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Bhutani B, Sharma V, Ganguly NK, Rana R. Unravelling the modified T cell receptor through Gen-Next CAR T cell therapy in Glioblastoma: Current status and future challenges. Biomed Pharmacother 2025; 186:117987. [PMID: 40117901 DOI: 10.1016/j.biopha.2025.117987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/05/2025] [Accepted: 03/10/2025] [Indexed: 03/23/2025] Open
Abstract
PURPOSE Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity. METHODS In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy. FINDINGS To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes. IMPLICATIONS CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.
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Affiliation(s)
- Bhavya Bhutani
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Vyoma Sharma
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Nirmal Kumar Ganguly
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Rashmi Rana
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India.
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2
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Nash A, DeBonis J, Murungi D, Castillo B, Kim B, Hu F, Chambers C, Nguyen A, Hernandez A, Wang Z, Rios PD, Ghani S, Joshi I, Isa D, Zheng N, Peng W, Igoshin OA, Oberholzer J, Hodges HC, Reticker-Flynn N, Veiseh O. IL-12-producing cytokine factories induce precursor exhausted T cells and elimination of primary and metastatic tumors. J Immunother Cancer 2025; 13:e010685. [PMID: 40169286 PMCID: PMC11962782 DOI: 10.1136/jitc-2024-010685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 03/17/2025] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND Curative responses to immunotherapy require the generation of robust systemic immunity with limited toxicity. Recruitment of T cell populations such as precursor exhausted T cells (Tpex) from lymphoid tissues to tumors is a hallmark of effective treatment. However, the ability to efficiently induce this recruitment is lacking in current immunotherapy approaches. Furthermore, systemic administration of immunotherapies frequently results in dose-limiting toxicities, yielding an inadequate therapeutic window for eliciting durable responses. METHODS In this investigation, we evaluated the safety and antitumor efficacy of locally administered interleukin 12 (IL-12) using a clinically translatable cytokine delivery platform (NCT05538624) to identify Tpex recruitment capabilities at tolerable cytokine doses. RESULTS We show IL-12 cytokine factories can effectively treat a broad spectrum of cancer types. Single-cell RNA sequencing data suggests that the antitumor efficacy seen in our studies was due to retinal pigmented epithelial cells-mIL12 treatment inducing differentiation of Tpex cells within the tumor microenvironment. When administered in combination with checkpoint therapy, IL-12 cytokine factory treatment generated systemic abscopal immunity, preventing subcutaneous tumor outgrowth in 8/9 mice with colorectal cancer and lung metastasis in mice with melanoma. Furthermore, this platform was well tolerated in a non-human primate without signs of toxicity. CONCLUSIONS Our new immunotherapy approach provides a robust strategy for inducing Tpex recruitment and systemic immunity against a range of solid peritoneal malignancies, many incurable with current immunotherapy strategies. Notably, these features were achieved using IL-12, and by leveraging our technology, we avoided the toxicities that have prevented the translation of IL-12 to the clinic. Our findings provide a strong rationale for the clinical development of IL-12 cytokine factories.
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Affiliation(s)
- Amanda Nash
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | - Jonathon DeBonis
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | - Danna Murungi
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | - Bertha Castillo
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | - Boram Kim
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | - Fangheng Hu
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | - Courtney Chambers
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Annie Nguyen
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | - Andrea Hernandez
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | - Zeshi Wang
- Department of Bioengineering, Rice University, Houston, Texas, USA
| | | | | | | | | | - Ningbo Zheng
- Biology and Biochemistry, University of Houston, Houston, Texas, USA
| | - Weiyi Peng
- Biology and Biochemistry, University of Houston, Houston, Texas, USA
| | - Oleg A Igoshin
- Department of Bioengineering, Rice University, Houston, Texas, USA
- Department of Biosciences, Rice University, Houston, Texas, USA
- Department of Chemistry, Rice University, Houston, Texas, USA
- Center for Theoretical Biological Physics, Rice University, HoustON, Texas, USA
| | - Jose Oberholzer
- Celltrans, Chicago, Illinois, USA
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - H Courtney Hodges
- Department of Bioengineering, Rice University, Houston, Texas, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Nathan Reticker-Flynn
- Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, California, USA
| | - Omid Veiseh
- Department of Bioengineering, Rice University, Houston, Texas, USA
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3
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Kamali MJ, Salehi M, Fath MK. Advancing personalized immunotherapy for melanoma: Integrating immunoinformatics in multi-epitope vaccine development, neoantigen identification via NGS, and immune simulation evaluation. Comput Biol Med 2025; 188:109885. [PMID: 40010174 DOI: 10.1016/j.compbiomed.2025.109885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/23/2025] [Accepted: 02/14/2025] [Indexed: 02/28/2025]
Abstract
The use of cancer vaccines represents a promising avenue in cancer immunotherapy. Advances in next-generation sequencing (NGS) technology, coupled with the development of sophisticated analysis tools, have enabled the identification of somatic mutations by comparing genetic sequences between normal and tumor samples. Tumor neoantigens, derived from these mutations, have emerged as potential candidates for therapeutic cancer vaccines. In this study, raw NGS data from two melanoma patients (NCI_3903 and NCI_3998) were analyzed using publicly available SRA datasets from NCBI to identify patient-specific neoantigens. A comprehensive pipeline was employed to select candidate peptides based on their antigenicity, immunogenicity, physicochemical properties, and toxicity profiles. These validated epitopes were utilized to design multi-epitope chimeric vaccines tailored to each patient. Peptide linkers were employed to connect the epitopes, ensuring optimal vaccine structure and function. The two-dimensional (2D) and three-dimensional (3D) structures of the chimeric vaccines were predicted and refined to ensure structural stability and immunogenicity. Furthermore, molecular docking simulations were conducted to evaluate the binding interactions between the vaccine chimeras and the HLA class I receptors, confirming their potential to elicit a robust immune response. This work highlights a personalized approach to cancer vaccine development, demonstrating the feasibility of utilizing neoantigen-based immunoinformatics pipelines to design patient-specific therapeutic vaccines for melanoma.
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Affiliation(s)
- Mohammad Javad Kamali
- Department of Medical Genetics, School of Medicine, Babol University of Medical Science, Babol, Iran
| | - Mohammad Salehi
- Department of Medical Genetics, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran.
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4
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Dong J, Wu J, Jin Y, Zheng Z, Su T, Shao L, Bei J, Chen S. In-depth analysis of the safety of CAR-T cell therapy for solid tumors. Front Immunol 2025; 16:1548979. [PMID: 40066440 PMCID: PMC11891211 DOI: 10.3389/fimmu.2025.1548979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 01/30/2025] [Indexed: 05/13/2025] Open
Abstract
In recent years, the rapid progress in oncology, immunology, and molecular biology has dramatically advanced cancer immunotherapy, particularly CAR-T cell therapy. This innovative approach involves engineering a patient's T cells to express receptors that specifically target tumor antigens, enhancing their ability to identify and eliminate cancer cells. However, the effectiveness of CAR-T therapy in solid tumors is often hampered by the challenging tumor microenvironment (TME). The complex TME includes dense stroma that obstructs T cell infiltration, abnormal blood vessel structures leading to hypoxia, and an acidic pH, all of which hinder CAR-T cell function. Additionally, the presence of immunosuppressive factors in the TME reduces the efficacy of CAR-T cells, making successful targeting of tumors more difficult. The safety of CAR-T therapy has gained interest, especially CAR-T therapy has shown considerable effectiveness in various cancers, with notable results in multiple myeloma and hepatocellular carcinoma, among others. Nonetheless, CAR-T cell therapy is associated with several adverse reactions primarily driven by heightened levels of proinflammatory cytokines. These reactions include cytokine release syndrome (CRS), neurotoxicity (CANS), and organ toxicity, often leading to serious complications. CRS, characterized by systemic inflammation due to cytokine release, can escalate to severe organ dysfunction. It typically occurs within the first week post-infusion, correlating with CAR-T cell expansion and often presents with fever and hypotension. Meanwhile, CANS encompasses neurological issues ranging from mild symptoms to severe seizures, possibly exacerbated by CRS. Organ toxicity can also arise from CAR-T therapy, with potential damage affecting the gastrointestinal tract, kidneys, liver, and lungs, often tied to shared antigens found in both tumor and healthy tissues. Moreover, long-term effects like cytokine-associated hematotoxicity (CAHT) and secondary malignancies represent significant concerns that could affect the patient's quality of life post-treatment. The long-term adverse effects and challenges in treating solid tumors underscore the need for ongoing research. Strategies to improve CAR-T cell efficacy, minimize adverse reactions, and enhance patient safety are critical. Future explorations could include designing CAR-T cells to better navigate the TME, identifying specific target antigen profiles to minimize off-target damage, and developing adjunct therapies to mitigate cytokine-related toxicity. Continued monitoring for long-term effects will also be paramount in improving patient outcomes and maintaining their quality of life. Overall, while CAR-T therapy holds great promise, it must be administered with careful consideration of potential side effects and rigorous management strategies to ensure patient safety and treatment efficacy.
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Affiliation(s)
- Jiayi Dong
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiexiong Wu
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ye Jin
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhu Zheng
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ting Su
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Lijuan Shao
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiaxin Bei
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
| | - Size Chen
- Department of Immuno-Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Monitoring Adverse Reactions Associated with Chimeric Antigen Receptor T-Cell Therapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Precision Medicine in Esophageal Cancer, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Cancer Immunotherapy, Guangdong Higher Education Institutions, Guangdong Pharmaceutical University, Guangzhou, China
- School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
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5
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Xu M, Pan Y. Chimeric Antigen Receptor (CAR)-T Cells: A New Era for Hepatocellular Carcinoma Treatment. J Biochem Mol Toxicol 2024; 38:e70091. [PMID: 39664011 DOI: 10.1002/jbt.70091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/24/2024] [Accepted: 11/29/2024] [Indexed: 12/13/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and a worldwide health concern that requires novel treatment approaches. Tyrosine kinase inhibitors (TKIs) and immune checkpoint blockades (ICBs) are the current standard of care; however, their clinical benefits are limited in some advanced and metastatic patients. With the help of gene engineering techniques, a novel adoptive cellular therapy (ACT) called chimeric antigen receptor (CAR)-T cells was recently introduced for treating HCC. A plethora of current clinical and preclinical studies are attempting to improve the efficacy of CAR-T cells by dominating the immunosuppressive environment of HCC and finding the best tumor-specific antigens (TSAs). The future of care for HCC patients might be drastically improved due to the convergence of novel therapeutic methods and the continuous progress in ACT research. However, the clinical application of CAR-T cells in solid tumors is still facing several challenges. In this study, we provide an overview of the advancement and prospects of CAR-T cell immunotherapy in HCC, as well as an investigation of how cutting-edge engineering could improve CAR-T cell efficacy and safety profile.
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Affiliation(s)
- Ming Xu
- Department of Liver, Gallbladder, Spleen and Stomach, Heilongjiang Academy of Chinese Mediceal Sciences, Harbin, Heilongjiang, China
| | - Yang Pan
- Department of Liver, Gallbladder, Spleen and Stomach, Heilongjiang Academy of Chinese Mediceal Sciences, Harbin, Heilongjiang, China
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6
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Laotee S, Arunmanee W. Genetically surface-modified Escherichia coli outer membrane vesicles targeting MUC1 antigen in cancer cells. BIOTECHNOLOGY REPORTS (AMSTERDAM, NETHERLANDS) 2024; 44:e00854. [PMID: 39290790 PMCID: PMC11406022 DOI: 10.1016/j.btre.2024.e00854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/06/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024]
Abstract
Outer membrane vesicles (OMVs), non-replicating spherical liposomes derived from Gram-negative bacteria, are a promising vaccine platform and multifunctional delivery systems. Their ability to be modified via genetic engineering for the incorporation and display of heterologous proteins enhances their functionality. In this study, we demonstrated a bio-ligation approach to display single-chain variable fragments (scFv) on the OMV surface using the SpyTag/SpyCatcher system. SpyTag-fused scFv, expressed by mammalian cells, bound to OMVs with SpyCatcher-fused Lpp'OmpA after a simple incubation. Biophysical analysis indicated that the conjugated OMVs maintained their physicochemical properties. We used an scFv targeting mucin 1 protein (MUC1) for specific cell targeting. Confocal microscopy revealed that conjugated OMVs specifically bound to and were internalized by MUC1-presenting cells, but not by MUC1-deficient cells. In conclusion, this rapid and efficient bio-ligation system facilitates the display of functional scFv on OMV surfaces, offering a promising approach for targeted delivery to MUC1-expressing cancer cells.
