Topic Editors

Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy
Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

Cancer Immunotherapies: From Laboratory to Clinical Studies

Abstract submission deadline
closed (31 August 2023)
Manuscript submission deadline
closed (31 December 2023)
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Topic Information

Dear Colleagues,

Immunotherapy is a potential cancer treatment aiming to boost or change the immune system in order to fight cancer. In the past few years, significant progresses have been made in this field developing several major types of immunotherapy applied in cancer care. Despite this success, immunotherapy only works in a subset of cancers, and only a fraction of patients with cancer respond to immunotherapy. Ongoing efforts to improve our understanding of tumor immunology and the roles of the immunosuppressive tumor microenvironment are necessary to provide insights into developing more effective therapies. Combination therapies using checkpoint inhibitors with personalized cancer vaccines and novel targeted therapies directed at the tumor microenvironment and the host microbiome could be the future of cancer immunotherapy. In this context, the interface between clinicians and laboratory is crucial to allow oncologists to make the best choice of treatment for the patient and to evaluate the clinical outcome of therapy. Clinical trials testing rational immunotherapy combinations that include biomarker analysis will accelerate clinical progress, moving to effective immunotherapy in the treatment of several type of cancers. The aim of this Special Issue is to publish original research and review articles related to recent progresses in clinical cancer immunotherapy, including in vivo and in vitro studies aiming at the identification and exploration of novel targets, novel strategies and biomarkers covering several facets of immunotherapy techniques.

Dr. Alessandra Carcereri De Prati
Dr. Zong Sheng Guo
Topic Editors

Keywords

  • cancer immunotherapy
  • checkpoint inhibitors
  • tumor microenvironment
  • biomarkers
  • tumor antigens

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomedicines
biomedicines
4.7 3.7 2013 15.4 Days CHF 2600
Cancers
cancers
5.2 7.4 2009 17.9 Days CHF 2900
Journal of Clinical Medicine
jcm
3.9 5.4 2012 17.9 Days CHF 2600
Journal of Personalized Medicine
jpm
3.4 2.6 2011 17.8 Days CHF 2600
Neurology International
neurolint
3.0 2.2 2009 23.3 Days CHF 1600

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Published Papers (9 papers)

