CAR-T Cell Therapy-Novel Approaches and Challenges

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (28 February 2019) | Viewed by 35779

Special Issue Editor


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Guest Editor
1. Research and Business Development, Promab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA
2. Department of Medicine, University of Oklahoma, Oklahoma, OK 73126, USA
Interests: immunotherapy; CAR-T cells; tumor microenvironment; checkpoint protein; hypoxia; tumor survival signaling
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Special Issue Information

Dear colleagues,

CAR (chimeric antigen receptor)-T cell therapy became a highly promising type of cell therapy with two recently FDA-approved CAR-T cell therapy agents: Kymriah (Novartis) and Yescarta (Kite/Gilead). CAR contains single chain variable fragment ScFv of antibody against tumor-associated antigen, followed by a hinge, transmembrane domain, co-activation domain (CD28, 4-1BB, CD27 or other) and activation CD3 zeta domain. Once CAR-T cell binds tumor-associated antigen, it becomes activated and kills target cancer cell. Recent clinical trials on hematological cancers demonstrated big success of this therapy. Unfortunately, in solid cancer there are many challenges exist to overcome for successful therapy such as presence of repressive tumor microenvironment, repressive T regulatory (Treg) cells, physical barriers for CAR-T cells to reach the tumor and other factors. This issue will highlight novel approaches and perspectives of CAR-T cell therapy and also focus on challenges on the road to clinic.

Dr. Vita Golubovskaya
Guest Editor

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Published Papers (5 papers)

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Research

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16 pages, 3225 KiB  
Article
CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth
by Robert Berahovich, Hua Zhou, Shirley Xu, Yuehua Wei, Jasper Guan, Jian Guan, Hizkia Harto, Shuxiang Fu, Kaihuai Yang, Shuying Zhu, Le Li, Lijun Wu and Vita Golubovskaya
Cancers 2018, 10(9), 323; https://doi.org/10.3390/cancers10090323 - 11 Sep 2018
Cited by 24 | Viewed by 8801
Abstract
The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong [...] Read more.
The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong and selective binding to human BCMA. BCMA CAR-T cells containing the 4C8A scFv were readily detected with recombinant BCMA protein by flow cytometry. The cells were cytolytic for RPMI8226, H929, and MM1S multiple myeloma cells and secreted high levels of IFN-γ in vitro. BCMA-dependent cytotoxicity and IFN-γ secretion were also observed in response to CHO (Chinese Hamster Ovary)-BCMA cells but not to parental CHO cells. In a mouse subcutaneous tumor model, BCMA CAR-T cells significantly blocked RPMI8226 tumor formation. When BCMA CAR-T cells were given to mice with established RPMI8226 tumors, the tumors experienced significant shrinkage due to CAR-T cell activity and tumor cell apoptosis. The same effect was observed with 3 humanized BCMA-CAR-T cells in vivo. These data indicate that novel CAR-T cells utilizing the BCMA 4C8A scFv are effective against multiple myeloma and warrant future clinical development. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy-Novel Approaches and Challenges)
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15 pages, 1331 KiB  
Article
Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors
by Antoni Xavier Torres-Collado and Ali R. Jazirehi
Cancers 2018, 10(6), 200; https://doi.org/10.3390/cancers10060200 - 14 Jun 2018
Cited by 33 | Viewed by 5542
Abstract
Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which [...] Read more.
Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8+ T cells (CTL)-resistance in NHL remain elusive. CD19CAR transduced primary human CTLs kill CD19+ human NHLs in a CD19- and caspase-dependent manner, mainly via the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptotic pathway. To understand the dynamics of the development of resistance, we analyzed several anti-CD19CAR CTL-resistant NHL sublines (R-NHL) derived by serial exposure of sensitive parental lines to excessive numbers of anti-CD19CAR CTLs followed by a limiting dilution analysis. The R-NHLs retained surface CD19 expression and were efficiently recognized by CD19CAR CTLs. However, R-NHLs developed cross-resistance to CD19CAR transduced human primary CTLs and the Jurkat human T cell line, activated Jurkat, and lymphokine activated killer (LAK) cells, suggesting the acquisition of resistance is independent of CD19-loss and might be due to aberrant apoptotic machinery. We hypothesize that the R-NHL refractoriness to CD19CAR CTL killing could be partially rescued by small molecule sensitizers with apoptotic-gene regulatory effects. Chromatin modifiers and Celecoxib partially reversed the resistance of R-NHL cells to the cytotoxic effects of anti-CD19CAR CTLs and rhTRAIL. These in vitro results, though they require further examination, may provide a rational biological basis for combination treatment in the management of CD19CAR CTL-based therapy of NHL. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy-Novel Approaches and Challenges)
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Review