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Affiliation(s)
- Sedthawut Laotee
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Wanatchaporn Arunmanee
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
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7
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Zhu S. CAR-T in cancer therapeutics and updates. JOURNAL OF THE NATIONAL CANCER CENTER 2024; 4:189-194. [PMID: 39281717 PMCID: PMC11402450 DOI: 10.1016/j.jncc.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 01/03/2024] [Accepted: 01/07/2024] [Indexed: 09/18/2024] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a groundbreaking approach in cancer treatment, utilizing the immune system's capabilities to combat malignancies. This innovative therapy involves extracting T-cells from a patient's blood, genetically modifying them to target specific cancer cells, and reinfusing them back into the patient's body. The genetically modified T-cells then seek out and eliminate cancer cells, offering a promising therapeutic strategy. Since its initial approval in 2017, CAR-T therapy has witnessed remarkable advancements and updates. Notably, CAR-T therapy, which was initially developed for hematological malignancies, has expanded its scope to target solid tumors. Currently, clinical trials are underway to explore the efficacy of CAR-T therapy in treating various solid tumors, such as lung cancer, breast cancer, and ovarian cancer. These trials hold great potential to revolutionize cancer treatment and provide new hope to patients with challenging-to-treat solid tumors. In this mini-review, we present an overview of CAR-T therapy's mechanisms, emphasizing its role in targeting cancer cells and the potential therapeutic benefits. Additionally, we discuss the recent progress and updates in CAR-T therapy, particularly its application in treating solid tumors, and highlight the ongoing clinical trials aimed at broadening its therapeutic horizon. The evolving landscape of CAR-T therapy signifies a promising direction in cancer therapeutics, with the potential to revolutionize the treatment of both hematological and solid tumor malignancies.
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Affiliation(s)
- Shigui Zhu
- Cellular Biomedical Group, Inc., Shanghai, China
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8
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Long J, Wang Y, Jiang X, Ge J, Chen M, Zheng B, Wang R, Wang M, Xu M, Ke Q, Wang J. Nanomaterials Boost CAR-T Therapy for Solid Tumors. Adv Healthc Mater 2024; 13:e2304615. [PMID: 38483400 DOI: 10.1002/adhm.202304615] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/29/2024] [Indexed: 05/22/2024]
Abstract
T cell engineering, particularly via chimeric antigen receptor (CAR) modifications for enhancing tumor specificity, has shown efficacy in treating hematologic malignancies. The extension of CAR-T cell therapy to solid tumors, however, is impeded by several challenges: The absence of tumor-specific antigens, antigen heterogeneity, a complex immunosuppressive tumor microenvironment, and physical barriers to cell infiltration. Additionally, limitations in CAR-T cell manufacturing capacity and the high costs associated with these therapies restrict their widespread application. The integration of nanomaterials into CAR-T cell production and application offers a promising avenue to mitigate these challenges. Utilizing nanomaterials in the production of CAR-T cells can decrease product variability and lower production expenses, positively impacting the targeting and persistence of CAR-T cells in treatment and minimizing adverse effects. This review comprehensively evaluates the use of various nanomaterials in the production of CAR-T cells, genetic modification, and in vivo delivery. It discusses their underlying mechanisms and potential for clinical application, with a focus on improving specificity and safety in CAR-T cell therapy.
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Affiliation(s)
- Jun Long
- Shenzhen Geim Graphene Center, Tsinghua-Berkeley Shenzhen Institute & Tsinghua Shenzhen International Graduate School, Tsinghua University, 1001 Xueyuan Road, Shenzhen, 518055, China
| | - Yian Wang
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, The Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Changsha, 410013, China
| | - Xianjie Jiang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Junshang Ge
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, 410078, China
| | - Mingfen Chen
- Department of Radiation Oncology, The Second Affiliated Hospital of Fujian Medical University, Fujian Medical University, Quanzhou, 362000, China
| | - Boshu Zheng
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, No.1 Xuefu North Road University Town, Fuzhou, 350122, China
| | - Rong Wang
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, No.1 Xuefu North Road University Town, Fuzhou, 350122, China
| | - Meifeng Wang
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, No.1 Xuefu North Road University Town, Fuzhou, 350122, China
| | - Meifang Xu
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, No.1 Xuefu North Road University Town, Fuzhou, 350122, China
| | - Qi Ke
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, No.1 Xuefu North Road University Town, Fuzhou, 350122, China
| | - Jie Wang
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, No.1 Xuefu North Road University Town, Fuzhou, 350122, China
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9
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Wang L, Zhang L, Dunmall LC, Wang YY, Fan Z, Cheng Z, Wang Y. The dilemmas and possible solutions for CAR-T cell therapy application in solid tumors. Cancer Lett 2024; 591:216871. [PMID: 38604310 DOI: 10.1016/j.canlet.2024.216871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 03/26/2024] [Accepted: 04/06/2024] [Indexed: 04/13/2024]
Abstract
Chimeric antigen receptor T (CAR-T) cell therapy, as an adoptive immunotherapy, is playing an increasingly important role in the treatment of malignant tumors. CAR-T cells are referred to as "living drugs" as they not only target tumor cells directly, but also induce long-term immune memory that has the potential to provide long-lasting protection. CD19.CAR-T cells have achieved complete response rates of over 90 % for acute lymphoblastic leukemia and over 60 % for non-Hodgkin's lymphoma. However, the response rate of CAR-T cells in the treatment of solid tumors remains extremely low and the side effects potentially severe. In this review, we discuss the limitations that the solid tumor microenvironment poses for CAR-T application and the solutions that are being developed to address these limitations, in the hope that in the near future, CAR-T cell therapy for solid tumors can attain the same success rates as are now being seen clinically for hematological malignancies.
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Affiliation(s)
- Lihong Wang
- Department of Oncology, Air Force Medical Center, PLA, Beijing, China; National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Lufang Zhang
- National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Louisa Chard Dunmall
- Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Yang Yang Wang
- Department of General Pediatrics, Newham General Hospital, E13 8SL, London, United Kingdom
| | - Zaiwen Fan
- Department of Oncology, Air Force Medical Center, PLA, Beijing, China
| | - Zhenguo Cheng
- National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yaohe Wang
- National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China; Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
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Grover P, Nunez-Cruz S, Leferovich J, Wentz T, Bagchi A, Milone MC, Greene MI. F77 antigen is a promising target for adoptive T cell therapy of prostate cancer. Biochem Biophys Res Commun 2023; 680:51-60. [PMID: 37717341 PMCID: PMC10591779 DOI: 10.1016/j.bbrc.2023.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/31/2023] [Accepted: 09/09/2023] [Indexed: 09/19/2023]
Abstract
Adoptive immunotherapy using chimeric antigen receptor (CAR) T cells has made significant success in treating hematological malignancies, paving the way for solid tumors like prostate cancer. However, progress is impeded by a paucity of suitable target antigens. A novel carbohydrate antigen, F77, is expressed on both androgen-dependent and androgen-independent prostate cancer cells, making it a potential immunotherapy target. This study entails the generation and evaluation of a second-generation CAR against a carbohydrate antigen on malignant prostate cancer cells. Using a single chain fragment variable (scFv) from an F77-specific mouse monoclonal antibody, we created second-generation CARs with CD28 and CD137 (4-1BB) costimulatory signals. F77 expressing lentiviral CAR T cells produce cytokines and kill tumor cells in a F77 expression-dependent manner. These F77-specific CAR T cells eradicate prostate tumors in a human xenograft model employing PC3 cells. These findings validate F77 as a promising immunotherapeutic target for prostate cancer and other malignancies with this aberrant carbohydrate structure.
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Affiliation(s)
- Payal Grover
- Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Selene Nunez-Cruz
- Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - John Leferovich
- Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Tyra Wentz
- Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Atrish Bagchi
- Loxo Oncology @ Lilly, South San Francisco, CA, 94080, USA
| | - Michael C Milone
- Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Mark I Greene
- Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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11
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Cui Y, Luo M, Gu C, He Y, Yao Y, Li P. CAR designs for solid tumors: overcoming hurdles and paving the way for effective immunotherapy. BIOPHYSICS REPORTS 2023; 9:279-297. [PMID: 38516299 PMCID: PMC10951476 DOI: 10.52601/bpr.2023.230020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/28/2023] [Indexed: 03/23/2024] Open
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized immunotherapy by modifying patients' immune cells genetically. By expressing CARs, these modified cells can specifically identify and eliminate tumor cells. The success of CAR-T therapy in hematological malignancies, such as leukemia and lymphoma, has been remarkable. Numerous studies have reported improved patient outcomes and increased survival rates. However, the application of CAR-T therapy in treating solid tumors faces significant challenges. Solid tumors possess complex microenvironments containing stromal cells, extracellular matrix components, and blood vessels. These factors can impede the infiltration and persistence of CAR-T cells within the tumor. Additionally, the lack of target antigens exclusively expressed on tumor cells raises concerns about off-target effects and potential toxicity. This review aims to discuss advancements achieved by CAR-T therapy in solid tumors and the clinical outcomes in the realm of solid tumors.
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Affiliation(s)
- Yuanbin Cui
- China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Mintao Luo
- China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Chuanyuan Gu
- China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yuxian He
- University of California San Diego, La Jolla, CA 92093-0021, USA
| | - Yao Yao
- China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Peng Li
- China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
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12
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Wang T, Zhang K, You F, Ma R, Yang N, Tian S, An G, Yang L. Preconditioning of radiotherapy enhances efficacy of B7-H3-CAR-T in treating solid tumor models. Life Sci 2023; 331:122024. [PMID: 37574043 DOI: 10.1016/j.lfs.2023.122024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/30/2023] [Accepted: 08/10/2023] [Indexed: 08/15/2023]
Abstract
AIMS Limited efficacy of chimeric antigen receptor T (CAR-T) cells in treating solid tumors is largely due to the antigen heterogeneity and immunosuppressive tumor microenvironment (TME). B7-H3 is over-expressed in most kind of solid tumors, making it a promising target for cancer treatment. This study aims to explore the effect of B7-H3-CAR-T therapy combined with radiotherapy in treating solid tumor models. METHODS Irradiated tumor cell lines were prepared and tested. A humanized B7-H3-CAR-T was constructed, and it was evaluated that B7-H3-CAR-T cytotoxicity against solid tumor models with preconditioning of radiotherapy in vitro and vivo. RESULTS Irradiation was found to increase expression level of B7-H3 in pancreatic cancer (PANC-1), colorectal cancer (HCT-15, SW620), acute myelocytic leukemia (AML-5), epidermoid carcinoma (KB) and glioma (U87-MG) human cell lines significantly. 6Gy irradiation was also found to up-regulate tumor-infiltration molecule like intracellular adhesion molecule-1 ICAM-1 or FAS in HCT-15 cells, supporting a possible synergistic enhancement effect of radiotherapy. In vitro and in vivo experiments demonstrated that irradiation indeed significantly enhanced the ability of B7-H3-CAR-T to infiltrate and kill tumors. Interestingly in dual-tumor mouse model study, not only tumor cells on irradiation side were eradicated completely, irradiation also enhanced CAR-T tumor-killing ability on non-irradiated side, confirming the abscopal effect of irradiation existed with CAR-T therapy. CONCLUSIONS Our results suggest that B7-H3-CAR-T therapy combined with radiotherapy may be a promising modality in treating solid tumors.
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Affiliation(s)
- Tian Wang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China; PersonGen BioTherapeutics Co., Ltd., Suzhou, PR China
| | - Kailu Zhang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Fengtao You
- PersonGen BioTherapeutics Co., Ltd., Suzhou, PR China
| | - Renyuxue Ma
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Nan Yang
- PersonGen BioTherapeutics Co., Ltd., Suzhou, PR China
| | - Shuaiyu Tian
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Gangli An
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Lin Yang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China; PersonGen BioTherapeutics Co., Ltd., Suzhou, PR China.