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11 pages, 1174 KiB  
Article
The Clinical Analysis of Checkpoint Inhibitor Pneumonitis with Different Severities in Lung Cancer Patients: A Retrospective Study
by Hui Huang, Ruxuan Chen, Yan Xu, Nan Fang, Chi Shao, Kai Xu and Mengzhao Wang
J. Clin. Med. 2024, 13(1), 255; https://doi.org/10.3390/jcm13010255 - 01 Jan 2024
Viewed by 883
Abstract
Immune-related adverse events (irAEs) of immunotherapy would lead to the temporary or permanent discontinuation of immune checkpoint inhibitors (ICIs). Among them, checkpoint inhibitor pneumonitis (CIP) is a potentially life-threatening irAE. This study aimed to identify the differences between patients with low-grade CIPs (grades [...] Read more.
Immune-related adverse events (irAEs) of immunotherapy would lead to the temporary or permanent discontinuation of immune checkpoint inhibitors (ICIs). Among them, checkpoint inhibitor pneumonitis (CIP) is a potentially life-threatening irAE. This study aimed to identify the differences between patients with low-grade CIPs (grades 1–2) and high-grade CIPs (grades 3–5) and to explore the prognostic factors. We retrospectively reviewed the medical records of 916 lung cancer patients who were treated with ICIs. Patients with CIPs were identified after multidisciplinary discussion, and their clinical, laboratory, radiological, and follow-up data were analyzed. Among the 74 enrolled CIP patients, there were 31 low-grade CIPs and 43 high-grade CIPs. Compared with low-grade CIP patients, patients with high-grade CIPs were older (65.8 years vs. 61.5 years) and had lower serum albumin (35.2 g/L vs. 37.9 g/L), higher D-dimer (5.1 mg/L vs. 1.7 mg/L), and more pulmonary infectious diseases (32.6% vs. 6.5%) during follow-up. In addition, complication with pulmonary infectious diseases, management with intravenous immunoglobulin, tocilizumab, and longer duration of large dosage corticosteroids might be associated with worse outcomes for patients with CIPs. This study highlights potential risk factors for high-grade CIP and poor prognosis among lung cancer patients who were treated with anti-cancer ICIs. Full article
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14 pages, 3448 KiB  
Review
Outcomes of CAR-T Cell Therapy Recipients Admitted to the ICU: In Search for a Standard of Care—A Brief Overview and Meta-Analysis of Proportions
by Catalin Constantinescu, Vlad Moisoiu, Bogdan Tigu, David Kegyes and Ciprian Tomuleasa
J. Clin. Med. 2023, 12(18), 6098; https://doi.org/10.3390/jcm12186098 - 21 Sep 2023
Viewed by 1166
Abstract
Objective: Our primary objective was to describe the baseline characteristics, main reasons for intensive care unit (ICU) admission, and interventions required in the ICU across patients who received CAR-T cell immunotherapy. The secondary objectives were to evaluate different outcomes (ICU mortality) across patients [...] Read more.
Objective: Our primary objective was to describe the baseline characteristics, main reasons for intensive care unit (ICU) admission, and interventions required in the ICU across patients who received CAR-T cell immunotherapy. The secondary objectives were to evaluate different outcomes (ICU mortality) across patients admitted to the ICU after having received CAR-T cell therapy. Materials and Methods. We performed a medical literature review, which included MEDLINE, Embase, and Cochrane Library, of studies published from the inception of the databases until 2022. We conducted a systematic review with meta-analyses of proportions of several studies, including CAR-T cell-treated patients who required ICU admission. Outcomes in the meta-analysis were evaluated using the random-effects model. Results: We included four studies and analyzed several outcomes, including baseline characteristics and ICU-related findings. CAR-T cell recipients admitted to the ICU are predominantly males (62% CI-95% (57–66)). Of the total CAR-T cell recipients, 4% CI-95% (3–5) die in the hospital, and 6% CI-95% (4–9) of those admitted to the ICU subsequently die. One of the main reasons for ICU admission is acute kidney injury (AKI) in 15% CI-95% (10–19) of cases and acute respiratory failure in 10% CI-95% (6–13) of cases. Regarding the interventions initiated in the ICU, 18% CI-95% (13–22) of the CAR-T recipients required invasive mechanical ventilation during their ICU stay, 23% CI-95% (16–30) required infusion of vasoactive drugs, and 1% CI-95% (0.1–3) required renal replacement therapy (RRT). 