human Lyb-2 Homolog CD72 Is a Marker for Progenitor B-Cell Leukemias. Am. J. Hematol. 1992, 41, 151–158. [Google Scholar] [CrossRef]
  147. Nix, M.A.; Mandal, K.; Geng, H.; Paranjape, N.; Lin, Y.H.T.; Rivera, J.M.; Marcoulis, M.; White, K.L.; Whitman, J.D.; Bapat, S.P.; et al. Surface Proteomics Reveals CD72 as a Target for In Vitro-Evolved Nanobody-Based CAR-T Cells in KMT2A/MLL1-Rearranged B-ALL. Cancer Discov. 2021, 11, 2032–2049. [Google Scholar] [CrossRef]
  148. Yin, A.H.; Miraglia, S.; Zanjani, E.D.; Almeida-Porada, G.; Ogawa, M.; Leary, A.G.; Olweus, J.; Kearney, J.; Buck, D.W. AC133, a Novel Marker for Human Hematopoietic Stem and Progenitor Cells. Blood 1997, 90, 5002–5012. [Google Scholar] [CrossRef] [Green Version]
  149. Li, D.; Hu, Y.; Jin, Z.; Zhai, Y.; Tan, Y.; Sun, Y.; Zhu, S.; Zhao, C.; Chen, B.; Zhu, J.; et al. TanCAR T Cells Targeting CD19 and CD133 Efficiently Eliminate MLL Leukemic Cells. Leukemia 2018, 32, 2012–2016. [Google Scholar] [CrossRef]
  150. Bueno, C.; Velasco-Hernandez, T.; Gutiérrez-Agüera, F.; Zanetti, S.R.; Baroni, M.L.; Sánchez-Martínez, D.; Molina, O.; Closa, A.; Agraz-Doblás, A.; Marín, P.; et al. CD133-Directed CAR T-Cells for MLL Leukemia: On-Target, off-Tumor Myeloablative Toxicity. Leukemia 2019, 33, 2090–2125. [Google Scholar] [CrossRef]
  151. Kubagawa, H.; Oka, S.; Kubagawa, Y.; Torii, I.; Takayama, E.; Kang, D.-W.; Gartland, G.L.; Bertoli, L.F.; Mori, H.; Takatsu, H.; et al. Identity of the Elusive IgM Fc Receptor (FcmuR) in Humans. J. Exp. Med. 2009, 206, 2779–2793. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Faitschuk, E.; Hombach, A.A.; Frenzel, L.P.; Wendtner, C.-M.; Abken, H. Chimeric Antigen Receptor T Cells Targeting Fc μ Receptor Selectively Eliminate CLL Cells While Sparing Healthy B Cells. Blood 2016, 128, 1711–1722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Kardava, L.; Moir, S.; Wang, W.; Ho, J.; Buckner, C.M.; Posada, J.G.; O’Shea, M.A.; Roby, G.; Chen, J.; Sohn, H.W.; et al. Attenuation of HIV-Associated Human B Cell Exhaustion by SiRNA Downregulation of Inhibitory Receptors. J. Clin. Investig. 2011, 121, 2614–2624. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Rumer, K.K.; Uyenishi, J.; Hoffman, M.C.; Fisher, B.M.; Winn, V.D. Siglec-6 Expression Is Increased in Placentas from Pregnancies Complicated by Preterm Preeclampsia. Reprod. Sci. 2013, 20, 646–653. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Yu, Y.; Blokhuis, B.R.J.; Diks, M.A.P.; Keshavarzian, A.; Garssen, J.; Redegeld, F.A. Functional Inhibitory Siglec-6 Is Upregulated in Human Colorectal Cancer-Associated Mast Cells. Front. Immunol. 2018, 9, 2138. [Google Scholar] [CrossRef]
  156. Kovalovsky, D.; Yoon, J.H.; Cyr, M.G.; Simon, S.; Voynova, E.; Rader, C.; Wiestner, A.; Alejo, J.; Pittaluga, S.; Gress, R.E. Siglec-6 Is a Target for Chimeric Antigen Receptor T-Cell Treatment of Chronic Lymphocytic Leukemia. Leukemia 2021, 35, 2581–2591. [Google Scholar] [CrossRef]
  157. Reche, P.A.; Soumelis, V.; Gorman, D.M.; Clifford, T.; Mr, L.; Travis, M.; Zurawski, S.M.; Johnston, J.; Liu, Y.J.; Spits, H.; et al. Human Thymic Stromal Lymphopoietin Preferentially Stimulates Myeloid Cells. J. Immunol. 2001, 167, 336–343. [Google Scholar] [CrossRef] [PubMed]
  158. Qin, H.; Cho, M.; Haso, W.; Zhang, L.; Tasian, S.K.; Oo, H.Z.; Negri, G.L.; Lin, Y.; Zou, J.; Mallon, B.S.; et al. Eradication of B-ALL Using Chimeric Antigen Receptor-Expressing T Cells Targeting the TSLPR Oncoprotein. Blood 2015, 126, 629–639. [Google Scholar] [CrossRef]
  159. Rodig, S.J.; Shahsafaei, A.; Li, B.; Mackay, C.R.; Dorfman, D.M. BAFF-R, the Major B Cell-Activating Factor Receptor, Is Expressed on Most Mature B Cells and B-Cell Lymphoproliferative Disorders. Hum. Pathol. 2005, 36, 1113–1119. [Google Scholar] [CrossRef]
  160. Saeland, S.; Duvert, V.; Pandrau, D.; Caux, C.; Durand, I.; Wrighton, N.; Wideman, J.; Lee, F.; Banchereau, J. Interleukin-7 Induces the Proliferation of Normal Human B-Cell Precursors. Blood 1991, 78, 2229–2238. [Google Scholar] [CrossRef] [Green Version]
  161. Wentink, M.W.J.; Kalina, T.; Perez-Andres, M.; Del Pino Molina, L.; IJspeert, H.; Kavelaars, F.G.; Lankester, A.C.; Lecrevisse, Q.; van Dongen, J.J.M.; Orfao, A.; et al. Delineating Human B Cell Precursor Development with Genetically Identified PID Cases as a Model. Front. Immunol. 2019, 10, 2680. [Google Scholar] [CrossRef] [PubMed]
  162. Otipoby, K.L.; Andersson, K.B.; Draves, K.E.; Klaus, S.J.; Farr, A.G.; Kerner, J.D.; Perlmutter, R.M.; Law, C.L.; Clark, E.A. CD22 Regulates Thymus-Independent Responses and the Lifespan of B Cells. Nature 1996, 384, 634–637. [Google Scholar] [CrossRef] [PubMed]
