Combination of 4-1BB and DAP10 promotes proliferation and persistence of NKG2D(bbz) CAR-T cells

Wei, Cheng; Xia, Kangfu; Xie, Yan; Ye, Sishi; Ding, Yanghui; Liu, Zairu; Zheng, Rong; Long, Jing; Wei, Qinchuan; Li, Yumei; Yang, Di; Xu, Xiaojun; Zhao, Aihua; Gao, Jimin

doi:10.3389/fonc.2022.893124

Cited by 7 publications

(7 citation statements)

References 44 publications

(24 reference statements)

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“…In addition, the PI3K/AKT pathway is involved in T cell proliferation and differentiation, and it plays an important role in CAR-T cell exhaustion. At present, It has been confirmed that the PI3K inhibitor could modulate the differentiation of CAR-T cells and enhance the persistence of CAR-T cells in vivo (58)(59)(60). Intriguingly, a recent study found that the second generation tyrosine kinase inhibitor dasatinib could reverse the exhausted phenotype of CAR-T cells through increasing the expression of memory-associated genes, such as TCF7 and CCR7, and decreasing the expression of immune checkpoint molecule PD1 and exhaustion-related regulators, such as NR4A1, BATF3, ATF4, and FOS (61).…”

Section: Inhibiting Exhaustion-related Signalsmentioning

confidence: 88%

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

Zhang

Zhang²,

Lan³

et al. 2023

Front. Immunol.

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Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export (SINEs), and T cell redirecting bispecific antibodies. However, MM remains an incurable neoplastic plasma cell disorder, and almost all MM patients inevitably relapse due to drug resistance. Encouragingly, B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy has achieved impressive success in the treatment of relapsed/refractory (R/R) MM and brought new hopes for R/R MM patients in recent years. Due to antigen escape, the poor persistence of CAR-T cells, and the complicated tumor microenvironment, a significant population of MM patients still experience relapse after anti-BCMA CAR-T cell therapy. Additionally, the high manufacturing costs and time-consuming manufacturing processes caused by the personalized manufacturing procedures also limit the broad clinical application of CAR-T cell therapy. Therefore, in this review, we discuss current limitations of CAR-T cell therapy in MM, such as the resistance to CAR-T cell therapy and the limited accessibility of CAR-T cell therapy, and summarize some optimization strategies to overcome these challenges, including optimizing CAR structure, such as utilizing dual-targeted/multi-targeted CAR-T cells and armored CAR-T cells, optimizing manufacturing processes, combing CAR-T cell therapy with existing or emerging therapeutic approaches, and performing subsequent anti-myeloma therapy after CAR-T cell therapy as salvage therapy or maintenance/consolidation therapy.

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Section: Inhibiting Exhaustion-related Signalsmentioning

confidence: 88%

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

Zhang

Zhang²,

Lan³

et al. 2023

Front. Immunol.

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“…However, third-generation CARs carry risks of off-target effects and excess cytokine production, with limited clinical data available. Consequently, fourth-generation CARs have been developed to address these concerns [43,44] Four Generation Fourth-generation CARs, derived from second-generation CARs, integrate domains regulating cytokine expression alongside costimulatory domains to bolster antitumor responses. These CARs, engineered to secrete IL-12, IL-18, or IL-21, enhance CAR-T cell cytotoxicity, proliferation, and memory T cell differentiation, thereby improving killing efficacy and sustaining antitumor effects in preclinical models [45][46][47]…”

Section: First Generationmentioning

confidence: 99%

The Future Directions of CAR-T Cell Therapy: Unlocking the Potential of Immunotherapy in Cancer Treatment

Justiz-Vaillant,

Soodeen,

Gopaul

et al. 2024

Preprint

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CAR-T cell therapy has emerged as a groundbreaking approach in cancer treatment, leveraging the immune system to target and eliminate cancer cells. While currently focused on hematologic malignancies, the future holds promise for expanding CAR-T cell therapy to diverse cancers, enhancing its efficacy, and improving safety profiles. Recent advances in tumor immunology have propelled CAR-T cell therapy as a game-changer in treating diseases such as relapsed/refractory B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Six CAR-T cell products have received FDA approval for treating R/R B cell malignancies. However, challenges persist, including complications like cytokine release syndrome (CRS), coagulopathy, and cytopenias. Strategies to mitigate these complications involve targeting distinct antigens with dual- or multi-targeted CAR-T cells and enhancing immunogenicity. Additionally, γδ CAR-T cells show promise in recognizing antigen- negative leukemia cells in an MHC-independent manner while reducing the risk of inducing graft-versus-host disease (GVHD). As CAR-T cell therapy continues to evolve through innovation and discovery, it holds the potential to revolutionize cancer treatment, offering new hope to patients and reshaping the landscape of oncology with its precision and efficacy.

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“…Wei et al. reported that the simultaneous activation of the costimulatory signals 4-1BB and DAP10 on NKG2D CAR-T cells resulted in the poor differentiation of T cells in vitro and in vivo , upregulation of Bcl-2 expression, and an increased proportion of T SCM subsets ( 215 ). CAR-T cell adoptive transfer therapy results in significant antitumor activity, but this effect is observed only in a small group of patients.…”

Section: Targeting T-cell Exhaustion and T Scm To ...mentioning

confidence: 99%

T-cell exhaustion and stemness in antitumor immunity: Characteristics, mechanisms, and implications

Chi

Luo²,

Ye³

et al. 2023

Front. Immunol.

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T cells play a crucial role in the regulation of immune response and are integral to the efficacy of cancer immunotherapy. Because immunotherapy has emerged as a promising treatment for cancer, increasing attention has been focused on the differentiation and function of T cells in immune response. In this review, we describe the research progress on T-cell exhaustion and stemness in the field of cancer immunotherapy and summarize advances in potential strategies to intervene and treat chronic infection and cancer by reversing T-cell exhaustion and maintaining and increasing T-cell stemness. Moreover, we discuss therapeutic strategies to overcome T-cell immunodeficiency in the tumor microenvironment and promote continuous breakthroughs in the anticancer activity of T cells.

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Combination of 4-1BB and DAP10 promotes proliferation and persistence of NKG2D(bbz) CAR-T cells

Cited by 7 publications

References 44 publications

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

The Future Directions of CAR-T Cell Therapy: Unlocking the Potential of Immunotherapy in Cancer Treatment

T-cell exhaustion and stemness in antitumor immunity: Characteristics, mechanisms, and implications

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