18% CI-95% (13–22) of the initially discharged patients were readmitted to the ICU within 30 days, and the mean length of hospital stay is 22 days CI-95% (19–25). The results paint a current state of matter in CAR-T cell recipients admitted to the ICU. Conclusions: To better understand immunotherapy-related complications from an ICU standpoint, acknowledge the deteriorating patient on the ward, reduce the ICU admission rate, advance ICU care, and improve the outcomes of these patients, a standard of care and research regarding CAR-T cell-based immunotherapies should be created. Studies that are looking from the perspective of intensive care are highly warranted because the available literature regarding this area is scarce. Full article
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18 pages, 1689 KiB  
Article
Therapeutic Modifications without Discontinuation of Atezolizumab Plus Bevacizumab Therapy Are Associated with Favorable Overall Survival and Time to Progression in Patients with Unresectable Hepatocellular Carcinoma
by Takayuki Tokunaga, Masakuni Tateyama, Yasuteru Kondo, Satoshi Miuma, Shiho Miyase, Kentaro Tanaka, Satoshi Narahara, Hiroki Inada, Sotaro Kurano, Yoko Yoshimaru, Katsuya Nagaoka, Takehisa Watanabe, Hiroko Setoyama, Kotaro Fukubayashi, Motohiko Tanaka and Yasuhito Tanaka
Cancers 2023, 15(5), 1568; https://doi.org/10.3390/cancers15051568 - 02 Mar 2023
Cited by 1 | Viewed by 1927
Abstract
We retrospectively evaluated the impact of therapeutic modifications of atezolizumab (Atezo) plus bevacizumab (Bev) therapy (Atezo/Bev), including the interruption or discontinuation of both Atezo and Bev, and the reduction or discontinuation of Bev, on the outcome of patients with unresectable hepatocellular carcinoma (uHCC) [...] Read more.
We retrospectively evaluated the impact of therapeutic modifications of atezolizumab (Atezo) plus bevacizumab (Bev) therapy (Atezo/Bev), including the interruption or discontinuation of both Atezo and Bev, and the reduction or discontinuation of Bev, on the outcome of patients with unresectable hepatocellular carcinoma (uHCC) (median observation period: 9.40 months). One hundred uHCC from five hospitals were included. Therapeutic modifications without discontinuation of both Atezo and Bev (n = 46) were associated with favorable overall survival (median not reached; hazard ratio (HR): 0.23) and time to progression (median: 10.00 months; HR: 0.23) with no therapeutic modification defined as the reference. In contrast, the discontinuation of both Atezo and Bev without other therapeutic modifications (n = 20) was associated with unfavorable overall survival (median: 9.63 months; HR: 2.72) and time to progression (median: 2.53 months; HR: 2.78). Patients with modified albumin–bilirubin grade 2b liver function (n = 43) or immune-related adverse events (irAEs) (n = 31) discontinued both Atezo and Bev without other therapeutic modifications more frequently (30.2% and 35.5%, respectively) than those with modified albumin–bilirubin grade 1 (10.2%) and without irAEs (13.0%). Patients with objective response (n = 48) experienced irAEs more frequently (n = 21) than those without (n = 10) (p = 0.027). Avoiding the discontinuation of both Atezo and Bev without other therapeutic modifications may be the optimal management of uHCC. Full article
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17 pages, 3171 KiB  
Article
Blood-Based Biomarker Analysis for Predicting Efficacy of Chemoradiotherapy and Durvalumab in Patients with Unresectable Stage III Non-Small Cell Lung Cancer
by Cheol-Kyu Park, Sung-Woo Lee, Hyun-Ju Cho, Hyung-Joo Oh, Young-Chul Kim, Yong-Hyub Kim, Sung-Ja Ahn, Jae-Ho Cho and In-Jae Oh
Cancers 2023, 15(4), 1151; https://doi.org/10.3390/cancers15041151 - 10 Feb 2023
Cited by 2 | Viewed by 1621
Abstract
We recruited 50 patients with unresectable stage III NSCLC who received CCRT between March 2020 and March 2021. Durvalumab consolidation (DC) was administered to patients (n = 23) without progression after CCRT and programmed death-ligand 1 (PD-L1) ≥ 1%. Blood samples were [...] Read more.