  163. Viemann, D.; Schlenke, P.; Hammers, H.J.; Kirchner, H.; Kruse, A. Differential Expression of the B Cell-Restricted Molecule CD22 on Neonatal B Lymphocytes Depending upon Antigen Stimulation. Eur. J. Immunol. 2000, 30, 550–559. [Google Scholar] [CrossRef]
  164. Gilfillan, M.C.; Noel, P.J.; Podack, E.R.; Reiner, S.L.; Thompson, C.B. Expression of the Costimulatory Receptor CD30 Is Regulated by Both CD28 and Cytokines. J. Immunol. 1998, 160, 2180–2187. [Google Scholar] [PubMed]
  165. Weniger, M.A.; Tiacci, E.; Schneider, S.; Arnolds, J.; Rüschenbaum, S.; Duppach, J.; Seifert, M.; Döring, C.; Hansmann, M.L.; Küppers, R. Human CD30+ B Cells Represent a Unique Subset Related to Hodgkin Lymphoma Cells. J. Clin. Investig. 2018, 128, 2996–3007. [Google Scholar] [CrossRef] [Green Version]
  166. De Winde, C.M.; Zuidscherwoude, M.; Vasaturo, A.; van der Schaaf, A.; Figdor, C.G.; van Spriel, A.B. Multispectral Imaging Reveals the Tissue Distribution of Tetraspanins in Human Lymphoid Organs. Histochem. Cell Biol. 2015, 144, 133–146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Krejcik, J.; Casneuf, T.; Nijhof, I.S.; Verbist, B.; Bald, J.; Plesner, T.; Syed, K.; Liu, K.; van de Donk, N.W.C.J.; Weiss, B.M.; et al. Daratumumab Depletes CD38+ Immune Regulatory Cells, Promotes T-Cell Expansion, and Skews T-Cell Repertoire in Multiple Myeloma. Blood 2016, 128, 384–394. [Google Scholar] [CrossRef] [Green Version]
  168. Garcia Vela, J.; Delgado, I.; Benito, L.; Monteserin, M.; Garcia Alonso, L.; Somolinos, N.; Andreu, M.; Oña, F. CD79b Expression in B Cell Chronic Lymphocytic Leukemia: Its Implication for Minimal Residual Disease Detection. Leukemia 1999, 13, 1501–1505. [Google Scholar] [CrossRef] [Green Version]
  169. Shi, J.; Ikeda, K.; Maeda, Y.; Shinagawa, K.; Ohtsuka, A.; Yamamura, H.; Tanimoto, M. Identification of CD123+ Myeloid Dendritic Cells as an Early-Stage Immature Subset with Strong Tumoristatic Potential. Cancer Lett. 2008, 270, 19–29. [Google Scholar] [CrossRef] [Green Version]
  170. Santos, A.F.; Bécares, N.; Stephens, A.; Turcanu, V.; Lack, G. The Expression of CD123 Can Decrease with Basophil Activation: Implications for the Gating Strategy of the Basophil Activation Test. Clin. Transl. Allergy 2016, 6, 11. [Google Scholar] [CrossRef] [Green Version]
  171. Chilosi, M.; Adami, F.; Lestani, M.; Montagna, L.; Cimarosto, L.; Semenzato, G.; Pizzolo, G.; Menestrina, F. CD138/Syndecan-1: A Useful Immunohistochemical Marker of Normal and Neoplastic Plasma Cells on Routine Trephine Bone Marrow Biopsies. Mod. Pathol. Off. J. USA Can. Acad. Pathol. 1999, 12, 1101–1106. [Google Scholar]
  172. Kind, S.; Merenkow, C.; Büscheck, F.; Möller, K.; Dum, D.; Chirico, V.; Luebke, A.M.; Höflmayer, D.; Hinsch, A.; Jacobsen, F.; et al. Prevalence of Syndecan-1 (CD138) Expression in Different Kinds of Human Tumors and Normal Tissues. Dis. Mark. 2019, 2019, 4928315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Smith, E.L.; Harrington, K.; Staehr, M.; Masakayan, R.; Jones, J.; Long, T.J.; Ng, K.Y.; Ghoddusi, M.; Purdon, T.J.; Wang, X.; et al. GPRC5D Is a Target for the Immunotherapy of Multiple Myeloma with Rationally Designed CAR T Cells. Sci. Transl. Med. 2019, 11, 7746. [Google Scholar] [CrossRef] [PubMed]
  174. Kodama, T.; Kochi, Y.; Nakai, W.; Mizuno, H.; Baba, T.; Habu, K.; Sawada, N.; Tsunoda, H.; Shima, T.; Miyawaki, K.; et al. Anti-GPRC5D/CD3 Bispecific T-Cell-Redirecting Antibody for the Treatment of Multiple Myeloma. Mol. Cancer Ther. 2019, 18, 1555–1564. [Google Scholar] [CrossRef]
  175. Verkleij, C.P.M.; Broekmans, M.E.C.; van Duin, M.; Frerichs, K.A.; Kuiper, R.; de Jonge, A.V.; Kaiser, M.; Morgan, G.; Axel, A.; Boominathan, R.; et al. Preclinical Activity and Determinants of Response of the GPRC5DxCD3 Bispecific Antibody Talquetamab in Multiple Myeloma. Blood Adv. 2021, 5, 2196–2215. [Google Scholar] [CrossRef] [PubMed]
  176. Salahuddin, S.; Fath, E.K.; Biel, N.; Ray, A.; Moss, C.R.; Patel, A.; Patel, S.; Hilding, L.; Varn, M.; Ross, T.; et al. Epstein-Barr Virus Latent Membrane Protein-1 Induces the Expression of SUMO-1 and SUMO-2/3 in LMP1-Positive Lymphomas and Cells. Sci. Rep. 2019, 9, 208. [Google Scholar] [CrossRef]
  177. Al-Shawi, R.; Ashton, S.V.; Underwood, C.; Simons, J.P. Expression of the Ror1 and Ror2 Receptor Tyrosine Kinase Genes during Mouse Development. Dev. Genes Evol. 2001, 211, 161–171. [Google Scholar] [CrossRef]
  178. Boles, K.S.; Mathew, P.A. Molecular Cloning of CS1, a Novel Human Natural Killer Cell Receptor Belonging to the CD2 Subset of the Immunoglobulin Superfamily. Immunogenetics 2001, 52, 302–307. [Google Scholar] [CrossRef]
  179. Bouchon, A.; Cella, M.; Grierson, H.L.; Cohen, J.I.; Colonna, M. Activation of NK Cell-Mediated Cytotoxicity by a SAP-Independent Receptor of the CD2 Family. J. Immunol. 2001, 167, 5517–5521. [Google Scholar] [CrossRef] [Green Version]