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13
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Lodewijk I, Dueñas M, Paramio JM, Rubio C. CD44v6, STn & O-GD2: promising tumor associated antigens paving the way for new targeted cancer therapies. Front Immunol 2023; 14:1272681. [PMID: 37854601 PMCID: PMC10579806 DOI: 10.3389/fimmu.2023.1272681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 09/14/2023] [Indexed: 10/20/2023] Open
Abstract
Targeted therapies are the state of the art in oncology today, and every year new Tumor-associated antigens (TAAs) are developed for preclinical research and clinical trials, but few of them really change the therapeutic scenario. Difficulties, either to find antigens that are solely expressed in tumors or the generation of good binders to these antigens, represent a major bottleneck. Specialized cellular mechanisms, such as differential splicing and glycosylation processes, are a good source of neo-antigen expression. Changes in these processes generate surface proteins that, instead of showing decreased or increased antigen expression driven by enhanced mRNA processing, are aberrant in nature and therefore more specific targets to elicit a precise anti-tumor therapy. Here, we present promising TAAs demonstrated to be potential targets for cancer monitoring, targeted therapy and the generation of new immunotherapy tools, such as recombinant antibodies and chimeric antigen receptor (CAR) T cell (CAR-T) or Chimeric Antigen Receptor-Engineered Natural Killer (CAR-NK) for specific tumor killing, in a wide variety of tumor types. Specifically, this review is a detailed update on TAAs CD44v6, STn and O-GD2, describing their origin as well as their current and potential use as disease biomarker and therapeutic target in a diversity of tumor types.
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Affiliation(s)
- Iris Lodewijk
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
| | - Marta Dueñas
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
| | - Jesus M. Paramio
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
| | - Carolina Rubio
- Biomedical Research Institute I+12, University Hospital “12 de Octubre”, Madrid, Spain
- Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
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14
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Jin W, Zhang M, Dong C, Huang L, Luo Q. The multifaceted role of MUC1 in tumor therapy resistance. Clin Exp Med 2023; 23:1441-1474. [PMID: 36564679 DOI: 10.1007/s10238-022-00978-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022]
Abstract
Tumor therapeutic resistances are frequently linked to the recurrence and poor prognosis of cancers and have been a key bottleneck in clinical tumor treatment. Mucin1 (MUC1), a heterodimeric transmembrane glycoprotein, exhibits abnormally overexpression in a variety of human tumors and has been confirmed to be related to the formation of therapeutic resistance. In this review, the multifaceted roles of MUC1 in tumor therapy resistance are summarized from aspects of pan-cancer principles shared among therapies and individual mechanisms dependent on different therapies. Concretely, the common mechanisms of therapy resistance across cancers include interfering with gene expression, promoting genome instability, modifying tumor microenvironment, enhancing cancer heterogeneity and stemness, and activating evasion and metastasis. Moreover, the individual mechanisms of therapy resistance in chemotherapy, radiotherapy, and biotherapy are introduced. Last but not least, MUC1-involved therapy resistance in different types of cancers and MUC1-related clinical trials are summarized.
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Affiliation(s)
- Weiqiu Jin
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China
- Department of Histoembryology, Genetics and Developmental Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Mengwei Zhang
- Department of Histoembryology, Genetics and Developmental Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Changzi Dong
- Department of Bioengineering, School of Engineering and Science, University of Pennsylvania, Philadelphia, 19104, USA
| | - Lei Huang
- Department of Histoembryology, Genetics and Developmental Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Innovative Research Team of High-Level Local Universities in Shanghai, Shanghai, China.
| | - Qingquan Luo
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China.
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15
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Zhang P, Zhang G, Wan X. Challenges and new technologies in adoptive cell therapy. J Hematol Oncol 2023; 16:97. [PMID: 37596653 PMCID: PMC10439661 DOI: 10.1186/s13045-023-01492-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 08/04/2023] [Indexed: 08/20/2023] Open
Abstract
Adoptive cell therapies (ACTs) have existed for decades. From the initial infusion of tumor-infiltrating lymphocytes to the subsequent specific enhanced T cell receptor (TCR)-T and chimeric antigen receptor (CAR)-T cell therapies, many novel strategies for cancer treatment have been developed. Owing to its promising outcomes, CAR-T cell therapy has revolutionized the field of ACTs, particularly for hematologic malignancies. Despite these advances, CAR-T cell therapy still has limitations in both autologous and allogeneic settings, including practicality and toxicity issues. To overcome these challenges, researchers have focused on the application of CAR engineering technology to other types of immune cell engineering. Consequently, several new cell therapies based on CAR technology have been developed, including CAR-NK, CAR-macrophage, CAR-γδT, and CAR-NKT. In this review, we describe the development, advantages, and possible challenges of the aforementioned ACTs and discuss current strategies aimed at maximizing the therapeutic potential of ACTs. We also provide an overview of the various gene transduction strategies employed in immunotherapy given their importance in immune cell engineering. Furthermore, we discuss the possibility that strategies capable of creating a positive feedback immune circuit, as healthy immune systems do, could address the flaw of a single type of ACT, and thus serve as key players in future cancer immunotherapy.
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Affiliation(s)
- Pengchao Zhang
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Avenue, Nanshan District, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Guizhong Zhang
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Avenue, Nanshan District, Shenzhen, 518055, People's Republic of China.
| | - Xiaochun Wan
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Avenue, Nanshan District, Shenzhen, 518055, People's Republic of China.
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16
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Andreu-Sanz D, Kobold S. Role and Potential of Different T Helper Cell Subsets in Adoptive Cell Therapy. Cancers (Basel) 2023; 15:cancers15061650. [PMID: 36980536 PMCID: PMC10046829 DOI: 10.3390/cancers15061650] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/27/2023] [Accepted: 03/03/2023] [Indexed: 03/30/2023] Open
Abstract
Historically, CD8+ T cells have been considered the most relevant effector cells involved in the immune response against tumors and have therefore been the focus of most cancer immunotherapy approaches. However, CD4+ T cells and their secreted factors also play a crucial role in the tumor microenvironment and can orchestrate both pro- and antitumoral immune responses. Depending on the cytokine milieu to which they are exposed, CD4+ T cells can differentiate into several phenotypically different subsets with very divergent effects on tumor progression. In this review, we provide an overview of the current knowledge about the role of the different T helper subsets in the immune system, with special emphasis on their implication in antitumoral immune responses. Furthermore, we also summarize therapeutic applications of each subset and its associated cytokines in the adoptive cell therapy of cancer.
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Affiliation(s)
- David Andreu-Sanz
- Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Lindwurmstrasse 2a, 80337 Munich, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Lindwurmstrasse 2a, 80337 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, 81675 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Munich, Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany
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17
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Maher J, Davies DM. CAR Based Immunotherapy of Solid Tumours-A Clinically Based Review of Target Antigens. BIOLOGY 2023; 12:287. [PMID: 36829563 PMCID: PMC9953298 DOI: 10.3390/biology12020287] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023]
Abstract
Immunotherapy with CAR-engineered immune cells has transformed the management of selected haematological cancers. However, solid tumours have proven much more difficult to control using this emerging therapeutic modality. In this review, we survey the clinical impact of solid tumour CAR-based immunotherapy, focusing on specific targets across a range of disease indications Among the many candidates which have been the subject of non-clinical CAR T-cell research, clinical data are available for studies involving 30 of these targets. Here, we map out this clinical experience, highlighting challenges such as immunogenicity and on-target off-tumour toxicity, an issue that has been both unexpected and devastating in some cases. We also summarise how regional delivery and repeated dosing have been used in an effort to enhance impact and safety. Finally, we consider how emerging armouring systems and multi-targeted CAR approaches might be used to enhance tumour access and better enable discrimination between healthy and transformed cell types.
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Affiliation(s)
- John Maher
- CAR Mechanics Group, Guy’s Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College London, Great Maze Pond, London SE1 9RT, UK
- Department of Immunology, Eastbourne Hospital, Kings Drive, Eastbourne BN21 2UD, UK
- Leucid Bio Ltd., Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK
| | - David M. Davies
- Leucid Bio Ltd., Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK
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18
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Zhang K, Chen H, Li F, Huang S, Chen F, Li Y. Bright future or blind alley? CAR-T cell therapy for solid tumors. Front Immunol 2023; 14:1045024. [PMID: 36761757 PMCID: PMC9902507 DOI: 10.3389/fimmu.2023.1045024] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 01/04/2023] [Indexed: 01/26/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval. However, the application of CAR-T cell therapy in solid tumors remains challenging, mostly due to lack of suitable CAR-T target antigens, insufficient trafficking and extravasation to tumor sites, and limited CAR-T survival in the hostile tumor microenvironment (TME). Herein, we reviewed the development of CARs and the clinical trials in solid tumors. Meanwhile, a "key-and-lock" relationship was used to describe the recognition of tumor antigen via CAR T cells. Some strategies, including dual-targets and receptor system switches or filter, have been explored to help CAR T cells matching targets specifically and to minimize on-target/off-tumor toxicities in normal tissues. Furthermore, the complex TME restricts CAT T cells activity through dense extracellular matrix, suppressive immune cells and cytokines. Recent innovations in engineered CARs to shield the inhibitory signaling molecules were also discussed, which efficiently promote CAR T functions in terms of expansion and survival to overcome the hurdles in the TME of solid tumors.
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Affiliation(s)
- Kai Zhang
- Department of Oncology, 920th Hospital of Joint Logistics Support Force, Kunming, Yunnan, China,Graduate School, Kunming Medical University, Kunming, Yunnan, China
| | - Hong Chen
- Department of Oncology, 920th Hospital of Joint Logistics Support Force, Kunming, Yunnan, China
| | - Fuqiang Li
- Department of Traditional Chinese Medicine, 920th Hospital of Joint Logistics Support Force, Kunming, Yunnan, China
| | - Sheng Huang
- Department of Breast Surgery, Breast Cancer Center of the Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, Yunnan, China
| | - Fei Chen
- Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yi Li
- Department of Oncology, 920th Hospital of Joint Logistics Support Force, Kunming, Yunnan, China,Graduate School, Kunming Medical University, Kunming, Yunnan, China,*Correspondence: Yi Li,
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19
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Daei Sorkhabi A, Mohamed Khosroshahi L, Sarkesh A, Mardi A, Aghebati-Maleki A, Aghebati-Maleki L, Baradaran B. The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies. Front Immunol 2023; 14:1113882. [PMID: 37020537 PMCID: PMC10067596 DOI: 10.3389/fimmu.2023.1113882] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/28/2023] [Indexed: 04/07/2023] Open
Abstract
The successful outcomes of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic cancers have increased the previously unprecedented excitement to use this innovative approach in treating various forms of human cancers. Although researchers have put a lot of work into maximizing the effectiveness of these cells in the context of solid tumors, few studies have discussed challenges and potential strategies to overcome them. Restricted trafficking and infiltration into the tumor site, hypoxic and immunosuppressive tumor microenvironment (TME), antigen escape and heterogeneity, CAR T-cell exhaustion, and severe life-threatening toxicities are a few of the major obstacles facing CAR T-cells. CAR designs will need to go beyond the traditional architectures in order to get over these limitations and broaden their applicability to a larger range of malignancies. To enhance the safety, effectiveness, and applicability of this treatment modality, researchers are addressing the present challenges with a wide variety of engineering strategies as well as integrating several therapeutic tactics. In this study, we reviewed the antigens that CAR T-cells have been clinically trained to recognize, as well as counterstrategies to overcome the limitations of CAR T-cell therapy, such as recent advances in CAR T-cell engineering and the use of several therapies in combination to optimize their clinical efficacy in solid tumors.