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21 pages, 1548 KiB  
Review
Chimeric Antigen Receptor T Cell Therapy for Solid Tumors: Current Status, Obstacles and Future Strategies
by Benjamin Heyman and Yiping Yang
Cancers 2019, 11(2), 191; https://doi.org/10.3390/cancers11020191 - 06 Feb 2019
Cited by 32 | Viewed by 5899
Abstract
Chimeric antigen receptor T cells (CAR T Cells) have led to dramatic improvements in the survival of cancer patients, most notably those with hematologic malignancies. Early phase clinical trials in patients with solid tumors have demonstrated them to be feasible, but unfortunately has [...] Read more.
Chimeric antigen receptor T cells (CAR T Cells) have led to dramatic improvements in the survival of cancer patients, most notably those with hematologic malignancies. Early phase clinical trials in patients with solid tumors have demonstrated them to be feasible, but unfortunately has yielded limited efficacy for various cancer types. In this article we will review the background on CAR T cells for the treatment of solid tumors, focusing on the unique obstacles that solid tumors present for the development of adoptive T cell therapy, and the novel approaches currently under development to overcome these hurdles. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy-Novel Approaches and Challenges)
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27 pages, 2385 KiB  
Review
Chimeric Antigen Receptor T-cell (CAR T) Therapy for Hematologic and Solid Malignancies: Efficacy and Safety—A Systematic Review with Meta-Analysis
by Wen-Liang Yu and Zi-Chun Hua
Cancers 2019, 11(1), 47; https://doi.org/10.3390/cancers11010047 - 07 Jan 2019
Cited by 58 | Viewed by 7713
Abstract
Chimeric antigen receptors T cells (CAR T) had been used for treating various tumor patients in clinic, and owned an incredible efficacy in part of malignancies. However, CAR T therapy remains controversial due to doubts about its efficacy and safety in the clinical [...] Read more.
Chimeric antigen receptors T cells (CAR T) had been used for treating various tumor patients in clinic, and owned an incredible efficacy in part of malignancies. However, CAR T therapy remains controversial due to doubts about its efficacy and safety in the clinical treatment of various malignancies. A total of 997 tumor patients from 52 studies were included in this review. Eligible studies were searched and reviewed from the databases of PubMed, Web of Science, Wanfang and Clinicaltrials.gov. Then meta-analysis and subgroup analysis were used to investigate the overall response rate (ORR), complete response rate (CRR), common side effect rate (CSER) and relapse rate (RR) of CAR T therapy for patients in clinical researches, respectively. The results further confirmed that CAR T therapy had a higher response rate for hematologic malignancies. More importantly, CAR T therapy had a higher CSER in patients with hematologic malignancies, and it had a similar RR in patients with different malignancies. Cell cultured without the addition of IL-2 and total administration less than 108 cells were recommended. This study offers a reference for future research regarding the application in solid and hematologic malignancies, side effects and relapse, and even the production processes of CAR T cells. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy-Novel Approaches and Challenges)
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Other

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18 pages, 2937 KiB  
Technical Note
Clinical-Scale Production of CAR-T Cells for the Treatment of Melanoma Patients by mRNA Transfection of a CSPG4-Specific CAR under Full GMP Compliance
by Manuel Wiesinger, Johannes März, Mirko Kummer, Gerold Schuler, Jan Dörrie, Beatrice Schuler-Thurner and Niels Schaft
Cancers 2019, 11(8), 1198; https://doi.org/10.3390/cancers11081198 - 16 Aug 2019
Cited by 46 | Viewed by 7066
Abstract
Chimeric antigen receptor (CAR)-T cells already showed impressive clinical regressions in leukemia and lymphoma. However, the development of CAR-T cells against solid tumors lags behind. Here we present the clinical-scale production of CAR-T cells for the treatment of melanoma under full GMP compliance. [...] Read more.
Chimeric antigen receptor (CAR)-T cells already showed impressive clinical regressions in leukemia and lymphoma. However, the development of CAR-T cells against solid tumors lags behind. Here we present the clinical-scale production of CAR-T cells for the treatment of melanoma under full GMP compliance. In this approach a CAR, specific for chondroitin sulfate proteoglycan 4 (CSPG4) is intentionally transiently expressed by mRNA electroporation for safety reasons. The clinical-scale protocol was optimized for: (i) expansion of T cells, (ii) electroporation efficiency, (iii) viability, (iv) cryopreservation, and (v) potency. Four consistency runs resulted in CAR-T cells in clinically sufficient numbers, i.e., 2.4 × 109 CAR-expressing T cells, starting from 1.77x108 PBMCs, with an average expansion of 13.6x, an electroporation efficiency of 88.0% CAR-positive cells, a survival of 74.1% after electroporation, and a viability of 84% after cryopreservation. Purity was 98.7% CD3+ cells, with 78.1% CD3+/CD8+ T cells and with minor contaminations of 1.2% NK cells and 0.6% B cells. The resulting CAR-T cells were tested for cytolytic activity after cryopreservation and showed antigen-specific and very efficient lysis of tumor cells. Although our work is descriptive rather than investigative in nature, we expect that providing this clinically applicable protocol to generate sufficient numbers of mRNA-transfected CAR-T cells will help in moving the field of adoptive cell therapy of cancer forward. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy-Novel Approaches and Challenges)
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