  180. Muta, T.; Kurosaki, T.; Misulovin, Z.; Sanchez, M.; Nussenzweig, M.C.; Ravetch, J. V A 13-Amino-Acid Motif in the Cytoplasmic Domain of Fc Gamma RIIB Modulates B-Cell Receptor Signalling. Nature 1994, 369, 340. [Google Scholar] [CrossRef]
  181. Espéli, M.; Bashford-Rogers, R.; Sowerby, J.M.; Alouche, N.; Wong, L.; Denton, A.E.; Linterman, M.A.; Smith, K.G.C. FcγRIIb Differentially Regulates Pre-Immune and Germinal Center B Cell Tolerance in Mouse and Human. Nat. Commun. 2019, 10, 1970. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  182. Zhou, P.; Comenzo, R.L.; Olshen, A.B.; Bonvini, E.; Koenig, S.; Maslak, P.G.; Fleisher, M.; Hoffman, J.; Jhanwar, S.; Young, J.W.; et al. CD32B Is Highly Expressed on Clonal Plasma Cells from Patients with Systemic Light-Chain Amyloidosis and Provides a Target for Monoclonal Antibody-Based Therapy. Blood 2008, 111, 3403–3406. [Google Scholar] [CrossRef] [PubMed]
  183. Lee, C.S.; Ashton-Key, M.; Cogliatti, S.; Rondeau, S.; Schmitz, S.F.H.; Ghielmini, M.; Cragg, M.S.; Johnson, P. Expression of the Inhibitory Fc Gamma Receptor IIB (FCGR2B, CD32B) on Follicular Lymphoma Cells Lowers the Response Rate to Rituximab Monotherapy (SAKK 35/98). Br. J. Haematol. 2015, 168, 145–148. [Google Scholar] [CrossRef] [Green Version]
  184. Nowicka, M.; Hilton, L.K.; Ashton-Key, M.; Hargreaves, C.E.; Lee, C.; Foxall, R.; Carter, M.J.; Beers, S.A.; Potter, K.N.; Bolen, C.R.; et al. Prognostic Significance of FCGR2B Expression for the Response of DLBCL Patients to Rituximab or Obinutuzumab Treatment. Blood Adv. 2021, 5, 2945–2957. [Google Scholar] [CrossRef] [PubMed]
  185. Roghanian, A.; Teige, I.; Mårtensson, L.; Cox, K.L.; Kovacek, M.; Ljungars, A.; Mattson, J.; Sundberg, A.; Vaughan, A.T.; Shah, V.; et al. Antagonistic Human FcγRIIB (CD32B) Antibodies Have Anti-Tumor Activity and Overcome Resistance to Antibody Therapy in Vivo. Cancer Cell 2015, 27, 473–488. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Bowman, M.R.; Crimmins, M.A.; Yetz-Aldape, J.; Kriz, R.; Kelleher, K.; Herrmann, S. The Cloning of CD70 and Its Identification as the Ligand for CD27. J. Immunol. 1994, 152, 1756–1761. [Google Scholar]
  187. Hintzen, R.Q.; Lens, S.M.; Beckmann, M.P.; Goodwin, R.G.; Lynch, D.; van Lier, R.A. Characterization of the Human CD27 Ligand, a Novel Member of the TNF Gene Family. J. Immunol. 1994, 152, 1762–1773. [Google Scholar]
  188. Jacquot, S. CD27/CD70 Interactions Regulate T Dependent B Cell Differentiation. Immunol. Res. 2000, 21, 23–30. [Google Scholar] [CrossRef]
  189. Borst, J.; Hendriks, J.; Xiao, Y. CD27 and CD70 in T Cell and B Cell Activation. Curr. Opin. Immunol. 2005, 17, 275–281. [Google Scholar] [CrossRef]
  190. Lens, S.M.; Drillenburg, P.; den Drijver, B.F.; van Schijndel, G.; Pals, S.T.; van Lier, R.A.; van Oers, M.H. Aberrant Expression and Reverse Signalling of CD70 on Malignant B Cells. Br. J. Haematol. 1999, 106, 491–503. [Google Scholar] [CrossRef]
  191. McEarchern, J.A.; Smith, L.M.; McDonagh, C.F.; Klussman, K.; Gordon, K.A.; Morris-Tilden, C.A.; Duniho, S.; Ryan, M.; Boursalian, T.E.; Carter, P.J.; et al. Preclinical Characterization of SGN-70, a Humanized Antibody Directed against CD70. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2008, 14, 7763–7772. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  192. Balsas, P.; Veloza, L.; Clot, G.; Sureda-Gómez, M.; Rodríguez, M.L.; Masaoutis, C.; Frigola, G.; Navarro, A.; Beà, S.; Nadeu, F.; et al. SOX11, CD70, and Treg Cells Configure the Tumor-Immune Microenvironment of Aggressive Mantle Cell Lymphoma. Blood 2021, 138, 2202–2215. [Google Scholar] [CrossRef] [PubMed]
  193. Yang, Z.Z.; Novak, A.J.; Ziesmer, S.C.; Witzig, T.E.; Ansell, S.M. CD70+ Non-Hodgkin Lymphoma B Cells Induce Foxp3 Expression and Regulatory Function in Intratumoral CD4+CD25 T Cells. Blood 2007, 110, 2537–2544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Israel, B.F.; Gulley, M.; Elmore, S.; Ferrini, S.; Feng, W.; Kenney, S.C. Anti-CD70 Antibodies: A Potential Treatment for EBV+ CD70-Expressing Lymphomas. Mol. Cancer Ther. 2005, 4, 2037–2044. [Google Scholar] [CrossRef] [Green Version]
  195. Wu, Y.; Nadler, M.J.; Brennan, L.A.; Gish, G.D.; Timms, J.F.; Fusaki, N.; Jongstra-Bilen, J.; Tada, N.; Pawson, T.; Wither, J.; et al. The B-Cell Transmembrane Protein CD72 Binds to and is an in Vivo Substrate of the Protein Tyrosine Phosphatase SHP-1. Curr. Biol. 1998, 8, 1009–1017. [Google Scholar] [CrossRef] [Green Version]
  196. Adachi, T.; Wakabayashi, C.; Nakayama, T.; Yakura, H.; Tsubata, T. CD72 Negatively Regulates Signaling through the Antigen Receptor of B Cells. J. Immunol. 2000, 164, 1223–1229. [Google Scholar] [CrossRef] [Green Version]
