Immune Checkpoint Proteins, Metabolism and Adhesion Molecules: Overlooked Determinants of CAR T-Cell Migration?

Simula, Luca; Ollivier, Emma; Icard, Philippe; Donnadieu, Emmanuel

doi:10.3390/cells11111854

Cited by 9 publications

(16 citation statements)

References 127 publications

(155 reference statements)

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“…CAR-T cell therapy, as 'the living drug,' is different from other immunotherapies because CAR-T cell therapy is more susceptible to the immunosuppressive TME that limits its efficacy. There is ample evidence that soluble factors, including IDO, IL-10, TGF-β [79], and immune checkpoints, such as PD-1 and CTLA-4 [80], cause T cell dysfunction. Furthermore, trafficking of CAR-T cells into the TME, aberrant tumor vasculature, and suppression of CAR-T cells due to immunosuppressive cells are some key challenges that the TME poses to CAR-T cells.…”

Section: Discussionmentioning

confidence: 99%

Challenges for CAR-T cell therapy in multiple myeloma: overcoming the tumor microenvironment

Cui

Qiu

2023

Hematology and Oncology Discovery

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Chimeric antigen receptor T (CAR-T) cell therapy has shown promising efficacy in multiple myeloma (MM) patients, leading to FDA approval of two B cell maturation antigen (BCMA)-specific CAR-T cell therapies (ide-cel and cilta-cel). Despite the remarkable response rates and response depth of MM patients to CAR-T cell therapy, patients inevitably relapse. A growing body of evidence suggests that the activity of CAR-T cells is affected by the immunosuppressive tumor microenvironment (TME). In this review we have summarized the main challenges that CAR-T cells face in the TME, including various immunosuppressive cells, structural components, hypoxia, nutrient starvation, and metabolism. Moreover, we also discussed some candidate strategies for CAR-T cell therapy to overcome immunosuppressive TME and improve the efficacy of CAR-T cell therapy in the treatment of MM.

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Section: Discussionmentioning

confidence: 99%

Challenges for CAR-T cell therapy in multiple myeloma: overcoming the tumor microenvironment

Cui

Qiu

2023

Hematology and Oncology Discovery

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“…However, the application of CAR-T cell therapy for solid tumors poses significant challenges, including tumor infiltration and trafficking difficulties, cytokine release syndrome, on-target offtumor toxicity, and T-cell exhaustion within the complex tumor microenvironment (38,(169)(170)(171)(172).Till date, various types of combination immunotherapies have been studied, such as CAR-T cell with anti PD-L1 (173), double immune checkpoint inhibitor therapy such as anti PD-1/PD-L1 plus anti-CTLA-4 (174), and CAR-T cells with anti PD-1 (175). In a study by Cheng et al (2023) combination of 4-1BB CAR-T and autocrine anti PD-L1 scFv improved the anti-tumor response of CAR-T cells along with improved persistence.…”

Section: Conclusion and Outlooksmentioning

confidence: 99%

The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review

Satapathy,

Sheoran,

Yadav

et al. 2024

Front. Immunol.

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Currently, therapies such as chimeric antigen receptor-T Cell (CAR-T) and immune checkpoint inhibitors like programmed cell death protein-1 (PD-1) blockers are showing promising results for numerous cancer patients. However, significant advancements are required before CAR-T therapies become readily available as off-the-shelf treatments, particularly for solid tumors and lymphomas. In this review, we have systematically analyzed the combination therapy involving engineered CAR-T cells and anti PD-1 agents. This approach aims at overcoming the limitations of current treatments and offers potential advantages such as enhanced tumor inhibition, alleviated T-cell exhaustion, heightened T-cell activation, and minimized toxicity. The integration of CAR-T therapy, which targets tumor-associated antigens, with PD-1 blockade augments T-cell function and mitigates immune suppression within the tumor microenvironment. To assess the impact of combination therapy on various tumors and lymphomas, we categorized them based on six major tumor-associated antigens: mesothelin, disialoganglioside GD-2, CD-19, CD-22, CD-133, and CD-30, which are present in different tumor types. We evaluated the efficacy, complete and partial responses, and progression-free survival in both pre-clinical and clinical models. Additionally, we discussed potential implications, including the feasibility of combination immunotherapies, emphasizing the importance of ongoing research to optimize treatment strategies and improve outcomes for cancer patients. Overall, we believe combining CAR-T therapy with PD-1 blockade holds promise for the next generation of cancer immunotherapy.

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“…Immunosuppressive TME [7,8,14,22,36,66,[75][76][77][78][79][80][81][82][83] • CAR-T cells that secrete cytokines or antibodies that lead to antibody-dependent cell-mediated cytotoxicity [16,32,36…”

Section: Current Challenges Potential Solutionsmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells in Glioblastoma—Current Concepts and Promising Future

Kringel

Lamszus

Mohme

2023

Cells

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Glioblastoma (GBM) is a highly aggressive primary brain tumor that is largely refractory to treatment and, therefore, invariably relapses. GBM patients have a median overall survival of 15 months and, given this devastating prognosis, there is a high need for therapy improvement. One of the therapeutic approaches currently tested in GBM is chimeric antigen receptor (CAR)-T cell therapy. CAR-T cells are genetically altered T cells that are redirected to eliminate tumor cells in a highly specific manner. There are several challenges to CAR-T cell therapy in solid tumors such as GBM, including restricted trafficking and penetration of tumor tissue, a highly immunosuppressive tumor microenvironment (TME), as well as heterogeneous antigen expression and antigen loss. In addition, CAR-T cells have limitations concerning safety, toxicity, and the manufacturing process. To date, CAR-T cells directed against several target antigens in GBM including interleukin-13 receptor alpha 2 (IL-13Rα2), epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and ephrin type-A receptor 2 (EphA2) have been tested in preclinical and clinical studies. These studies demonstrated that CAR-T cell therapy is a feasible option in GBM with at least transient responses and acceptable adverse effects. Further improvements in CAR-T cells regarding their efficacy, flexibility, and safety could render them a promising therapy option in GBM.

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Immune Checkpoint Proteins, Metabolism and Adhesion Molecules: Overlooked Determinants of CAR T-Cell Migration?

Cited by 9 publications

References 127 publications

Challenges for CAR-T cell therapy in multiple myeloma: overcoming the tumor microenvironment

Challenges for CAR-T cell therapy in multiple myeloma: overcoming the tumor microenvironment

The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review

Chimeric Antigen Receptor T Cells in Glioblastoma—Current Concepts and Promising Future

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