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Affiliation(s)
- Amin Daei Sorkhabi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Aila Sarkesh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Mardi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Aghebati-Maleki
- Stem Cell Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Leili Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- *Correspondence: Leili Aghebati-Maleki, ; Behzad Baradaran,
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- *Correspondence: Leili Aghebati-Maleki, ; Behzad Baradaran,
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20
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Wu G, Li L, Liu M, Chen C, Wang G, Jiang Z, Qin Y, He L, Li H, Cao J, Gu H. Therapeutic effect of a MUC1-specific monoclonal antibody-drug conjugates against pancreatic cancer model. Cancer Cell Int 2022; 22:417. [PMID: 36572921 PMCID: PMC9793597 DOI: 10.1186/s12935-022-02839-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most aggressive malignancies without effective targeted therapies. MUC1 has emerged as a potential common target for cancer therapy because it is overexpressed in a variety of different cancers including the majority of pancreatic cancer. However, there are still no approved monoclonal antibody drugs targeting MUC1 have been reported. Recently, we generated a humanized MUC1 antibody (HzMUC1) specific to the interaction region between MUC1-N and MUC1-C. In this study, we generated the antibody drug conjugate (ADC) by conjugating HzMUC1 with monomethyl auristatin (MMAE), and examined the efficacy of HzMUC1-MMAE against the MUC1-positive pancreatic cancer in vitro and in vivo. METHODS Western blot and immunoprecipitation were used to detect MUC1 in pancreatic cancer cells. MUC1 localization in pancreatic cancer cells was determined by confocal microscopy. HzMUC1 was conjugated with the monomethyl auristatin (MMAE), generating the HzMUC1-MMAE ADC. Colony formation assay and flow cytometry were used to assess the effects of the HzMUC1-MMAE cell viability, cell cycle progression and apoptosis. Capan-2 and CFPAC-1 xenograft model were used to test the efficacy of HzMUC1-MMAE against pancreatic cancer. RESULTS HzMUC1 antibody binds to MUC1 on the cell surface of pancreatic cancer cells. HzMUC1-MMAE significantly inhibited cell growth by inducing G2/M cell cycle arrest and apoptosis in pancreatic cancer cells. Importantly, HzMUC1-MMAE significantly reduced the growth of pancreatic xenograft tumors by inhibiting cell proliferation and enhancing cell death. CONCLUSION Our results indicate that HzMUC1-ADC is a promising novel targeted therapy for pancreatic cancer. HzMUC1-ADC should also be an effective drug for the treatment of different MUC1-positive cancers.
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Affiliation(s)
- Guang Wu
- grid.268099.c0000 0001 0348 3990Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, 325035 China
| | - Lan Li
- grid.268099.c0000 0001 0348 3990School of Public Health and Management, Wenzhou Medical University, 325035 Wenzhou, China
| | - Mengnan Liu
- grid.268099.c0000 0001 0348 3990Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, 325035 China
| | - Chunyan Chen
- grid.268099.c0000 0001 0348 3990Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, 325035 China
| | - Guangze Wang
- grid.268099.c0000 0001 0348 3990Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, 325035 China
| | - Zewei Jiang
- grid.268099.c0000 0001 0348 3990Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, 325035 China
| | - Yaqian Qin
- grid.414906.e0000 0004 1808 0918Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 China
| | - Licai He
- grid.268099.c0000 0001 0348 3990Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, 325035 China
| | - Hongzhi Li
- grid.268099.c0000 0001 0348 3990Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, 325035 China
| | - Jiawei Cao
- grid.268099.c0000 0001 0348 3990Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, 325035 China
| | - Haihua Gu
- grid.268099.c0000 0001 0348 3990Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou, 325035 China
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21
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Chen X, Li P, Tian B, Kang X. Serious adverse events and coping strategies of CAR-T cells in the treatment of malignant tumors. Front Immunol 2022; 13:1079181. [PMID: 36569917 PMCID: PMC9772271 DOI: 10.3389/fimmu.2022.1079181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 11/24/2022] [Indexed: 12/12/2022] Open
Abstract
Chimeric antigen receptor T (CAR-T) cells technology has been successfully used in the treatment of B cell-derived hematological tumors and multiple myeloma. CAR-T cells are also being studied in a variety of solid tumors. Current clinical reports on CAR-T cells in the treatment of malignant tumors are abundant. The tumor-killing activity of CAR-T cells and the unique adverse effects of CAR-T cells have been confirmed by many studies. There is evidence that serious adverse events can be life-threatening. CAR-T cells therapy is increasingly used in clinical settings, so it is important to pay attention to its serious adverse events. In this review, we summarized the serious adverse events of CAR-T cells in the treatment of malignant tumors by reading literature and searching relevant clinical studies, and discussed the management and treatment of serious adverse events in an effort to provide theoretical support for clinicians who deal with such patients.
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22
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Li X, Dai H, Wang Y, Wu Z, Wang H, Qian W, Liang A, Han W. Regional empowerment through decentralised governance under a centralised regulatory system facilitates the development of cellular therapy in China. THE LANCET HAEMATOLOGY 2022; 9:e942-e954. [DOI: 10.1016/s2352-3026(22)00331-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 09/22/2022] [Accepted: 10/07/2022] [Indexed: 11/30/2022]
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23
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Chatterjee A, Asija S, Yadav S, Purwar R, Goda JS. Clinical utility of CAR T cell therapy in brain tumors: Lessons learned from the past, current evidence and the future stakes. Int Rev Immunol 2022; 41:606-624. [PMID: 36191126 DOI: 10.1080/08830185.2022.2125963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2022]
Abstract
The unprecedented clinical success of Chimeric Antigen Receptor (CAR) T cell therapy in hematological malignancies has led researchers to study its role in solid tumors. Although, its utility in solid tumors especially in neuroblastoma has begun to emerge, preclinical studies of its efficacy in other solid tumors like osteosarcomas or gliomas has caught the attention of oncologist to be tried in clinical trials. Malignant high-grade brain tumors like glioblastomas or midline gliomas in children represent some of the most difficult malignancies to be managed with conventionally available therapeutics, while relapsed gliomas continue to have the most dismal prognosis due to limited therapeutic options. Innovative therapies such as CAR T cells could give an additional leverage to the treating oncologists by potentially improving outcomes and ameliorating the toxicity of the currently available therapies. Moreover, CAR T cell therapy has the potential to be integrated into the therapeutic paradigm for aggressive gliomas in the near future. In this review we discuss the challenges in using CAR T cell therapy in brain tumors, enumerate the completed and ongoing clinical trials of different types of CAR T cell therapy for different brain tumors with special emphasis on glioblastoma and also discuss the future role of CAR T cells in Brain tumors.
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Affiliation(s)
- Abhishek Chatterjee
- Department of Radiation Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India.,Homi Bhabha National Institute, Mumbai, India
| | - Sweety Asija
- Department of Biosciences & Bioengineering, Indian Institute of Technology, Mumbai, India
| | - Sandhya Yadav
- Department of Radiation Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India.,Homi Bhabha National Institute, Mumbai, India
| | - Rahul Purwar
- Department of Biosciences & Bioengineering, Indian Institute of Technology, Mumbai, India
| | - Jayant S Goda
- Department of Radiation Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India.,Homi Bhabha National Institute, Mumbai, India
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24
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Li Y, Yang X, Sun Y, Li Z, Yang W, Ju B, Easton J, Pei D, Cheng C, Lee S, Pui CH, Yu J, Chi H, Yang JJ. Impact of T-cell immunity on chemotherapy response in childhood acute lymphoblastic leukemia. Blood 2022; 140:1507-1521. [PMID: 35675514 PMCID: PMC9523375 DOI: 10.1182/blood.2021014495] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 05/29/2022] [Indexed: 11/20/2022] Open
Abstract
Although acute lymphoblastic leukemia (ALL) is highly responsive to chemotherapy, it is unknown how or which host immune factors influence the long-term remission of this cancer. To this end, we systematically evaluated the effects of T-cell immunity on Ph+ ALL therapy outcomes. Using a murine Arf-/-BCR-ABL1 B-cell ALL model, we showed that loss of T cells in the host drastically increased leukemia relapse after dasatinib or cytotoxic chemotherapy. Although ABL1 mutations emerged early during dasatinib treatment in both immunocompetent and immunocompromised hosts, T-cell immunity was essential for suppressing the outgrowth of drug-resistant leukemia. Bulk and single-cell transcriptome profiling of T cells during therapy pointed to the activation of type 1 immunity-related cytokine signaling being linked to long-term leukemia remission in mice. Consistent with these observations, interferon γ and interleukin 12 directly modulated dasatinib antileukemia efficacy in vivo. Finally, we evaluated peripheral blood immune cell composition in 102 children with ALL during chemotherapy and observed a significant association of T-cell abundance with treatment outcomes. Together, these results suggest that T-cell immunity plays pivotal roles in maintaining long-term remission of ALL, highlighting that the interplay between host immunity and drug resistance can be harnessed to improve ALL chemotherapy outcomes.
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Affiliation(s)
- Yizhen Li
- Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
| | - Xu Yang
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN
| | - Yu Sun
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
| | - Zhenhua Li
- Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
| | - Wenjian Yang
- Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
| | - Bensheng Ju
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN
| | - John Easton
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN
| | - Deqing Pei
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
| | - Cheng Cheng
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN
| | - Shawn Lee
- Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ching-Hon Pui
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN
- Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN
| | - Jiyang Yu
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN
| | - Hongbo Chi
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
| | - Jun J Yang
- Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN
- Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN
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25
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Keshavarz A, Salehi A, Khosravi S, Shariati Y, Nasrabadi N, Kahrizi MS, Maghsoodi S, Mardi A, Azizi R, Jamali S, Fotovat F. Recent findings on chimeric antigen receptor (CAR)-engineered immune cell therapy in solid tumors and hematological malignancies. Stem Cell Res Ther 2022; 13:482. [PMID: 36153626 PMCID: PMC9509604 DOI: 10.1186/s13287-022-03163-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 08/12/2022] [Indexed: 11/10/2022] Open
Abstract
Advancements in adoptive cell therapy over the last four decades have revealed various new therapeutic strategies, such as chimeric antigen receptors (CARs), which are dedicated immune cells that are engineered and administered to eliminate cancer cells. In this context, CAR T-cells have shown significant promise in the treatment of hematological malignancies. However, many obstacles limit the efficacy of CAR T-cell therapy in both solid tumors and hematological malignancies. Consequently, CAR-NK and CAR-M cell therapies have recently emerged as novel therapeutic options for addressing the challenges associated with CAR T-cell therapies. Currently, many CAR immune cell trials are underway in various human malignancies around the world to improve antitumor activity and reduce the toxicity of CAR immune cell therapy. This review will describe the comprehensive literature of recent findings on CAR immune cell therapy in a wide range of human malignancies, as well as the challenges that have emerged in recent years.
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Affiliation(s)
- Ali Keshavarz
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Salehi
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Islamic Azad University,, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Setareh Khosravi
- Department of Orthodontics, School of Dentistry, Alborz University of Medical Sciences, Karaj, Iran
| | - Yasaman Shariati
- Department of General Surgery, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Navid Nasrabadi
- Department of Endodontics, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Sairan Maghsoodi
- Department of Paramedical, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Amirhossein Mardi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramyar Azizi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samira Jamali
- Department of Endodontics, College of Stomatology, Stomatological Hospital, Xi’an Jiaotong University, Shaanxi, People’s Republic of China
| | - Farnoush Fotovat
- Department of Prosthodontics, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran
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26
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Jia Z, Ragoonanan D, Mahadeo KM, Gill J, Gorlick R, Shpal E, Li S. IL12 immune therapy clinical trial review: Novel strategies for avoiding CRS-associated cytokines. Front Immunol 2022; 13:952231. [PMID: 36203573 PMCID: PMC9530253 DOI: 10.3389/fimmu.2022.952231] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/29/2022] [Indexed: 11/24/2022] Open
Abstract
Interleukin 12 (IL-12) is a naturally occurring cytokine that plays a key role in inducing antitumor immune responses, including induction of antitumor immune memory. Currently, no IL-12-based therapeutic products have been approved for clinical application because of its toxicities. On the basis of this review of clinical trials using primarily wild-type IL-12 and different delivery methods, we conclude that the safe utilization of IL-12 is highly dependent on the tumor-specific localization of IL-12 post administration. In this regard, we have developed a cell membrane-anchored and tumor-targeted IL-12-T (attIL12-T) cell product for avoiding toxicity from both IL-12 and T cells-induced cytokine release syndrome in peripheral tissues. A phase I trial using this product which seeks to avoid systemic toxicity and boost antitumor efficacy is on the horizon. Of note, this product also boosts the impact of CAR-T or TCR-T cell efficacy against solid tumors, providing an alternative approach to utilize CAR-T to overcome tumor resistance.