  197. Planken, E.V.; Van de Velde, H.; Falkenburg, J.H.; Thielemans, K.; Willemze, R.; Kluin-Nelemans, J.C. Selective Response of CD5+ B Cell Malignancies to Activation of the CD72 Antigen. Clin. Immunol. Immunopathol. 1998, 87, 42–49. [Google Scholar] [CrossRef]
  198. Kumanogoh, A.; Watanabe, C.; Lee, I.; Wang, X.; Shi, W.; Araki, H.; Hirata, H.; Iwahori, K.; Uchida, J.; Yasui, T.; et al. Identification of CD72 as a Lymphocyte Receptor for the Class IV Semaphorin CD100: A Novel Mechanism for Regulating B Cell Signaling. Immunity 2000, 13, 621–631. [Google Scholar] [CrossRef] [Green Version]
  199. Akatsu, C.; Shinagawa, K.; Numoto, N.; Liu, Z.; Ucar, A.K.; Aslam, M.; Phoon, S.; Adachi, T.; Furukawa, K.; Ito, N.; et al. CD72 Negatively Regulates B Lymphocyte Responses to the Lupus-Related Endogenous Toll-like Receptor 7 Ligand Sm/RNP. J. Exp. Med. 2016, 213, 2691–2706. [Google Scholar] [CrossRef]
  200. Li, D.H.H.; Winslow, M.M.; Cao, T.M.; Chen, A.H.; Davis, C.R.; Mellins, E.D.; Utz, P.J.; Crabtree, G.R.; Parnes, J.R. Modulation of Peripheral B Cell Tolerance by CD72 in a Murine Model. Arthritis Rheum. 2008, 58, 3192–3204. [Google Scholar] [CrossRef]
  201. Asmiyou, A.; Bakr, A.M.; Shahin, D.A.; Wahba, Y. CD40 and CD72 Expression and Prognostic Values among Children with Systemic Lupus Erythematosus: A Case-Control Study. Lupus 2020, 29, 1270–1276. [Google Scholar] [CrossRef] [PubMed]
  202. Garand, R.; Robillard, N.; Bataille, R. CD72 Is Constantly Expressed in Chronic Lymphocytic Leukemia and Other B-Cell Lymphoproliferative Disorders. Leuk. Res. 1994, 18, 651–652. [Google Scholar] [CrossRef]
  203. Alcón, V.L.; Luther, C.; Balce, D.; Takei, F. B-Cell Co-Receptor CD72 Is Expressed on NK Cells and Inhibits IFN-Gamma Production but Not Cytotoxicity. Eur. J. Immunol. 2009, 39, 826–832. [Google Scholar] [CrossRef] [PubMed]
  204. Kataoka, T.R.; Kumanogoh, A.; Bandara, G.; Metcalfe, D.D.; Gilfillan, A.M. CD72 Negatively Regulates KIT-Mediated Responses in Human Mast Cells. J. Immunol. 2010, 184, 2468–2475. [Google Scholar] [CrossRef] [PubMed]
  205. Bossen, C.; Schneider, P. BAFF, APRIL and Their Receptors: Structure, Function and Signaling. Semin. Immunol. 2006, 18, 263–275. [Google Scholar] [CrossRef] [Green Version]
  206. Shulga-Morskaya, S.; Dobles, M.; Walsh, M.E.; Ng, L.G.; MacKay, F.; Rao, S.P.; Kalled, S.L.; Scott, M.L. B Cell-Activating Factor Belonging to the TNF Family Acts through Separate Receptors to Support B Cell Survival and T Cell-Independent Antibody Formation. J. Immunol. 2004, 173, 2331–2341. [Google Scholar] [CrossRef] [Green Version]
  207. Sasaki, Y.; Casola, S.; Kutok, J.L.; Rajewsky, K.; Schmidt-Supprian, M. TNF Family Member B Cell-Activating Factor (BAFF) Receptor-Dependent and-Independent Roles for BAFF in B Cell Physiology. J. Immunol. 2004, 173, 2245–2252. [Google Scholar] [CrossRef] [Green Version]
  208. Warnatz, K.; Salzer, U.; Rizzi, M.; Fischer, B.; Gutenberger, S.; Böhm, J.; Kienzler, A.-K.; Pan-Hammarström, Q.; Hammarström, L.; Rakhmanov, M.; et al. B-Cell Activating Factor Receptor Deficiency Is Associated with an Adult-Onset Antibody Deficiency Syndrome in Humans. Proc. Natl. Acad. Sci. USA 2009, 106, 13945–13950. [Google Scholar] [CrossRef] [Green Version]
  209. Wada, K.; Maeda, K.; Tajima, K.; Kato, T.; Kobata, T.; Yamakawa, M. Expression of BAFF-R and TACI in Reactive Lymphoid Tissues and B-Cell Lymphomas. Histopathology 2009, 54, 221–232. [Google Scholar] [CrossRef]
  210. Takahata, H.; Ohara, N.; Ichimura, K.; Tanaka, T.; Sato, Y.; Morito, T.; Takata, K.; Kojima, M.; Kobata, T.; Yoshino, T. BAFF-R Is Expressed on B-Cell Lymphomas Depending on Their Origin and Is Related to Proliferation Index of Nodal Diffuse Large B-Cell Lymphomas. J. Clin. Exp. Hematop. 2010, 50, 121–127. [Google Scholar] [CrossRef] [Green Version]
  211. Li, Y.J.; Jiang, W.Q.; Rao, H.L.; Huang, J.J.; Xia, Y.; Huang, H.Q.; Lin, T.Y.; Xia, Z.J.; Li, S.; Li, Z.-M. Expression of BAFF and BAFF-R in Follicular Lymphoma: Correlation with Clinicopathologic Characteristics and Survival Outcomes. PLoS ONE 2012, 7, e50936. [Google Scholar] [CrossRef]
  212. Wang, Y.; Li, Y.J.; Jiang, W.Q.; Rao, H.L.; Huang, J.J.; Xia, Y.; Bi, X.; Sun, P.; Huang, H.Q.; Lin, T.Y.; et al. Expression of BAFF-R, but Not BAFF, Is an Independent Prognostic Factor in Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP. Annu. Hematol. 2015, 94, 1865–1873. [Google Scholar] [CrossRef] [PubMed]
  213. Zhang, K.; Roy, N.K.; Vicioso, Y.; Woo, J.; Beck, R.; de Lima, M.; Caimi, P.; Feinberg, D.; Parameswaran, R. BAFF Receptor Antibody for Mantle Cell Lymphoma Therapy. Oncoimmunology 2021, 10, 1893501. [Google Scholar] [CrossRef] [PubMed]
  214. Endo, T.; Nishio, M.; Enzler, T.; Cottam, H.B.; Fukuda, T.; James, D.F.; Karin, M.; Kipps, T.J. BAFF and APRIL Support Chronic Lymphocytic Leukemia B-Cell Survival through Activation of the Canonical NF-ΚB Pathway. Blood 2006, 109, 703–710. [Google Scholar] [CrossRef]