We recruited 50 patients with unresectable stage III NSCLC who received CCRT between March 2020 and March 2021. Durvalumab consolidation (DC) was administered to patients (n = 23) without progression after CCRT and programmed death-ligand 1 (PD-L1) ≥ 1%. Blood samples were collected before (C0) and after CCRT (C1) to calculate PBC counts and analyze CTCs. CTCs, isolated by the CD-PRIMETM system, exhibited EpCAM/CK+/CD45− phenotype in BioViewCCBSTM. At median follow-up of 27.4 months, patients with residual CTC clusters at C1 had worse median PFS than those without a detectable CTC cluster (11.0 vs. 27.8 months, p = 0.032), and this trend was noted only in the DC group (p = 0.034). Patients with high platelets at C1 (PLThi, >252 × 103/µL) had worse median PFS than those with low platelets (PLTlo) (5.9 vs. 17.1 months, p < 0.001). In multivariable analysis, PLThi and residual CTC clusters at C1 were independent risk factors for PFS, and DC group with PLThi and residual CTC clusters at C1 showed the worst median PFS (2.6 months, HR 45.16, p = 0.001), even worse than that of the CCRT alone group with PLThi (5.9 months, HR 15.39, p = 0.001). The comprehensive analysis of CTCs and PBCs before and after CCRT revealed that the clearance of CTC clusters and platelet counts at C1 might be potential biomarkers for predicting survival. Full article
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7 pages, 881 KiB  
Case Report
Pathological Complete Response Following Neoadjuvant Tislelizumab Monotherapy in Treatment-Naive Locally Advanced, MMR-Deficient/MSI-High Ascending Colon Cancer: A Case Report
by Yue Hei, Ruixia Yang, Shengnan Kong, Hongmei Zhang and Yan Chen
J. Clin. Med. 2023, 12(1), 240; https://doi.org/10.3390/jcm12010240 - 28 Dec 2022
Viewed by 1830
Abstract
Although recent trials started the use of neoadjuvant immunotherapy (NIT) in instability-high (MSI-H) or mismatch repair deficient (dMMR) early-stage or locally advanced colorectal cancer (LACRC), little data on the treatment strategy of NIT has been shown, and whether the tirelizumab mono-immune checkpoint inhibitor [...] Read more.
Although recent trials started the use of neoadjuvant immunotherapy (NIT) in instability-high (MSI-H) or mismatch repair deficient (dMMR) early-stage or locally advanced colorectal cancer (LACRC), little data on the treatment strategy of NIT has been shown, and whether the tirelizumab mono-immune checkpoint inhibitor (ICI) can be used as NIT for patients with LACRC has not been reported as yet. In this study we report on a locally advanced ascending colon cancer case with a history of incomplete intestinal obstruction which achieved a pathologic complete response (pCR) after treated with Tirelizumab as NIT. A 32-year-old man was diagnosed with locally advanced ascending colon cancer with MSI-H and dMMR. An incomplete intestinal obstruction accompanied with hyperpyrexia occurred unexpectedly and was eased by symptomatic treatment. There was no peritonitis or other acute complications. NIT (three cycles of Tirelizumab) was suggested by the MDT board and partial response was achieved according to CT scanning, and pCR was further revealed by postoperative pathology. A ctDNA clearance confirmed the R0 resection and some immunotherapy related predictors were also detected using the NGS method. Our case study contributes to the evidence on the feasibility, efficacy, and safety of f Tirelizumab as a mono ICI for an optional neoadjuvant therapy in patients with MSI-H/dMMR LACRC. Full article
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16 pages, 4037 KiB  
Article
Screening and Identification of Key Biomarkers in Metastatic Uveal Melanoma: Evidence from a Bioinformatic Analysis
by Tan Wang, Zixing Wang, Jingyuan Yang, Youxin Chen and Hanyi Min
J. Clin. Med. 2022, 11(23), 7224; https://doi.org/10.3390/jcm11237224 - 05 Dec 2022
Cited by 1 | Viewed by 1799
Abstract
Purpose: To identify key biomarkers in the metastasis of uveal melanoma (UM). Methods: The microarray datasets GSE27831 and GSE22138 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified, and functional enrichment analyses were performed. A protein–protein interaction network [...] Read more.
