Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy
Chao MaAnn CheungThinle ChodonRichard C. KoyaZhongqi WuCharles NgEarl AvramisAlistair J. CochranOwen N. WitteDavid BaltimoreBartosz ChmielowskiJames S. EconomouBegonya Comin-AnduixAntoni RibasJames R. Heath
139
Citation
39
Reference
10
Related Paper
Citation Trend
Abstract:
Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy.A longitudinal functional study of adoptively transferred TCR–engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma.Keywords:
Adoptive Cell Transfer
Cancer Immunotherapy
Cell therapy
Streptamer
Cell therapy
CAR T-cell therapy
Cite
Citations (72)
Chimeric antigen receptor (CAR-T) cell therapy is a newly developed immunotherapy strategy and has achieved satisfactory outcomes in the treatment of hematological malignancies. However, some adverse effects related to CAR-T cell therapy have to be resolved before it is widely used in clinics as a cancer treatment. Furthermore, the application of CAR-T cell therapy in the treatment of solid tumors has been hampered by numerous limitations. Therefore, it is essential to explore novel strategies to improve the therapeutic effect of CAR-T cell therapy. In this review, we summarized the recently developed strategies aimed at optimizing the generation of CAR-T cells and improving the anti-tumor efficiency of CAR-T cell therapy. Furthermore, the discovery of new targets for CAR-T cell therapy and the combined treatment strategies of CAR-T cell therapy with chemotherapy, radiotherapy, cancer vaccines and nanomaterials are highlighted.
Cell therapy
Cancer Therapy
CAR T-cell therapy
Cancer Immunotherapy
Targeted Therapy
Cite
Citations (1)
Abstract Chimeric antigen receptor (CAR) therapy is a method directing T lymphocytes against antigens on the surface of tumors, increasing target cell elimination. Genetic engineering enhances the capability of immune cells to detect new antigens expressed on cell surfaces. CAR T cell therapy is a significant breakthrough for treating human malignancies; however, different side effects (e.g., cytokine release syndrome) restrict its application. Improving design and using various combined receptors enhance the performance of these cells. This review discusses limitations and risk factors associated with CAR T cell therapy. We also review some alternative approaches for developing the next generation of CAR T cells.
Cell therapy
Cytokine Release Syndrome
Cite
Citations (3)
Chimeric antigen receptor (CAR) T-cell therapy is a novel therapeutic T-cell engineering option, where T-cells obtained from a patient’s blood are engineered ex vivo to express specific tumour antigen receptors. The highly selective nature of CAR T-cell therapy has led to a revolution in cancer treatment. The use of CAR T-cell therapy has been successful in treating haematological malignancies and there is also a growing interest in using CAR T-cell therapy to target solid tumours. However, there are notable challenges with CAR T-cell therapy, including non-sustained responses, antigen escape, and life-threatening adverse effects. Studies are underway to improve the safety of CAR T-cell therapy by limiting their expression, producing switchable CAR T-cells, and producing genetically engineered T-cells that are equipped with genes to reduce adverse effects.
Cell therapy
CAR T-cell therapy
Cite
Citations (0)
The development of chimeric antigen receptor T (CAR-T) cell therapy, a specific type of immunotherapy, in recent decades was a fantastic breakthrough for the treatment of hematological malignancies. However, difficulties in collecting normal T cells from patients and the time cost of manufacturing CAR-T cells have limited the application of CAR-T-cell therapy. In addition, the termination of related clinical trials on universal CAR-T cell therapy has made further research more difficult. Natural killer (NK) cells have drawn great attention in recent years. Chimeric antigen receptor-NK (CAR-NK) cell therapy is a promising strategy in the treatment of malignant tumors because of its lack of potential for causing graft-versus-host disease (GVHD). In this review, we will address the advances in and achievements of CAR-NK cell therapy.
Cell therapy
CAR T-cell therapy
Cite
Citations (55)
Cell therapy
Homing (biology)
Cite
Citations (123)
Adoptive cell therapy with chimeric antigen receptor T (CAR-T) cells has achieved remarkable efficacy in the treatment of hematological malignancies, which has inspired researchers to expand the application of CAR-T-cell therapy to other medical conditions. Here, we review the current understanding and development of CAR-T-cell therapy for infectious diseases, autoimmune diseases and allotransplantation. The limitations and challenges of CAR-T-cell therapy in the treatment of these diseases and potential solutions to overcome these shortcomings are also discussed. With the development of novel designs of CARs and preclinical/clinical investigations, CAR-T-cell therapy is expected to be a potential cure option in a wide array of disease settings in the future.
Cell therapy
Cancer Therapy
Cite
Citations (3)
Abstract BACKGROUND We have entered a new era of cancer therapy, with a number of immune-based therapies already used clinically as a standard of care. Adoptive cellular immunotherapy using T cells genetically modified with chimeric antigen receptors (CAR-T cells) represents a novel therapeutic approach. CAR-T cells have produced clinical responses in B-cell malignancies that are otherwise refractory to conventional therapies. Two CAR-T cell therapies obtained regulatory approval in 2017, with many more of these therapies under clinical development. CONTENT This review focuses on the current state of adoptive cellular immunotherapy, specifically CAR-T cells, in the clinic and how this therapy differs from traditional small molecule and biologic therapies. Areas in which the clinical laboratory is affected by these novel therapies are discussed. Opportunities for the clinical laboratory to help guide these therapies are also highlighted. SUMMARY The clinical laboratory will play an integral role in the care of patients undergoing adoptive cellular therapy with engineered T cells. There are many ways that this new therapeutic approach affects the clinical laboratory, and the clinical laboratory will likely play a critical role in managing patients that are treated with CAR-T cell therapy.
Cell therapy
Adoptive Cell Transfer
Cancer Immunotherapy
Adoptive immunotherapy
Cite
Citations (4)
Chimeric antigen receptor T cell (CAR-T cell) therapy has shown impressive success in the treatment of hematological malignancies, but the systemic toxicity and complex manufacturing process of current autologous CAR-T cell therapy hinder its broader applications. Universal CAR-T cells have been developed to simplify the production process through isolation and editing of allogeneic T cells from healthy persons, but the allogeneic CAR-T cells have recently encountered safety concerns, and clinical trials have been halted by the FDA. Thus, there is an urgent need to seek new ways to overcome the barriers of current CAR-T cell therapy. In-vivo CAR-T cells induced by nanocarriers loaded with CAR-genes and gene-editing tools have shown efficiency for regressing leukemia and reducing systemic toxicity in a mouse model. The in-situ programming of autologous T-cells avoids the safety concerns of allogeneic T cells, and the manufacture of nanocarriers can be easily standardized. Therefore, the in-vivo induced CAR-T cells can potentially overcome the abovementioned limitations of current CAR-T cell therapy. Here, we provide a review on CAR structures, gene-editing tools, and gene delivery techniques applied in immunotherapy to help design and develop new in-vivo induced CAR-T cells.
Cell therapy
Nanocarriers
Cite
Citations (55)
Cell therapy
Cancer Immunotherapy
Cancer Therapy
Reprogramming
Cite
Citations (22)