  215. Parameswaran, R.; Müschen, M.; Kim, Y.M.; Groffen, J.; Heisterkamp, N. A Functional Receptor for B-Cell-Activating Factor Is Expressed on Human Acute Lymphoblastic Leukemias. Cancer Res. 2010, 70, 4346–4356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  216. Maia, S.; Pelletier, M.; Ding, J.; Hsu, Y.M.; Sallan, S.E.; Rao, S.P.; Nadler, L.M.; Cardoso, A.A. Aberrant Expression of Functional BAFF-System Receptors by Malignant B-Cell Precursors Impacts Leukemia Cell Survival. PLoS ONE 2011, 6, e20787. [Google Scholar] [CrossRef] [Green Version]
  217. Fazio, G.; Turazzi, N.; Cazzaniga, V.; Kreuzaler, M.; Maglia, O.; Magnani, C.F.; Biagi, E.; Rolink, A.; Biondi, A.; Cazzaniga, G. TNFRSF13C (BAFFR) Positive Blasts Persist after Early Treatment and at Relapse in Childhood B-Cell Precursor Acute Lymphoblastic Leukaemia. Br. J. Haematol. 2018, 182, 434–436. [Google Scholar] [CrossRef] [Green Version]
  218. Parameswaran, R.; Lim, M.; Fei, F.; Abdel-Azim, H.; Arutyunyan, A.; Schiffer, I.; McLaughlin, M.E.; Gram, H.; Huet, H.; Groffen, J.; et al. Effector-Mediated Eradication of Precursor B Acute Lymphoblastic Leukemia with a Novel Fc-Engineered Monoclonal Antibody Targeting the BAFF-R. Mol. Cancer Ther. 2014, 13, 1567–1577. [Google Scholar] [CrossRef] [Green Version]
  219. McWilliams, E.M.; Lucas, C.R.; Chen, T.; Harrington, B.K.; Wasmuth, R.; Campbell, A.; Rogers, K.A.; Cheney, C.M.; Mo, X.; Andritsos, L.A.; et al. Anti-BAFF-R Antibody VAY-736 Demonstrates Promising Preclinical Activity in CLL and Enhances Effectiveness of Ibrutinib. Blood Adv. 2019, 3, 447–460. [Google Scholar] [CrossRef]
  220. Qin, H.; Dong, Z.; Wang, X.; Cheng, W.A.; Wen, F.; Xue, W.; Sun, H.; Walter, M.; Wei, G.; Smith, D.L.; et al. CAR T Cells Targeting BAFF-R Can Overcome CD19 Antigen Loss in B Cell Malignancies. Sci. Transl. Med. 2019, 11, 9414. [Google Scholar] [CrossRef]
  221. Schwartz-Albiez, R.; Dörken, B.; Hofmann, W.; Moldenhauer, G. The B Cell-Associated CD37 Antigen (Gp40–52). Structure and Subcellular Expression of an Extensively Glycosylated Glycoprotein. J. Immunol. 1988, 140, 905–914. [Google Scholar] [PubMed]
  222. Jones, E.L.; Demaria, M.C.; Wright, M.D. Tetraspanins in Cellular Immunity. Biochem. Soc. Trans. 2011, 39, 506–511. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  223. van Spriel, A.B. Tetraspanins in the Humoral Immune Response. Biochem. Soc. Trans. 2011, 39, 512–517. [Google Scholar] [CrossRef] [PubMed]
  224. Barrena, S.; Almeida, J.; Yunta, M.; López, A.; Fernández-Mosteirín, N.; Giralt, M.; Romero, M.; Perdiguer, L.; Delgado, M.; Orfao, A.; et al. Aberrant Expression of Tetraspanin Molecules in B-Cell Chronic Lymphoproliferative Disorders and Its Correlation with Normal B-Cell Maturation. Leukemia 2005, 19, 1376–1383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  225. Bobrowicz, M.; Kubacz, M.; Slusarczyk, A.; Winiarska, M. CD37 in B Cell Derived Tumors-More than Just a Docking Point for Monoclonal Antibodies. Int. J. Mol. Sci. 2020, 21, 9531. [Google Scholar] [CrossRef] [PubMed]
  226. Pagel, J.M.; Spurgeon, S.E.; Byrd, J.C.; Awan, F.T.; Flinn, I.W.; Lanasa, M.C.; Eisenfeld, A.J.; Stromatt, S.C.; Gopal, A.K. Otlertuzumab (TRU-016), an Anti-CD37 Monospecific ADAPTIR(TM) Therapeutic Protein for Relapsed or Refractory NHL Patients. Br. J. Haematol. 2015, 168, 38–45. [Google Scholar] [CrossRef] [PubMed]
  227. Kroschinsky, F.; Middeke, J.M.; Janz, M.; Lenz, G.; Witzens-Harig, M.; Bouabdallah, R.; La Rosée, P.; Viardot, A.; Salles, G.; Kim, S.J.; et al. Phase I Dose Escalation Study of BI 836826 (CD37 Antibody) in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma. Investig. New Drugs 2020, 38, 1472–1482. [Google Scholar] [CrossRef]
  228. Pereira, D.S.; Guevara, C.I.; Jin, L.; Mbong, N.; Verlinsky, A.; Hsu, S.J.; Aviña, H.; Karki, S.; Abad, J.D.; Yang, P.; et al. AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML. Mol. Cancer Ther. 2015, 14, 1650–1660. [Google Scholar] [CrossRef] [Green Version]
  229. Stathis, A.; Flinn, I.W.; Madan, S.; Maddocks, K.; Freedman, A.; Weitman, S.; Zucca, E.; Munteanu, M.C.; Lia Palomba, M. Safety, Tolerability, and Preliminary Activity of IMGN529, a CD37-Targeted Antibody-Drug Conjugate, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma: A Dose-Escalation, Phase I Study. Investig. New Drugs 2018, 36, 869–876. [Google Scholar] [CrossRef] [Green Version]
  230. Repetto-Llamazares, A.H.V.; Larsen, R.H.; Giusti, A.M.; Riccardi, E.; Bruland, Ø.S.; Selbo, P.K.; Dahle, J. 177Lu-DOTA-HH1, a Novel Anti-CD37 Radio-Immunoconjugate: A Study of Toxicity in Nude Mice. PLoS ONE 2014, 9, e103070. [Google Scholar] [CrossRef] [Green Version]