Purpose: To identify key biomarkers in the metastasis of uveal melanoma (UM). Methods: The microarray datasets GSE27831 and GSE22138 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified, and functional enrichment analyses were performed. A protein–protein interaction network was constructed, and four algorithms were performed to increase the reliability of hub genes. Biomarker analysis and metastasis-free survival analysis were performed to screen and verify prognostic hub genes. Results: A total of 138 DEGs were identified, consisting of 71 downregulated genes and 67 upregulated genes. Four genes (ROBO1, FMN1, FYN and FXR1) were selected as hub genes. Biomarker analysis and metastasis-free survival analysis showed that ROBO1, FMN1, FYN and FXR1 were factors affecting the metastasis and metastasis-free survival of UM (all p < 0.05). High expression of ROBO1 and low expression of FMN1 were associated with longer metastasis-free survival. Multivariable logistic regression and Cox analyses in GSE 27831 indicated that ROBO1 was an independent factor affecting metastasis and metastasis-free survival of UM (p = 0.010 and p = 0.009), while ROBO1 and FMN1 were independent factors affecting metastasis and metastasis-free survival of UM in GSE22138 (all p < 0.05). Conclusions: ROBO1, FMN1, FYN and FXR1 should be regarded as diagnostic biomarkers for the metastasis of UM, especially ROBO1 and FMN1. High expression of ROBO1 and low expression of FMN1 were associated with longer metastasis-free survival. This study may facilitate the understanding of the molecular mechanisms underlying the metastasis of UM. Full article
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20 pages, 309 KiB  
Article
Hypoxia-Nitric Oxide Axis and the Associated Damage Molecular Pattern in Cutaneous Melanoma
by Corina Daniela Ene and Ilinca Nicolae
J. Pers. Med. 2022, 12(10), 1646; https://doi.org/10.3390/jpm12101646 - 04 Oct 2022
Cited by 3 | Viewed by 1193
Abstract
Hypoxia was intensively studied in cancer during the last few decades, being considered a characteristic of the tumor microenvironment. The aim of the study was to evaluate the capacity of tumor cells to adapt to the stress generated by limited oxygen tissue in [...] Read more.
Hypoxia was intensively studied in cancer during the last few decades, being considered a characteristic of the tumor microenvironment. The aim of the study was to evaluate the capacity of tumor cells to adapt to the stress generated by limited oxygen tissue in cutaneous melanoma. We developed a case–control prospective study that included 52 patients with cutaneous melanoma and 35 healthy subjects. We focused on identifying and monitoring hypoxia, the dynamic of nitric oxide (NO) serum metabolites and posttranslational metabolic disorders induced by NO signaling according to the clinical, biological and tumoral characteristics of the melanoma patients. Our study showed high levels of hypoxia-inducible factor-1a (HIF-1a) and hypoxia-inducible factor-2a (HIF-2a) in the melanoma patients. Hypoxia-inducible factors (HIFs) control the capacity of tumor cells to adapt to low levels of oxygen. Hypoxia regulated the nitric oxide synthase (NOS) expression and activity. In the cutaneous melanoma patients, disorders in NO metabolism were detected. The serum levels of the NO metabolites were significantly higher in the melanoma patients. NO signaling influenced the tumor microenvironment by modulating tumoral proliferation and sustaining immune suppression. Maintaining NO homeostasis in the hypoxic tumoral microenvironment could be considered a future therapeutic target in cutaneous melanoma. Full article
14 pages, 3743 KiB  
Case Report
Immune Checkpoint Inhibitor-Induced Myositis/Myocarditis with Myasthenia Gravis-like Misleading Presentation: A Case Series in Intensive Care Unit
by François Deharo, Julien Carvelli, Jennifer Cautela, Maxime Garcia, Claire Sarles, Andre Maues de Paula, Jérémy Bourenne, Marc Gainnier and Amandine Bichon
J. Clin. Med. 2022, 11(19), 5611; https://doi.org/10.3390/jcm11195611 - 23 Sep 2022
Cited by 6 | Viewed by 2299
Abstract
Introduction: Immune checkpoint inhibitors (ICIs) are a major breakthrough in cancer treatment. Their increasingly frequent use leads to an uprising incidence of immune-related adverse events (irAEs). Among those, myocarditis is the most reported fatal cardiovascular irAE, frequently associated with ICI-related myositis. Case series: [...] Read more.
Introduction: Immune checkpoint inhibitors (ICIs) are a major breakthrough in cancer treatment. Their increasingly frequent use leads to an uprising incidence of immune-related adverse events (irAEs). Among those, myocarditis is the most reported fatal cardiovascular irAE, frequently associated with ICI-related myositis. Case series: Here, we report three cases of ICI-induced myocarditis/myositis with an extremely severe myasthenia gravis-like (MG-like) presentation, highlighting the main challenges in irAEs management. These patients were over 60 years old and presented an ongoing melanoma, either locally advanced or metastatic, treated with ICI combinations. Shortly after the first or second ICI infusion, they were admitted in an intensive care unit (ICU) for grade 3 ICI-induced MG-like symptoms leading to acute respiratory failure (ARF) requiring invasive mechanical ventilation (IMV). The initial misdiagnosis was later corrected to severe ICI-induced seronegative myocarditis/myositis upon biological results and histopathology from muscular/endomyocardial biopsies. All of them received urgent high-dose corticosteroids pulses. The oldest patient died prematurely, but the two others received targeted therapies leading to complete recovery for one of them. Discussion: These cases highlight the four main challenges of irAEs, encompassing the lack of knowledge among physicians, the risk of misdiagnosis due to numerous and non-specific symptoms, the frequent overlapping forms of irAEs, and the extremely rare MG-like misleading presentation of myocarditis/myositis. The exact pathophysiology of irAEs remains unclear, although a major involvement of the lymphoid compartment (specifically T lymphocytes) was evidenced. Therapeutic management is based on urgent high-dose corticosteroids. For the severest forms of irAEs, case-by-case targeted immunosuppressive therapies should be urgently administered upon multidisciplinary meetings. Conclusion: These cases highlight the lack of knowledge of irAEs among physicians, aggravated by misleading overlapping forms, requiring specific management in trained units and multidisciplinary care. Severe MG-like presentation of irAEs constitutes an absolute therapeutic emergency with high-dose corticosteroids and targeted immunosuppressive therapy. Full article
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11 pages, 1557 KiB  
Article
Developing ROR1 Targeting CAR-T Cells against Solid Tumors in Preclinical Studies
by Boon kiat Lee, Yuhua Wan, Zan lynn Chin, Linyan Deng, Mo Deng, Tze ming Leung, Jian Hua and Hua Zhang
Cancers 2022, 14(15), 3618; https://doi.org/10.3390/cancers14153618 - 25 Jul 2022
Cited by 4 | Viewed by 3361
Abstract
Chimeric antigen receptor (CAR)-modified T-cells (CAR-T) have demonstrated promising clinical benefits against B-cell malignancies. Yet, its application for solid tumors is still facing challenges. Unlike haematological cancers, solid tumors often lack good targets, which are ideally expressed on the tumor cells, but not [...] Read more.
Chimeric antigen receptor (CAR)-modified T-cells (CAR-T) have demonstrated promising clinical benefits against B-cell malignancies. Yet, its application for solid tumors is still facing challenges. Unlike haematological cancers, solid tumors often lack good targets, which are ideally expressed on the tumor cells, but not by the normal healthy cells. Fortunately, receptor tyrosine kinase-like orphan receptor 1 (ROR1) is among a few good cancer targets that is aberrantly expressed on various tumors but has a low expression on normal tissue, suggesting it as a good candidate for CAR-T therapy. Here, we constructed two ROR1 CARs with the same antigen recognition domain that was derived from Zilovertamab but differing in hinge regions. Both CARs target ROR1+ cancer cells specifically, but CAR with a shorter IgG4 hinge exhibits a higher surface expression and better in vitro functionality. We further tested the ROR1 CAR-T in three human solid tumor xenografted mouse models. Our ROR1 CAR-T cells controlled the solid tumor growth without causing any severe toxicity. Our results demonstrated that ROR1 CAR-T derived from Zilovertamab is efficacious and safe to suppress ROR1+ solid tumors in vitro and in vivo, providing a promising therapeutic option for future clinical application. Full article
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