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Affiliation(s)
- Zhiliang Jia
- Department of Pediatric Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Dristhi Ragoonanan
- Department of Pediatric Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Kris Michael Mahadeo
- Department of Pediatric Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jonathan Gill
- Department of Pediatric Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Richard Gorlick
- Department of Pediatric Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizabeth Shpal
- Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Shulin Li
- Department of Pediatric Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States,*Correspondence: Shulin Li,
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27
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Karam A, Mjaess G, Martinez Chanza N, Aoun F, Bou Kheir G, Younes H, Kazzi H, Albisinni S, Roumeguère T. CAR-T cell therapy for solid tumors: are we still that far? A systematic review of literature. Cancer Invest 2022; 40:923-937. [DOI: 10.1080/07357907.2022.2125004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
- Aya Karam
- Hotel-Dieu de France, University of Saint Joseph, Faculty of Medicine, Beirut, Lebanon
| | - Georges Mjaess
- Department of Urology, Hôpital Universitaire de Bruxelles, Hôpital Érasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Nieves Martinez Chanza
- Department of Medical Oncology, Hôpital Universitaire de Bruxelles, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Fouad Aoun
- Hotel-Dieu de France, University of Saint Joseph, Faculty of Medicine, Beirut, Lebanon
| | - George Bou Kheir
- Department of Urology, Hôpital Universitaire de Bruxelles, Hôpital Érasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Hadi Younes
- Hotel-Dieu de France, University of Saint Joseph, Faculty of Medicine, Beirut, Lebanon
| | - Hanane Kazzi
- Department of Radiology, Saint Joseph Medical Center, Beirut, Lebanon
| | - Simone Albisinni
- Department of Urology, Hôpital Universitaire de Bruxelles, Hôpital Érasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Thierry Roumeguère
- Department of Urology, Hôpital Universitaire de Bruxelles, Hôpital Érasme, Université Libre de Bruxelles, Brussels, Belgium
- Department of Urology, Hôpital Universitaire de Bruxelles, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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28
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Ren P, Zhang C, Li W, Wang X, Liang A, Yang G, Xu H, Ma P. CAR-T Therapy in Clinical Practice: Technical Advances and Current Challenges. Adv Biol (Weinh) 2022; 6:e2101262. [PMID: 35652169 DOI: 10.1002/adbi.202101262] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 03/22/2022] [Indexed: 01/28/2023]
Abstract
Chimeric antigen receptors (CAR) redirect T cells to specifically recognize and eliminate tumor cells. CAR-T therapy has achieved successful clinical outcomes, and it has been transformed into commercially available products to treat acute lymphoblastic leukemia and B cell lymphoma. These breakthroughs have motivated hundreds of CAR-T clinical trials initiated each year, with ≈900 cases registered on the ClinicalTrials website till 2021. Accumulating clinical experiences have highlighted some limitations of this strategy, e.g., relapse after complete response, poor efficacy in solid tumors, on-target off-tumor toxicities, lack of persistence, and tumor resistance. These challenges limit the therapeutic application of CAR-T cells. Multidisciplinary approaches are actively investigated to address these issues. In this review, the antigens, CAR designs, and cell sources are summarized in clinical trials from 2020 to 2021. The innovative modular and programmable designs in CAR-T cells, including advances in signaling domains, antigen-recognition domains, T cell engineering, and cell resources, are further discussed. Integrative genetic and chemical engineering strategies are promising to improve the versatility, antitumor efficacy, persistence, and safety of CAR-T cells. In the future, the next generation of CAR-T cell therapies will offer more options for patients who are refractory to standard tumor therapies.
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Affiliation(s)
- Ping Ren
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, 201210, P. R. China
| | - Chuyue Zhang
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, 201210, P. R. China
| | - Wenping Li
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, 201210, P. R. China
| | - Xian Wang
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, 201210, P. R. China
| | - Aibing Liang
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, P. R. China
| | - Guang Yang
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, 201210, P. R. China
| | - Hongtao Xu
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, 201210, P. R. China
| | - Peixiang Ma
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.,Zhejiang Laboratory, Hangzhou, Zhejiang, 311121, P. R. China
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29
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Liu K, Zhao S, Li J, Zheng Y, Wu H, Kong J, Shen Z. Knowledge mapping and research hotspots of immunotherapy in renal cell carcinoma: A text-mining study from 2002 to 2021. Front Immunol 2022; 13:969217. [PMID: 35967367 PMCID: PMC9367473 DOI: 10.3389/fimmu.2022.969217] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 07/06/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Renal cell carcinoma (RCC) is one of the most lethal urological malignancies, and because early-stage RCC is asymptomatic, many patients present metastatic diseases at first diagnosis. With the development of immunotherapy, the treatment of RCC has entered a new stage and has made a series of progress. This study mainly outlines the knowledge map and detects the potential research hotspots by using bibliometric analysis. METHODS Publications concerning RCC immunotherapy from 2002 to 2021 in the Web of Science Core Collection were collected. Visualization and statistical analysis were mainly performed by freeware tools VOSviewer, CiteSpace, R software, and Microsoft Office Excel 2019. RESULTS A total of 3,432 papers were collected in this study, and the annual number of papers and citations showed a steady growth trend. The United States is the leading country with the most high-quality publications and is also the country with the most international cooperation. The University of Texas MD Anderson Cancer Center is the most productive organization. The Journal of Clinical Oncology is the highest co-cited journal, and Brian I. Rini is both the most prolific author and the author with the largest centrality. The current research hotspots may be focused on "immune checkpoint inhibitors (ICIs)," "PD-1," and "mammalian target of rapamycin." CONCLUSION Immunotherapy has a bright future in the field of RCC treatment, among which ICIs are one of the most important research hotspots. The main future research directions of ICI-based immunotherapy may focus on combination therapy, ICI monotherapy, and the development of new predictive biomarkers.
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Affiliation(s)
- Kun Liu
- Department of Urology, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, China
| | - Seling Zhao
- Department of Urology, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, China
| | - Jian Li
- Department of Urology, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, China
| | - Yikun Zheng
- Department of Urology, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, China
| | - Haiyang Wu
- Graduate School of Tianjin Medical University, Tianjin, China
| | - Jianqiu Kong
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China
| | - Zefeng Shen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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30
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Sun J, Li X, Chen P, Gao Y. From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer. J Inflamm Res 2022; 15:4061-4085. [PMID: 35873388 PMCID: PMC9304417 DOI: 10.2147/jir.s368138] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 06/29/2022] [Indexed: 11/23/2022] Open
Abstract
Current Therapeutic modalities provide no survival advantage to gastric cancer (GC) patients. Targeting the human epidermal growth factor receptor-2 (HER-2) is a viable therapeutic strategy against advanced HER-2 positive GC. Antibody-drug conjugates, small-molecule tyrosine kinase inhibitors (TKIs), and bispecific antibodies are emerging as novel drug forms that may abrogate the resistance to HER-2-specific drugs and monoclonal antibodies. Chimeric antigen receptor-modified T cells (CAR-T) targeting HER-2 have shown considerable therapeutic potential in GC and other solid tumors. However, due to the high heterogeneity along with the complex tumor microenvironment (TME) of GC that often leads to immune escape, the immunological treatment of GC still faces many challenges. Here, we reviewed and discussed the current progress in the research of anti-HER-2-CAR-T cell immunotherapy against GC.
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Affiliation(s)
- Jiangang Sun
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Xiaojing Li
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Peng Chen
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Yongshun Gao
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
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31
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Sorieul C, Papi F, Carboni F, Pecetta S, Phogat S, Adamo R. Recent advances and future perspectives on carbohydrate-based cancer vaccines and therapeutics. Pharmacol Ther 2022; 235:108158. [PMID: 35183590 DOI: 10.1016/j.pharmthera.2022.108158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 01/30/2022] [Accepted: 02/14/2022] [Indexed: 12/13/2022]
Abstract
Carbohydrates are abundantly expressed on the surface of both eukaryotic and prokaryotic cells, often as post translational modifications of proteins. Glycoproteins are recognized by the immune system and can trigger both innate and humoral responses. This feature has been harnessed to generate vaccines against polysaccharide-encapsulated bacteria such as Streptococcus pneumoniae, Hemophilus influenzae type b and Neisseria meningitidis. In cancer, glycosylation plays a pivotal role in malignancy development and progression. Since glycans are specifically expressed on the surface of tumor cells, they have been targeted for the discovery of anticancer preventive and therapeutic treatments, such as vaccines and monoclonal antibodies. Despite the various efforts made over the last years, resulting in a series of clinical studies, attempts of vaccination with carbohydrate-based candidates have proven unsuccessful, primarily due to the immune tolerance often associated with these glycans. New strategies are thus deployed to enhance carbohydrate-based cancer vaccines. Moreover, lessons learned from glycan immunobiology paved the way to the development of new monoclonal antibodies specifically designed to recognize cancer-bound carbohydrates and induce tumor cell killing. Herein we provide an overview of the immunological principles behind the immune response towards glycans and glycoconjugates and the approaches exploited at both preclinical and clinical level to target cancer-associated glycans for the development of vaccines and therapeutic monoclonal antibodies. We also discuss gaps and opportunities to successfully advance glycan-directed cancer therapies, which could provide patients with innovative and effective treatments.
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32
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Bashiri Dezfouli A, Yazdi M, Benmebarek MR, Schwab M, Michaelides S, Miccichè A, Geerts D, Stangl S, Klapproth S, Wagner E, Kobold S, Multhoff G. CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells. Front Immunol 2022; 13:883694. [PMID: 35720311 PMCID: PMC9198541 DOI: 10.3389/fimmu.2022.883694] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 05/02/2022] [Indexed: 11/25/2022] Open
Abstract
Strategies to boost anti-tumor immunity are urgently needed to treat therapy-resistant late-stage cancers, including colorectal cancers (CRCs). Cytokine stimulation and genetic modifications with chimeric antigen receptors (CAR) represent promising strategies to more specifically redirect anti-tumor activities of effector cells like natural killer (NK) and T cells. However, these approaches are critically dependent on tumor-specific antigens while circumventing the suppressive power of the solid tumor microenvironment and avoiding off-tumor toxicities. Previously, we have shown that the stress-inducible heat shock protein 70 (Hsp70) is frequently and specifically expressed on the cell surface of many different, highly aggressive tumors but not normal tissues. We could take advantage of tumors expressing Hsp70 on their membrane (‘mHsp70’) to attract and engage NK cells after in vitro stimulation with the 14-mer Hsp70 peptide TKDNNLLGRFELSG (TKD) plus low dose interleukin (IL)-2. However, a potential limitation of activated primary NK cells after adoptive transfer is their comparably short life span. T cells are typically long-lived but do not recognize mHsp70 on tumor cells, even after stimulation with TKD/IL-2. To combine the advantages of mHsp70-specificity with longevity, we constructed a CAR having specificity for mHsp70 and retrovirally transduced it into primary T cells. Co-culture of anti-Hsp70 CAR-transduced T cells with mHsp70-positive tumor cells stimulates their functional responsiveness. Herein, we demonstrated that human CRCs with a high mHsp70 expression similarly attract TKD/IL-2 stimulated NK cells and anti-Hsp70 CAR T cells, triggering the release of their lytic effector protein granzyme B (GrB) and the pro-inflammatory cytokine interferon (IFN)-γ, after 4 and 24 hours, respectively. In sum, stimulated NK cells and anti-Hsp70 CAR T cells demonstrated comparable anti-tumor effects, albeit with somewhat differing kinetics. These findings, together with the fact that mHsp70 is expressed on a large variety of different cancer entities, highlight the potential of TKD/IL-2 pre-stimulated NK, as well as anti-Hsp70 CAR T cells to provide a promising direction in the field of targeted, cell-based immunotherapies which can address significant unmet clinical needs in a wide range of cancer settings.