  231. Scarfò, I.; Ormhøj, M.; Frigault, M.J.; Castano, A.P.; Lorrey, S.; Bouffard, A.A.; van Scoyk, A.; Rodig, S.J.; Shay, A.J.; Aster, J.C.; et al. Anti-CD37 Chimeric Antigen Receptor T Cells Are Active against B- and T-Cell Lymphomas. Blood 2018, 132, 1495–1506. [Google Scholar] [CrossRef] [PubMed]
  232. Köksal, H.; Dillard, P.; Josefsson, S.E.; Maggadottir, S.M.; Pollmann, S.; Fåne, A.; Blaker, Y.N.; Beiske, K.; Huse, K.; Kolstad, A.; et al. Preclinical Development of CD37CAR T-Cell Therapy for Treatment of B-Cell Lymphoma. Blood Adv. 2019, 3, 1230–1243. [Google Scholar] [CrossRef] [PubMed]
  233. Frigault, M.J.; Chen, Y.B.; Gallagher, K.M.E.; Horick, N.K.; El-Jawahri, A.; Scarfò, I.; Wehrli, M.; Huang, L.; Casey, K.; Cook, D.; et al. Phase 1 Study of CD37-Directed CAR T Cells in Patients with Relapsed or Refractory CD37+ Hematologic Malignancies. Blood 2021, 138, 653. [Google Scholar] [CrossRef]
  234. Bräuner-Osborne, H.; Jensen, A.A.; Sheppard, P.O.; Brodin, B.; Krogsgaard-Larsen, P.; O’Hara, P. Cloning and Characterization of a Human Orphan Family C G-Protein Coupled Receptor GPRC5D. Biochim. Biophys. Acta 2001, 1518, 237–248. [Google Scholar] [CrossRef]
  235. Inoue, S.; Nambu, T.; Shimomura, T. The RAIG Family Member, GPRC5D, Is Associated with Hard-Keratinized Structures. J. Investig. Dermatol. 2004, 122, 565–573. [Google Scholar] [CrossRef] [Green Version]
  236. Pillarisetti, K.; Edavettal, S.; Mendonça, M.; Li, Y.; Tornetta, M.; Babich, A.; Majewski, N.; Husovsky, M.; Reeves, D.; Walsh, E.; et al. A T-Cell-Redirecting Bispecific G-Protein-Coupled Receptor Class 5 Member D x CD3 Antibody to Treat Multiple Myeloma. Blood 2020, 135, 1232–1243. [Google Scholar] [CrossRef]
  237. Atamaniuk, J.; Gleiss, A.; Porpaczy, E.; Kainz, B.; Grunt, T.W.; Raderer, M.; Hilgarth, B.; Drach, J.; Ludwig, H.; Gisslinger, H.; et al. Overexpression of G Protein-Coupled Receptor 5D in the Bone Marrow Is Associated with Poor Prognosis in Patients with Multiple Myeloma. Eur. J. Clin. Investig. 2012, 42, 953–960. [Google Scholar] [CrossRef]
  238. Chari, A.; Berdeja, J.G.; Oriol, A.; van de Donk, N.W.C.J.; Rodriguez, P.; Askari, E.; Mateos, M.-V.; Minnema, M.C.; Verona, R.; Girgis, S.; et al. A Phase 1, First-in-Human Study of Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) x CD3 Bispecific Antibody, in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM). Blood 2020, 136, 40–41. [Google Scholar] [CrossRef]
  239. Smith, E.L.; Harrington, K.; Staehr, M.; Masakayan, R.; Jones, J.; Long, T.; Ghoddusi, M.; Purdon, T.J.; Do, T.; Wang, X.; et al. CAR T Cell Therapy Targeting G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D), a Novel Target for the Immunotherapy of Multiple Myeloma. Blood 2018, 132, 589. [Google Scholar] [CrossRef]
  240. Mailankody, S.; Diamonte, C.; Fitzgerald, L.; Kane, P.; Wang, X.; Sikder, D.S.; Senechal, B.; Bermudez, V.P.; Frias, D.; Morgan, J.; et al. Phase I First-in-Class Trial of MCARH109, a G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D) Targeted CAR T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma. Blood 2021, 138, 827. [Google Scholar] [CrossRef]
  241. Shi, X.; Yan, L.; Shang, J.; Qu, S.; Kang, L.; Zhou, J.; Jin, S.; Yao, W.; Yao, Y.; Yan, S.; et al. Tandom Autologous Transplantation and Combined Infusion of CD19 and Bcma-Specific Chimeric Antigen Receptor T Cells for High Risk MM: Initial Safety and Efficacy Report from a Clinical Pilot Study. Blood 2018, 132, 1009. [Google Scholar] [CrossRef]
  242. Jiang, H.; Dong, B.; Gao, L.; Liu, L.; Ge, J.; He, A.; Du, J.; Li, L.; Lu, J.; Chen, X.; et al. Clinical Results of a Multicenter Study of the First-in-Human Dual BCMA and CD19 Targeted Novel Platform Fast CAR-T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma. Blood 2020, 136, 25–26. [Google Scholar] [CrossRef]
  243. Tang, Y.; Yin, H.; Zhao, X.; Jin, D.; Liang, Y.; Xiong, T.; Li, L.; Tang, W.; Zhang, J.; Liu, M.; et al. High Efficacy and Safety of CD38 and BCMA Bispecific CAR-T in Relapsed or Refractory Multiple Myeloma. J. Exp. Clin. Cancer Res. 2021, 41, 2. [Google Scholar] [CrossRef] [PubMed]
  244. Shah, N.N.; Johnson, B.D.; Schneider, D.; Zhu, F.; Szabo, A.; Keever-Taylor, C.A.; Krueger, W.; Worden, A.A.; Kadan, M.J.; Yim, S.; et al. Bispecific Anti-CD20, Anti-CD19 CAR T Cells for Relapsed B Cell Malignancies: A Phase 1 Dose Escalation and Expansion Trial. Nat. Med. 2020, 26, 1569–1575. [Google Scholar] [CrossRef] [PubMed]
  245. Qin, H.; Ramakrishna, S.; Nguyen, S.; Fountaine, T.J.; Ponduri, A.; Stetler-Stevenson, M.; Yuan, C.M.; Haso, W.; Shern, J.F.; Shah, N.N.; et al. Preclinical Development of Bivalent Chimeric Antigen Receptors Targeting Both CD19 and CD22. Mol. Ther. Oncol. 2018, 11, 127–137. [Google Scholar] [CrossRef] [Green Version]
  246. Spiegel, J.Y.; Patel, S.; Muffly, L.; Hossain, N.M.; Oak, J.; Baird, J.H.; Frank, M.J.; Shiraz, P.; Sahaf, B.; Craig, J.; et al. CAR T Cells with Dual Targeting of CD19 and CD22 in Adult Patients with Recurrent or Refractory B Cell Malignancies: A Phase 1 Trial. Nat. Med. 2021, 27, 1419–1431. [Google Scholar] [CrossRef]
  247. Cordoba, S.; Onuoha, S.; Thomas, S.; Pignataro, D.S.; Hough, R.; Ghorashian, S.; Vora, A.; Bonney, D.; Veys, P.; Rao, K.; et al. CAR T Cells with Dual Targeting of CD19 and CD22 in Pediatric and Young Adult Patients with Relapsed or Refractory B Cell Acute Lymphoblastic Leukemia: A Phase 1 Trial. Nat. Med. 2021, 27, 1797–1805. [Google Scholar] [CrossRef]
  248. Ramakrishna, S.; Highfill, S.L.; Walsh, Z.; Nguyen, S.M.; Lei, H.; Shern, J.F.; Qin, H.; Kraft, I.L.; Stetler-Stevenson, M.; Yuan, C.M.; et al. Modulation of Target Antigen Density Improves CAR T-Cell Functionality and Persistence. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2019, 25, 5329–5341. [Google Scholar] [CrossRef] [Green Version]
  249. Damm, J.K.; Gordon, S.; Ehinger, M.; Jerkeman, M.; Gullberg, U.; Hultquist, A.; Drott, K. Pharmacologically Relevant Doses of Valproate Upregulate CD20 Expression in Three Diffuse Large B-Cell Lymphoma Patients in Vivo. Exp. Hematol. Oncol. 2015, 4, 4. [Google Scholar] [CrossRef] [Green Version]
  250. Bobrowicz, M.; Dwojak, M.; Pyrzynska, B.; Stachura, J.; Muchowicz, A.; Berthel, E.; Dalla-Venezia, N.; Kozikowski, M.; Siernicka, M.; Miazek, N.; et al. HDAC6 Inhibition Upregulates CD20 Levels and Increases the Efficacy of Anti-CD20 Monoclonal Antibodies. Blood 2017, 130, 1628–1638. [Google Scholar] [CrossRef] [Green Version]
  251. Scialdone, A.; Hasni, M.S.; Damm, J.K.; Lennartsson, A.; Gullberg, U.; Drott, K. The HDAC Inhibitor Valproate Induces a Bivalent Status of the CD20 Promoter in CLL Patients Suggesting Distinct Epigenetic Regulation of CD20 Expression in CLL in Vivo. Oncotarget 2017, 8, 37409–37422. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  252. Poorebrahim, M.; Mohammadkhani, N.; Mahmoudi, R.; Gholizadeh, M.; Fakhr, E.; Cid-Arregui, A. TCR-like CARs and TCR-CARs Targeting Neoepitopes: An Emerging Potential. Cancer Gene Ther. 2021, 28, 581–589. [Google Scholar] [CrossRef] [PubMed]
  253. Raskin, S.; Van Pelt, S.; Toner, K.; Balakrishnan, P.B.; Dave, H.; Bollard, C.M.; Yvon, E. Novel TCR-like CAR-T Cells Targeting an HLA * 0201-Restricted SSX2 Epitope Display Strong Activity against Acute Myeloid Leukemia. Molecular therapy. Methods Clin. Dev. 2021, 23, 296–306. [Google Scholar] [CrossRef] [PubMed]
  254. Dragon, A.C.; Zimmermann, K.; Nerreter, T.; Sandfort, D.; Lahrberg, J.; Klöß, S.; Kloth, C.; Mangare, C.; Bonifacius, A.; Tischer-Zimmermann, S.; et al. CAR-T Cells and TRUCKs That Recognize an EBNA-3C-Derived Epitope Presented on HLA-B*35 Control Epstein-Barr Virus-Associated Lymphoproliferation. J. Immunother. Cancer 2020, 8, 736. [Google Scholar] [CrossRef]
Cells 11 01804 g001 550
Figure 1. B cell-derived cancers develop various mechanisms of resistance to CD19 CAR-T therapy. Left panel: the mechanisms related to downregulation of target antigen include genetic and epigenetic aberrations within CD19 gene or alternative splicing of CD19 transcripts. Another possibility of resistance development is CD19 epitope masking by either a CD19-specific CAR construct, or therapeutic anti-CD19 antibody. Target antigen loss can also occur as a consequence of phenotypic changes due to the lineage switch of malignant B cell precursors. Right panel: target antigen-independent mechanisms of resistance cover structural aberrations and mutations in selected genes of malignant lymphoma cells. Additionally, disruption of the apoptosis pathway or CD58-CD2 co-stimulation could be involved in this process.
Figure 1. B cell-derived cancers develop various mechanisms of resistance to CD19 CAR-T therapy. Left panel: the mechanisms related to downregulation of target antigen include genetic and epigenetic aberrations within CD19 gene or alternative splicing of CD19 transcripts. Another possibility of resistance development is CD19 epitope masking by either a CD19-specific CAR construct, or therapeutic anti-CD19 antibody. Target antigen loss can also occur as a consequence of phenotypic changes due to the lineage switch of malignant B cell precursors. Right panel: target antigen-independent mechanisms of resistance cover structural aberrations and mutations in selected genes of malignant lymphoma cells. Additionally, disruption of the apoptosis pathway or CD58-CD2 co-stimulation could be involved in this process.
Cells 11 01804 g001
Table
Table 1. Clinically approved CAR-T therapies in B cell and plasma cell-derived malignancies.
Table 1. Clinically approved CAR-T therapies in B cell and plasma cell-derived malignancies.