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Affiliation(s)
- Ali Bashiri Dezfouli
- Central Institute for Translational Cancer Research Technische Universität München (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich, Germany
| | - Mina Yazdi
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität (LMU), Munich, Germany
| | - Mohamed-Reda Benmebarek
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research Deutsches Zentrum für Lungenforschung (DZL), Munich, Germany
| | - Melissa Schwab
- Central Institute for Translational Cancer Research Technische Universität München (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich, Germany
| | - Stefanos Michaelides
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research Deutsches Zentrum für Lungenforschung (DZL), Munich, Germany
| | | | | | - Stefan Stangl
- Central Institute for Translational Cancer Research Technische Universität München (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich, Germany.,Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany
| | - Sarah Klapproth
- Institute of Experimental Hematology, Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität (LMU), Munich, Germany
| | - Sebastian Kobold
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research Deutsches Zentrum für Lungenforschung (DZL), Munich, Germany.,German Center for Translational Cancer Research Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, Germany
| | - Gabriele Multhoff
- Central Institute for Translational Cancer Research Technische Universität München (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich, Germany
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Safarzadeh Kozani P, Safarzadeh Kozani P, Rahbarizadeh F. CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success? Front Med 2022; 16:322-338. [PMID: 35687277 DOI: 10.1007/s11684-021-0901-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 09/23/2021] [Indexed: 11/04/2022]
Abstract
Immune-based therapies have experienced a pronounced breakthrough in the past decades as they acquired multiple US Food and Drug Administration (FDA) approvals for various indications. To date, six chimeric antigen receptor T cell (CAR-T) therapies have been permitted for the treatment of certain patients with relapsed/refractory hematologic malignancies. However, several clinical trials of solid tumor CAR-T therapies were prematurely terminated, or they reported life-threatening treatment-related damages to healthy tissues. The simultaneous expression of target antigens by healthy organs and tumor cells is partly responsible for such toxicities. Alongside targeting tumor-specific antigens, targeting the aberrantly glycosylated glycoforms of tumor-associated antigens can also minimize the off-tumor effects of CAR-T therapies. Tn, T, and sialyl-Tn antigens have been reported to be involved in tumor progression and metastasis, and their expression results from the dysregulation of a series of glycosyltransferases and the endoplasmic reticulum protein chaperone, Cosmc. Moreover, these glycoforms have been associated with various types of cancers, including prostate, breast, colon, gastric, and lung cancers. Here, we discuss how underglycosylated antigens emerge and then detail the latest advances in the development of CAR-T-based immunotherapies that target some of such antigens.
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Affiliation(s)
- Pooria Safarzadeh Kozani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, P.O. Box 14115/111, Iran
| | - Pouya Safarzadeh Kozani
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, P.O. Box 44771/66595, Iran
| | - Fatemeh Rahbarizadeh
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, P.O. Box 14115/111, Iran. .,Research and Development Center of Biotechnology, Tarbiat Modares University, Tehran, P.O. Box 14115/111, Iran.
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Leite-Gomes E, Dias AM, Azevedo CM, Santos-Pereira B, Magalhães M, Garrido M, Amorim R, Lago P, Marcos-Pinto R, Pinho SS. Bringing to Light the Risk of Colorectal Cancer in Inflammatory Bowel Disease: Mucosal Glycosylation as a Key Player. Inflamm Bowel Dis 2022; 28:947-962. [PMID: 34849933 DOI: 10.1093/ibd/izab291] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Colitis-associated cancer is a major complication of inflammatory bowel disease remaining an important clinical challenge in terms of diagnosis, screening, and prognosis. Inflammation is a driving factor both in inflammatory bowel disease and cancer, but the mechanism underlying the transition from colon inflammation to cancer remains to be defined. Dysregulation of mucosal glycosylation has been described as a key regulatory mechanism associated both with colon inflammation and colorectal cancer development. In this review, we discuss the major molecular mechanisms of colitis-associated cancer pathogenesis, highlighting the role of glycans expressed at gut epithelial cells, at lamina propria T cells, and in serum proteins in the regulation of intestinal inflammation and its progression to colon cancer, further discussing its potential clinical and therapeutic applications.
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Affiliation(s)
- Eduarda Leite-Gomes
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Ana M Dias
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Catarina M Azevedo
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Beatriz Santos-Pereira
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Mariana Magalhães
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Mónica Garrido
- Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Rita Amorim
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,Pediatrics Department, Centro Hospitalar e Universitário São João, Porto, Portugal.,Medical Faculty, University of Porto, Porto, Portugal
| | - Paula Lago
- Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal
| | - Ricardo Marcos-Pinto
- Department of Gastroenterology, Centro Hospitalar e Universitário do Porto, Porto, Portugal.,School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,Centre for Research in Health Technologies and Information Systems, University of Porto, Portugal
| | - Salomé S Pinho
- i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.,School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.,Medical Faculty, University of Porto, Porto, Portugal
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Guerrero-Ochoa P, Ibáñez-Pérez R, Berbegal-Pinilla G, Aguilar D, Marzo I, Corzana F, Minjárez-Sáenz M, Macías-León J, Conde B, Raso J, Hurtado-Guerrero R, Anel A. Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment. Biomedicines 2022; 10:biomedicines10061223. [PMID: 35740244 PMCID: PMC9219680 DOI: 10.3390/biomedicines10061223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/20/2022] [Accepted: 05/20/2022] [Indexed: 01/27/2023] Open
Abstract
Two granulysin (GRNLY) based immunotoxins were generated, one containing the scFv of the SM3 mAb (SM3GRNLY) and the other the scFv of the AR20.5 mAb (AR20.5GRNLY). These mAb recognize different amino acid sequences of aberrantly O-glycosylated MUC1, also known as the Tn antigen, expressed in a variety of tumor cell types. We first demonstrated the affinity of these immunotoxins for their antigen using surface plasmon resonance for the purified antigen and flow cytometry for the antigen expressed on the surface of living tumor cells. The induction of cell death of tumor cell lines of different origin positive for Tn antigen expression was stronger in the cases of the immunotoxins than that induced by GRNLY alone. The mechanism of cell death induced by the immunotoxins was studied, showing that the apoptotic component demonstrated previously for GRNLY was also present, but that cell death induced by the immunotoxins included also necroptotic and necrotic components. Finally, we demonstrated the in vivo tumor targeting by the immunotoxins after systemic injection using a xenograft model of the human pancreatic adenocarcinoma CAPAN-2 in athymic mice. While GRNLY alone did not have a therapeutic effect, SM3GRNLY and AR20.5GRNLY reduced tumor volume by 42 and 60%, respectively, compared with untreated tumor-bearing mice, although the results were not statistically significant in the case of AR20.5GRNLY. Histological studies of tumors obtained from treated mice demonstrated reduced cellularity, nuclear morphology compatible with apoptosis induction and active caspase-3 detection by immunohistochemistry. Overall, our results exemplify that these immunotoxins are potential drugs to treat Tn-expressing cancers.
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Affiliation(s)
- Patricia Guerrero-Ochoa
- Apoptosis, Immunity and Cancer Group, Aragón Health Research Institute (IIS-Aragón), University of Zaragoza, 50009 Zaragoza, Spain; (P.G.-O.); (R.I.-P.); (G.B.-P.); (I.M.); (B.C.)
| | - Raquel Ibáñez-Pérez
- Apoptosis, Immunity and Cancer Group, Aragón Health Research Institute (IIS-Aragón), University of Zaragoza, 50009 Zaragoza, Spain; (P.G.-O.); (R.I.-P.); (G.B.-P.); (I.M.); (B.C.)
| | - Germán Berbegal-Pinilla
- Apoptosis, Immunity and Cancer Group, Aragón Health Research Institute (IIS-Aragón), University of Zaragoza, 50009 Zaragoza, Spain; (P.G.-O.); (R.I.-P.); (G.B.-P.); (I.M.); (B.C.)
| | - Diederich Aguilar
- Department of Food Technology, Facultad de Veterinaria, Instituto Agroalimentario de Aragón-IA2, Universidad de Zaragoza-CITA, 50013 Zaragoza, Spain; (D.A.); (J.R.)
| | - Isabel Marzo
- Apoptosis, Immunity and Cancer Group, Aragón Health Research Institute (IIS-Aragón), University of Zaragoza, 50009 Zaragoza, Spain; (P.G.-O.); (R.I.-P.); (G.B.-P.); (I.M.); (B.C.)
| | - Francisco Corzana
- Research Center for Chemical Synthesis, Department of Chemistry, University of La Rioja, 26006 Logroño, Spain;
| | - Martha Minjárez-Sáenz
- Biocomputation and Physics of Complex Systems Institute (BIFI), University of Zaragoza, 50018 Zaragoza, Spain; (M.M.-S.); (J.M.-L.); (R.H.-G.)
| | - Javier Macías-León
- Biocomputation and Physics of Complex Systems Institute (BIFI), University of Zaragoza, 50018 Zaragoza, Spain; (M.M.-S.); (J.M.-L.); (R.H.-G.)
| | - Blanca Conde
- Apoptosis, Immunity and Cancer Group, Aragón Health Research Institute (IIS-Aragón), University of Zaragoza, 50009 Zaragoza, Spain; (P.G.-O.); (R.I.-P.); (G.B.-P.); (I.M.); (B.C.)
| | - Javier Raso
- Department of Food Technology, Facultad de Veterinaria, Instituto Agroalimentario de Aragón-IA2, Universidad de Zaragoza-CITA, 50013 Zaragoza, Spain; (D.A.); (J.R.)
| | - Ramón Hurtado-Guerrero
- Biocomputation and Physics of Complex Systems Institute (BIFI), University of Zaragoza, 50018 Zaragoza, Spain; (M.M.-S.); (J.M.-L.); (R.H.-G.)
- ARAID Foundation, University of Zaragoza, 50018 Zaragoza, Spain
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
- Laboratorio de Microscopías Avanzada (LMA), University of Zaragoza, 50018 Zaragoza, Spain
| | - Alberto Anel
- Apoptosis, Immunity and Cancer Group, Aragón Health Research Institute (IIS-Aragón), University of Zaragoza, 50009 Zaragoza, Spain; (P.G.-O.); (R.I.-P.); (G.B.-P.); (I.M.); (B.C.)
- Correspondence: ; Tel.: +34-976-761279; Fax: +34-976-762123
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Liu K, Cui JJ, Zhan Y, Ouyang QY, Lu QS, Yang DH, Li XP, Yin JY. Reprogramming the tumor microenvironment by genome editing for precision cancer therapy. Mol Cancer 2022; 21:98. [PMID: 35410257 PMCID: PMC8996591 DOI: 10.1186/s12943-022-01561-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/11/2022] [Indexed: 12/12/2022] Open
Abstract
The tumor microenvironment (TME) is essential for immune escape by tumor cells. It plays essential roles in tumor development and metastasis. The clinical outcomes of tumors are often closely related to individual differences in the patient TME. Therefore, reprogramming TME cells and their intercellular communication is an attractive and promising strategy for cancer therapy. TME cells consist of immune and nonimmune cells. These cells need to be manipulated precisely and safely to improve cancer therapy. Furthermore, it is encouraging that this field has rapidly developed in recent years with the advent and development of gene editing technologies. In this review, we briefly introduce gene editing technologies and systematically summarize their applications in the TME for precision cancer therapy, including the reprogramming of TME cells and their intercellular communication. TME cell reprogramming can regulate cell differentiation, proliferation, and function. Moreover, reprogramming the intercellular communication of TME cells can optimize immune infiltration and the specific recognition of tumor cells by immune cells. Thus, gene editing will pave the way for further breakthroughs in precision cancer therapy.
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Zhang PF, Wang C, Zhang L, Li Q. Reversing chemokine/chemokine receptor mismatch to enhance the antitumor efficacy of CAR-T cells. Immunotherapy 2022; 14:459-473. [PMID: 35232284 DOI: 10.2217/imt-2021-0228] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Currently, the antitumor efficacy of chimeric antigen receptor T cells in solid tumors is modest. Both chemokines and their receptors play a key role in the proliferation of cancer cells, tumor angiogenesis, organ-selective metastasis and migration of immune cells to solid tumors. Unfortunately, frequent chemokine/chemokine receptor 'mismatch' between effector cells and the tumor microenvironment results in inefficient T-cell infiltration and antitumor efficacy. Thus, reversing the 'mismatch' of chemokines and chemokine receptors appears to be a promising method for promoting T-cell infiltration into the tumor and enhancing their antitumor efficacy. In this review, we discuss functions of the chemokine/chemokine receptor axis in cancer immunity and the current understanding, challenges and prospects for improving the effect of chimeric antigen receptor T cells by reversing the mismatch between chemokines and chemokine receptors.
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Affiliation(s)
- Peng-Fei Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.,Laboratory of Human Diseases & Immunotherapies, West China Hospital, Sichuan University, Chengdu, 610041, China.,Institute of Immunology & Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chuang Wang
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.,Laboratory of Human Diseases & Immunotherapies, West China Hospital, Sichuan University, Chengdu, 610041, China.,Institute of Immunology & Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Le Zhang
- College of Computer Science, Sichuan University, Chengdu, 610065, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
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Shi X, Wu H. Recent advances in the prevention and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. EUR J INFLAMM 2022. [DOI: 10.1177/1721727x221078727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Adoptive immunotherapy has recently garnered widespread interests owing to the successful application of chimeric antigen receptor T cell therapy. CAR-T cells are “living drugs” that can live in patients for several years and act as an effective antitumor agent. Over the last few years, five types of CAR-T cells have been approved by Food and Drug Administration (FDA) for treatment of hematologic malignancies. Despite their impressive clinical efficacy, the current application of CAR-T cell therapy is restricted by the uncontrollable release of cytokines (cytokine release syndrome and cytokine release syndrome) due to serious treatment-related toxicities resulting from synchronous activation and rapid proliferation of CAR-T cells. CRS is the most common toxicity and its severity can range from low-grade physical symptoms to a high-grade syndrome linked with life-threatening multiple organ dysfunction. Treatment-related deaths from severe CRS have been reported, suggesting the importance of appropriate intervention. Gaining a better understanding of CRS and developing new treatments for CRS are active areas of laboratory and clinical research. Herein, we summarize the current studies on prevention and management of CRS to expand the safety and applicability of CAR-T cell therapy in various malignancies.
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Affiliation(s)
- Xiaoxue Shi
- Affiliated Hospital of Hebei Engineering University, Hebei Province, Handan, China
| | - Hongfang Wu
- Affiliated Hospital of Hebei Engineering University, Hebei Province, Handan, China
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Mehrabadi AZ, Ranjbar R, Farzanehpour M, Shahriary A, Dorostkar R, Hamidinejad MA, Ghaleh HEG. Therapeutic potential of CAR T cell in malignancies: A scoping review. Biomed Pharmacother 2022; 146:112512. [PMID: 34894519 DOI: 10.1016/j.biopha.2021.112512] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/20/2021] [Accepted: 12/06/2021] [Indexed: 02/08/2023] Open
Abstract
Although tremendous advancements in cancer therapy over the last several years, cancer still is a complex illness to cure. Traditional cancer treatments, including chemotherapy, radiotherapy, and surgery, have a poor therapeutic effect, emphasizing the significance of employing innovative treatments like activated cell therapy. Chimeric antigen receptor T cell is one of the most prevalent types of activated cell therapy have been developed to direct T lymphocytes toward cancers (CAR-T cells). CAR-T cells therapy has illustrated poor impact versus solid tumors despite the remarkable success in patients suffering from hematological malignancies. CAR-T cells must overcome various hurdles to obtain full responses to solid tumors, including growth, stability, trafficking, and destiny inside tumors. As a result, novel treatment methods will entail overcoming the challenges that CAR-T cells face in solid tumors. The use of CAR-T cells in combination with other therapeutic approaches such as chemotherapy, radiotherapy, immuno-checkpoint inhibitors, and oncolytic viruses can promote the effectiveness of CAR-T cell therapy for the treatment of solid tumors. However, more research is needed to determine the safety and effectiveness of these therapies. CAR-T cell treatment success rates vary by type of disease, but are predicted to reach up to 90% in patients with leukemia. However, since this kind of immunotherapy is still in its infancy, there is much to learn about its efficacy. This review provided an in-depth examination of CAR-T cell therapy and its success and failure as a cancer treatment approach. We also discuss combination therapies with CAR-T Cell.
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Affiliation(s)
| | - Reza Ranjbar
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahdieh Farzanehpour
- Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Alireza Shahriary
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ruhollah Dorostkar
- Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Hamidinejad
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
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Berois N, Pittini A, Osinaga E. Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives. Cancers (Basel) 2022; 14:cancers14030645. [PMID: 35158915 PMCID: PMC8833780 DOI: 10.3390/cancers14030645] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Aberrant glycosylation is a common feature of many cancers, and it plays crucial roles in tumor development and biology. Cancer progression can be regulated by several physiopathological processes controlled by glycosylation, such as cell–cell adhesion, cell–matrix interaction, epithelial-to-mesenchymal transition, tumor proliferation, invasion, and metastasis. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs), which are suitable for selective cancer targeting, as well as novel antitumor immunotherapy approaches. This review summarizes the strategies developed in cancer immunotherapy targeting TACAs, analyzing molecular and cellular mechanisms and state-of-the-art methods in clinical oncology. Abstract Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.
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Affiliation(s)
- Nora Berois
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay;
- Correspondence: (N.B.); (E.O.)
| | - Alvaro Pittini
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay;
- Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
| | - Eduardo Osinaga
- Laboratorio de Glicobiología e Inmunología Tumoral, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay;
- Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay
- Correspondence: (N.B.); (E.O.)
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Zhang T, Wang T, You F, Li Z, Chen D, Zhang K, Tian S, Sheng B, Wu H, Jiang L, Ma R, An G, Meng H, Yang L. Nanobody-based anti-CD22-chimeric antigen receptor T cell immunotherapy exhibits improved remission against B-cell acute lymphoblastic leukemia. Transpl Immunol 2022; 71:101538. [PMID: 35051588 DOI: 10.1016/j.trim.2022.101538] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 10/19/2022]
Abstract
Chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 can achieve impressive clinical remission rates in the treatment of B-cell non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia. However, relapse after CD19-CAR T treatment remains a major issue, with CD19 antigen-negative relapse being one of the main reasons. CD22, another antigen expressed in a B-cell lineage-specific pattern, is retained following CD19 loss. Accordingly, we hypothesized that CD22 could represent an alternative target to alleviate or compensate for the ineffectiveness of CD19-CAR T therapy. To this end, we generated camelid-derived CD22 nanobodies, whose smaller size, greater stability, and lower immunogenicity offer better quality than classical antibodies, and we used them to construct third-generation CD22-CARs containing 4-1BB and ICOS co-stimulatory domains. The novel CD22-CAR T cells exhibited impressive cytotoxicity both in vitro and in vivo and significantly prolonged the overall survival of tumor-bearing NSG mice. These findings provide the basis for further translational studies employing CD22-CARs.
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Affiliation(s)
- Tingting Zhang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Tian Wang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Fengtao You
- PersonGen BioTherapeutics Co., Ltd., Suzhou, PR China
| | - Zixuan Li
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Dan Chen
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Kailu Zhang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Shuaiyu Tian
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Binjie Sheng
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Hai Wu
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Licui Jiang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Renyuxue Ma
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Gangli An
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Huimin Meng
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China
| | - Lin Yang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China; PersonGen BioTherapeutics Co., Ltd., Suzhou, PR China.
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Hanssens H, Meeus F, De Veirman K, Breckpot K, Devoogdt N. The antigen-binding moiety in the driver's seat of CARs. Med Res Rev 2022; 42:306-342. [PMID: 34028069 PMCID: PMC9292017 DOI: 10.1002/med.21818] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 02/17/2021] [Accepted: 04/21/2021] [Indexed: 12/16/2022]
Abstract
Immuno-oncology has been at the forefront of cancer treatment in recent decades. In particular immune checkpoint and chimeric antigen receptor (CAR)-T cell therapy have achieved spectacular results. Over the years, CAR-T cell development has followed a steady evolutionary path, focusing on increasing T cell potency and sustainability, which has given rise to different CAR generations. However, there was less focus on the mode of interaction between the CAR-T cell and the cancer cell; more specifically on the targeting moiety used in the CAR and its specific properties. Recently, the importance of optimizing this domain has been recognized and the possibilities have been exploited. Over the last 10 years-in addition to the classical scFv-based CARs-single domain CARs, natural receptor-ligand CARs, universal CARs and CARs targeting more than one antigen have emerged. In addition, the specific parameters of the targeting domain and their influence on T cell activation are being examined. In this review, we concisely present the history of CAR-T cell therapy, and then expand on various developments in the CAR ectodomain. We discuss different formats, each with their own advantages and disadvantages, as well as the developments in affinity tuning, avidity effects, epitope location, and influence of the extracellular spacer.
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Affiliation(s)
- Heleen Hanssens
- In Vivo Cellular and Molecular Imaging LaboratoryVrije Universiteit BrusselBrusselsBelgium
- Laboratory of Hematology and ImmunologyVrije Universiteit BrusselBrusselsBelgium
- Laboratory for Molecular and Cellular Therapy, Department of Biomedical SciencesVrije Universiteit BrusselBrusselsBelgium
| | - Fien Meeus
- In Vivo Cellular and Molecular Imaging LaboratoryVrije Universiteit BrusselBrusselsBelgium
- Laboratory for Molecular and Cellular Therapy, Department of Biomedical SciencesVrije Universiteit BrusselBrusselsBelgium
| | - Kim De Veirman
- Laboratory of Hematology and ImmunologyVrije Universiteit BrusselBrusselsBelgium
| | - Karine Breckpot
- Laboratory for Molecular and Cellular Therapy, Department of Biomedical SciencesVrije Universiteit BrusselBrusselsBelgium
| | - Nick Devoogdt
- In Vivo Cellular and Molecular Imaging LaboratoryVrije Universiteit BrusselBrusselsBelgium
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Wu G, Li L, Qiu Y, Sun W, Ren T, Lv Y, Liu M, Wang X, Tao H, Zhao L, Cao J, He L, Li H, Gu H. A novel humanized MUC1 antibody-drug conjugate for the treatment of trastuzumab-resistant breast cancer. Acta Biochim Biophys Sin (Shanghai) 2021; 53:1625-1639. [PMID: 34586349 DOI: 10.1093/abbs/gmab141] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Indexed: 01/10/2023] Open
Abstract
Mucin 1 (MUC1) has been regarded as an ideal target for cancer treatment, since it is overexpressed in a variety of different cancers including the majority of breast cancer. However, there are still no approved monoclonal antibody drugs targeting MUC1. In this study, we generated a humanized MUC1 (HzMUC1) antibody from our previously developed MUC1 mouse monoclonal antibody that only recognizes MUC1 on the surface of tumor cells. Furthermore, an antibody-drug conjugate (ADC) was generated by conjugating HzMUC1 with monomethyl auristatin (MMAE), and the efficacy of HzMUC1-MMAE on the MUC1-positive HER2+ breast cancer in vitro and in 'Xenograft' model was tested. Results from western blot analysis and immunoprecipitation revealed that the HzMUC1 antibody did not recognize cell-free MUC1-N in sera from breast cancer patients. Confocal microscopy analysis showed that HzMUC1 antibody bound to MUC1 on the surface of breast cancer cells. Results from mapping experiments suggested that HzMUC1 may recognize an epitope present in the interaction region between MUC1-N and MUC1-C. Results from colony formation assay and flow cytometry demonstrated that HzMUC1-MMAE significantly inhibited cell growth by inducing G2/M cell cycle arrest and apoptosis in trastuzumab-resistant HER2-positive breast cancer cells. Meanwhile, HzMUC1-MMAE significantly reduced the growth of HCC1954 xenograft tumors by inhibiting cell proliferation and enhancing cell death. In conclusion, our results indicate that HzMUC1-ADC is a novel therapeutic drug that can overcome trastuzumab resistance of breast cancer. HzMUC1-ADC should also be an effective therapeutic drug for the treatment of different MUC1-positive cancers in clinic.
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Affiliation(s)
- Guang Wu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Lan Li
- School of Public Health and Management, Wenzhou Medical University, Wenzhou 325035, China
| | - Yuxin Qiu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Wei Sun
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Tianhao Ren
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Yingshuai Lv
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Mengnan Liu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Xiaoxia Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Hongqun Tao
- Department of Clinical Laboratory, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Lingjie Zhao
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Jiawei Cao
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Licai He
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Hongzhi Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Haihua Gu
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China
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Taefehshokr S, Parhizkar A, Hayati S, Mousapour M, Mahmoudpour A, Eleid L, Rahmanpour D, Fattahi S, Shabani H, Taefehshokr N. Cancer immunotherapy: Challenges and limitations. Pathol Res Pract 2021; 229:153723. [PMID: 34952426 DOI: 10.1016/j.prp.2021.153723] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 11/19/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023]
Abstract
Although cancer immunotherapy has taken center stage in mainstream oncology inducing complete and long-lasting tumor regression, only a subset of patients receiving treatment respond and others relapse after an initial response. Different tumor types respond differently, and even in cancer types that respond (hot tumors), we still observe tumors that are unresponsive (cold tumors), suggesting the presence of resistance. Hence, the development of intrinsic or acquired resistance is a big challenge for the cancer immunotherapy field. Resistance to immunotherapy, including checkpoint inhibitors, CAR-T cell therapy, oncolytic viruses, and recombinant cytokines arises due to cancer cells employing several mechanisms to evade immunosurveillance.
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Affiliation(s)
- Sina Taefehshokr
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Aram Parhizkar
- Faculty of Natural Science, Tabriz University, Tabriz, Iran
| | - Shima Hayati
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Morteza Mousapour
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Amin Mahmoudpour
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Liliane Eleid
- Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom
| | - Dara Rahmanpour
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahand Fattahi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Hadi Shabani
- Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Nima Taefehshokr
- Department of Microbiology and Immunology, Center for Human Immunology, The University of Western Ontario, London, Ontario, Canada
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Using chimeric antigen receptor T-cell therapy to fight glioblastoma multiforme: past, present and future developments. J Neurooncol 2021; 156:81-96. [PMID: 34825292 PMCID: PMC8714623 DOI: 10.1007/s11060-021-03902-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 11/12/2021] [Indexed: 12/19/2022]
Abstract
Introduction Glioblastoma multiforme (GBM) constitutes one of the deadliest tumors to afflict humans, although it is still considered an orphan disease. Despite testing multiple new and innovative therapies in ongoing clinical trials, the median survival for this type of malignancy is less than two years after initial diagnosis, regardless of therapy. One class of promising new therapies are chimeric antigen receptor T cells or CAR-T which have been shown to be very effective at treating refractory liquid tumors such as B-cell malignancies. However, CAR-T effectivity against solid tumors such as GBM has been limited thus far. Methods A Pubmed, Google Scholar, Directory of Open Access Journals, and Web of Science literature search using the terms chimeric antigen receptor or CAR-T, GBM, solid tumor immunotherapy, immunotherapy, and CAR-T combination was performed for publication dates between January 1987 and November 2021. Results In the current review, we present a comprehensive list of CAR-T cells developed to treat GBM, we describe new possible T-cell engineering strategies against GBM while presenting a short introductory history to the reader regarding the origin(s) of this cutting-edge therapy. We have also compiled a unique list of anti-GBM CAR-Ts with their specific protein sequences and their functions as well as an inventory of clinical trials involving CAR-T and GBM. Conclusions The aim of this review is to introduce the reader to the field of T-cell engineering using CAR-Ts to treat GBM and describe the obstacles that may need to be addressed in order to significantly delay the relentless growth of GBM. Supplementary Information The online version contains supplementary material available at 10.1007/s11060-021-03902-8.
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Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
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47
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Abken H. Building on Synthetic Immunology and T Cell Engineering: A Brief Journey Through the History of Chimeric Antigen Receptors. Hum Gene Ther 2021; 32:1011-1028. [PMID: 34405686 PMCID: PMC10112879 DOI: 10.1089/hum.2021.165] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Advancement in our understanding of immune cell recognition and emerging cellular engineering technologies during the last decades made active manipulation of the T cell response possible. Synthetic immunology is providing us with an expanding set of composite receptor molecules capable to reprogram immune cell function in a predefined fashion. Since the first prototypes in the late 1980s, the design of chimeric antigen receptors (CARs; T-bodies, immunoreceptors), has followed a clear line of stepwise improvements from antigen-redirected targeting to designed "living factories" delivering transgenic products on demand. Building on basic research and creative clinical exploration, CAR T cell therapy has been achieving spectacular success in the treatment of hematologic malignancies, now beginning to improve the outcome of cancer patients. In this study, we briefly review the history of CARs and outline how the progress in the basic understanding of T cell recognition and of cell engineering technologies made novel therapies possible.
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Affiliation(s)
- Hinrich Abken
- Department of Genetic Immunotherapy, Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
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48
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PI3K/Akt Pathway: The Indestructible Role of a Vintage Target as a Support to the Most Recent Immunotherapeutic Approaches. Cancers (Basel) 2021; 13:cancers13164040. [PMID: 34439194 PMCID: PMC8392360 DOI: 10.3390/cancers13164040] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/02/2021] [Accepted: 08/06/2021] [Indexed: 11/18/2022] Open
Abstract
Simple Summary PI3K/Akt pathway has an impressive story as tumor marker. PI3K-dependent solid tumors have been studied for several years in order to inhibit the pathway at different levels along the signaling. Despite the highly satisfactory results obtained in vitro and in xenograft mouse tumor models, the use of PI3K/Akt inhibitors in clinical trials resulted in being not as efficient as expected. With the emerging role of the tumor microenvironment in the response to therapy and the awareness, increasing in recent years, of the necessity to army the immune system against the tumor, new opportunities have emerged for PI3K/Akt inhibitors. Here, we show that PI3K/Akt, in addition to its function as tumor marker, exerts a pivotal role as an immunomodulator. Recent studies demonstrate that PI3K/Akt pathway is crucial for the regulation of the immune system and that its inhibition in combination with immunomodulatory agents may provide a new therapeutic approach for cancer. Abstract Pathologic activation of PI3Ks and the subsequent deregulation of its downstream signaling pathway is among the most frequent events associated with cellular transformation, cancer, and metastasis. PI3Ks are also emerging as critical factors in regulating anti-tumor immunity by either promoting an immunosuppressive tumor microenvironment or by controlling the activity and the tumor infiltration of cells involved in the immune response. For these reasons, significant pharmaceutical efforts are dedicated to inhibiting the PI3K pathway, with the main goal to target the tumor and, at the same time, to enhance the anti-tumor immunity. Recent immunotherapeutic approaches involving the use of adoptive cell transfer of autologous genetically modified T cells or immune check-point inhibitors showed high efficacy. However, mechanisms of resistance to these kinds of therapy are emerging, due in part to the inhibition of effector T cell functions exerted by the immunosuppressive tumor microenvironment. Here, we first describe how inhibition of PI3K/Akt pathway contribute to enhance anti-tumor immunity and further discuss how inhibitors of the pathway are used in combination with different immunomodulatory and immunotherapeutic agents to improve anti-tumor efficacy.
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Razeghian E, Nasution MKM, Rahman HS, Gardanova ZR, Abdelbasset WK, Aravindhan S, Bokov DO, Suksatan W, Nakhaei P, Shariatzadeh S, Marofi F, Yazdanifar M, Shamlou S, Motavalli R, Khiavi FM. A deep insight into CRISPR/Cas9 application in CAR-T cell-based tumor immunotherapies. Stem Cell Res Ther 2021; 12:428. [PMID: 34321099 PMCID: PMC8317439 DOI: 10.1186/s13287-021-02510-7] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/12/2021] [Indexed: 12/15/2022] Open
Abstract
To date, two chimeric antigen receptors (CAR)-T cell products from autologous T cells have been approved by The United States Food and Drug Administration (FDA). The case-by-case autologous T cell generation setting is largely considered as a pivotal restraining cause for its large-scale clinical use because of the costly and prolonged manufacturing procedure. Further, activated CAR-T cells mainly express immune checkpoint molecules, including CTLA4, PD1, LAG3, abrogating CAR-T anti-tumor activity. In addition, CAR-T cell therapy potently results in some toxicity, such as cytokine releases syndrome (CRS). Therefore, the development of the universal allogeneic T cells with higher anti-tumor effects is of paramount importance. Thus, genome-editing technologies, in particular, clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 are currently being used to establish "off-the-shelf" CAR-T cells with robust resistance to immune cell-suppressive molecules. In fact, that simultaneous ablation of PD-1, T cell receptor alpha constant (TRAC or TCR), and also β-2 microglobulin (B2M) by CRISPR-Cas9 technique can support the manufacture of universal CAR-T cells with robust resistance to PD-L1. . Indeed, the ablation of β2M or TARC can severely hinder swift elimination of allogeneic T cells those express foreign HLA-I molecules, and thereby enables the generation of CAR-T cells from allogeneic healthy donors T cells with higher persistence in vivo. Herein, we will deliver a brief overview of the CAR-T cell application in the context of tumor immunotherapy. More importantly, we will discuss recent finding concerning the application of genome editing technologies for preparing universal CAR-T cells or cells that can effectively counter tumor escape, with a special focus on CRISPR-Cas9 technology.
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Affiliation(s)
- Ehsan Razeghian
- Human Genetics Division, Medical Biotechnology Department, National Institute of Genetics Engineering and Biotechnology (NIGEB), Tehran, Iran
| | | | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaymaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Zhanna R. Gardanova
- Department of Psychotherapy, Pirogov Russian National Research Medical University, 1 Ostrovityanova St, 117997 Moscow, Russia
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Surendar Aravindhan
- Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Dmitry O. Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow, 119991 Russian Federation
- Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr, Moscow, 109240 Russian Federation
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, 10210 Thailand
| | - Pooria Nakhaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Siavash Shariatzadeh
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Faroogh Marofi
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahboubeh Yazdanifar
- Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA USA
| | - Somayeh Shamlou
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Roza Motavalli
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Zhang Z, Miao L, Ren Z, Tang F, Li Y. Gene-Edited Interleukin CAR-T Cells Therapy in the Treatment of Malignancies: Present and Future. Front Immunol 2021; 12:718686. [PMID: 34386015 PMCID: PMC8353254 DOI: 10.3389/fimmu.2021.718686] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/09/2021] [Indexed: 01/05/2023] Open
Abstract
In recent years, chimeric antigen receptor T cells (CAR-T cells) have been faced with the problems of weak proliferation and poor persistence in the treatment of some malignancies. Researchers have been trying to perfect the function of CAR-T by genetically modifying its structure. In addition to the participation of T cell receptor (TCR) and costimulatory signals, immune cytokines also exert a decisive role in the activation and proliferation of T cells. Therefore, genetic engineering strategies were used to generate cytokines to enhance tumor killing function of CAR-T cells. When CAR-T cells are in contact with target tumor tissue, the proliferation ability and persistence of T cells can be improved by structurally or inductively releasing immunoregulatory molecules to the tumor region. There are a large number of CAR-T cells studies on gene-edited cytokines, and the most common cytokines involved are interleukins (IL-7, IL-12, IL-15, IL-18, IL-21, IL-23). Methods for the construction of gene-edited interleukin CAR-T cells include co-expression of single interleukin, two interleukin, interleukin combined with other cytokines, interleukin receptors, interleukin subunits, and fusion inverted cytokine receptors (ICR). Preclinical and clinical trials have yielded positive results, and many more are under way. By reading a large number of literatures, we summarized the functional characteristics of some members of the interleukin family related to tumor immunotherapy, and described the research status of gene-edited interleukin CAR-T cells in the treatment of malignant tumors. The objective is to explore the optimized strategy of gene edited interleukin-CAR-T cell function.
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Affiliation(s)
- Zhengchao Zhang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Lele Miao
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhijian Ren
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Futian Tang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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