Generic Name and Brand NameIndicationTarget
(Single Chain Variable Fragment, scFv)		Signaling
Domain/
Hinge and TM		Gene Editing VectorFirst
FDA/EMA
Registration Date		Approval-Based Clinical Trials, Number of
Participants		CR or ORR RateLong-Term
Follow-Up
Studies,
Number of
Participants		Survival
(Median
Follow-Up in Years)
Tisagenlecleucel
(KYMRIAH)		R/R pediatric and YA B-ALLCD19
(FMC63)		4-1BB-CD3ζ/CD8αLentivirusAugust 2017/
August 2018		ELIANA, n = 75 [NCT02435849] [12]CR 60%NCT01593696, n = 50
[13]		median OS
10.5 months
(4.8 years)
R/R adult DLBCLMay 2018/
August 2018		JULIET, n = 93 [NCT02445248] [14]CR 40%JULIET follow-up,
n = 115 [15]		median OS
11.1 months
(3.4 years)
Axicabtagene
Ciloleucel
(YESCARTA)		R/R adult DLBCL
(including DLBCL
arising from FL)		CD19
(FMC63)		CD28-CD3ζ/CD28RetrovirusOctober 2017/
August 2018		ZUMA-1, n = 101
[NCT02348216] [16]		CR 54%ZUMA-1 follow up, n = 101 [17]median OS
25.8 months
(4 years)
R/R adult PMBCL
R/R adult FLMar 2021/
not yet
registered		ZUMA-5, n = 84
[NCT03105336] [18]		CR 79%not yet
available		not yet
available
Brexucabtagene
Autoleucel
(TECARTUS)		R/R adult
MCL		CD19
(FMC63)		CD28-CD3ζ/CD28RetrovirusJuly 2020/
December 2020		ZUMA-2, n = 60 (efficacy group) [NCT02601313] [19]CR 67%not yet
available		not yet
available
R/R adult
B-ALL		October 2021/
not yet registered		ZUMA-3, n = 55
[NCT02614066] [20]		CR 56%not yet
available		not yet
available
Lisocabtagene
Maraleucel
(BREYANZI)		R/R adult DLBCL
(including DLBCL
arising from indolent lymphoma)		CD19
(FMC63)		4-1BB-CD3ζ/IgG4 and CD28LentivirusMay 2021/
pending registration		TRANCEND NHL 001,
n = 256 [NCT02631044]
[21]		CR 53%TRANCEND
NHL 001 follow-up, n = 257 [22]		median OS
27.3 months
(2.4 year)
R/R adult PMBCL
R/R FL3B
Idecabtagene
Vicleucel
(ABECMA)		R/R MMBCMA4-1BB-CD3ζ/CD8αLentivirusMar 2021/
August 2021		KarMMa, n = 100 (efficacy group) [NCT03361748] [23,24]ORR 72%
sCR 28%		not yet
available		not yet
available
Note: Above 2 years of follow-up was considered long-term. Abbreviations: B-ALL—B cell acute lymphoblastic leukemia, CR—complete response, DLBCL—diffuse large B cell lymphoma, FL—follicular lymphoma, FL3B—follicular lymphoma grade 3B, MCL—mantle cell lymphoma, MM—multiple myeloma, ORR—overall response rate, OS—overall survival, PMBCL—primary mediastinal large B cell lymphoma, R/R—relapse/refractory, sCR—stringent complete response, YA—young adults.
Table
Table 2. Alternative targets for CAR-T therapy in B cell and plasma cell-derived malignancies (listed alphabetically).
Table 2. Alternative targets for CAR-T therapy in B cell and plasma cell-derived malignancies (listed alphabetically).
Targeted MoleculePhysiological FunctionsExpression in Non-Malignant Cells
[References]		Targeted
Disease		References or Numbers of Clinical Trials
pre-clinical studies
CD23regulation of IgE responsesa subset of T and B cells,
monocytes, leukocytes,
follicular DCs,
intestinal epithelial cells,
bone marrow stromal cells
[129,130,131,132,133,134,135]		CLL[136,137]
CD32Bregulation of B cell activation,
antibody production		B cells, DCs, granulocytes,
liver endothelial cells,
airway smooth muscle cells
[138,139,140]		CLL[141]
CD70T cell activation and
proliferation
(cytokine, CD27 ligand)		subsets of activated T cells,
B cells, NK cells, mature DCs,
epithelial cells of the thymic medulla [142,143]		B cell
lymphoma		[144,145]
CD72B cell proliferation,
B cell differentiation,
negative regulation of BCR
signaling		B cells [146]B-ALL[147]
CD133unclear, a marker
of undifferentiated cells		hematopoietic stem and
progenitor cells
[148]		B-ALL[149,150]
FcμRIgM receptorsubsets of B cells,
T cells, NK cells
[151]		CLL[152]
Siglec-6inhibition of immune responsememory B cells, exhausted B cells,
placenta, mast cells
[153,154,155]		CLL[156]
TSLPRT and B cell developmentDCs, monocytes
[157]		B-ALL[158]
clinical trials
BAFF-Rpromotion of B cell survivalB cells (except plasma cells),
memory T cells [159]		B-ALLNCT04690595
CD20B cell proliferation,
B cell differentiation		pre-B cells and mature B cells
[160,161]		CLL,
B cell
lymphoma		NCT04169932
NCT04030195
NCT03664635
CD22regulation of BCR signaling,
B cell migration		B cells
[162,163]		B-ALL,
B cell
lymphoma		NCT04546906
NCT04088864
NCT04088890
NCT04007978
NCT03262298
NCT04340167
NCT03244306
NCT04571138
NCT02650414
NCT02315612
NCT04150497
NCT03620058
CD30possibly T cell survival and/or
establishment of memory responses		a subset of activated T
and B lymphocytes
[164,165]		DLBCL,
Hodgkin
lymphoma		NCT04526834
NCT03049449
CD37regulation of humoral and cellular immune responsesmature B cells [166]CLL,
B cell
lymphoma		NCT04136275
CD38cell adhesion and migration,
generation of nucleotide
metabolites		T cells, B cells, NK cells,
plasma cells, monocytes
[167]		B-ALL,
MM		NCT03754764
NCT03464916
CD70T cell activation and proliferation (cytokine, CD27 ligand)APCs, activated T and B cells
[142,143]		MMNCT04662294
CD79Bpromotion of B cell survivalB cells [168]B-ALL,
B cell NHL		NCT04609241
CD123IL-3 signal transmission,
regulation of hematopoiesis		Basophils,
plasmacytoid DCs
[169,170]		B-ALLNCT04318678
CD138cell adhesion, endocytosisepithelial cells, hepatocytes,
plasma cells
[171,172]		MMNCT03672318
GPRC5Dhard keratinizationepithelial cells of the hair follicles,
plasma cells, B cells
[173,174,175]		MMNCT05016778
LMP1induction and maintenance
of virus latency by modulation
of host’s immune responses		EBV-infected cells
[176]		B cell
lymphoma		NCT04657965
ROR1cell differentiation,
proliferation and survival		various cells
during embryogenesis
[177]		CLL, MCL,
ALL		NCT02706392
SLAMF7inhibition of proinflammatory
immune responses		B cells, T cells, DCs,
NK cells, monocytes
[178,179]		MMNCT04499339
NCT03958656
Abbreviations: APCs—antigen presenting cells, BAFF-R—B cell activating factor receptor, DCs—dendritic cells, FcμR—immunoglobulin M Fc receptor, GPRC5D—G protein-coupled receptor class C group 5 member D, LMP1—latent membrane protein 1, ROR1—receptor tyrosine kinase like orphan receptor 1, SLAMF7—signaling lymphocytic activation molecule F7, TSLPR—thymic stromal lymphopoietin protein receptor.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Marhelava, K.; Krawczyk, M.; Firczuk, M.; Fidyt, K. CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies. Cells 2022, 11, 1804. https://doi.org/10.3390/cells11111804

AMA Style

Marhelava K, Krawczyk M, Firczuk M, Fidyt K. CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies. Cells. 2022; 11(11):1804. https://doi.org/10.3390/cells11111804

Chicago/Turabian Style

Marhelava, Katsiaryna, Marta Krawczyk, Malgorzata Firczuk, and Klaudyna Fidyt. 2022. "CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies" Cells 11, no. 11: 1804. https://doi.org/10.3390/cells11111804

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop