Identification of IL-4 As a Key Regulator of CAR T-Cell Exhaustion Using Functional Genomics and Correlates of the Zuma-1 Clinical Trial

Stewart, Carli M.; Cox, Michelle J.; Sakemura, Reona; Ogbodo, Ekene J.; Can, İsmail; Manriquez-Roman, Claudia; Yun, Kun; Sirpilla, Olivia; Girsch, James H.; Huynh, Truc; Siegler, Elizabeth L.; Kim, Jaeyeon; Mattie, Mike; Scholler, Nathalie; Filosto, Simone; Kenderian, Saad S.

doi:10.1182/blood-2022-160219

Cited by 3 publications

(2 citation statements)

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“…After the two chips are combined and closed, cells can move freely in a single row in their respective closed microchambers, in which combinations of cells with different effector-target ratios and spatial effects naturally occur. The multi-indexed barcode arrays used for CAR-T assessment (Figure 1B) were divided into six groups of categories, assessing key immune functions (e.g., cytotoxic, 30 effector, 31 regulatory, 32,33 chemokine, 34 stimulatory, 35 and inflammatory 36,37 ) of CAR-T cells, which were microprinted with the help of an accompanying secreted factor detection chip. For the cytotoxic category, which mainly plays a role in destroying tumor cells, GZMB and Perforin were the prime effectors.…”

Section: High-throughput Multiperformance Systematic Evaluation Platf...mentioning

confidence: 99%

Immune function assessing of TIM3/CD28‐modified CD19 CAR‐T cells and general CD19 CAR‐T cells through a high‐throughput single‐cell microarray platform

Wang,

Liu

et al. 2024

Interdisciplinary Medicine

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Chimeric antigen receptor (CAR) T cells are widely used to treat hematological tumors due to their powerful ability to target and kill cancer cells, of which accurate function evaluation at the single‐cell level is crucial to ensuring the efficacy of diagnosis and treatment. Currently, a universal platform to evaluate the efficacy of immune single cells rapidly, efficiently, and systematically is urgently needed. Here, the cytotoxicity, proliferative potential, and persistence of TIM3/CD28‐modified CD19 CAR‐T cells are evaluated in comparison with ordinary CD19 CAR‐T cells through high‐performance and throughput graphene oxide quantum dot (GOQD)‐based single‐cell microfluidic chips. Overall secretory factor expression, immune‐therapy effect of different effector‐target ratios, spatial immune‐therapy effects, and subgroup type profiling are demonstrated to explicit the immunotherapy effect of TIM3/CD28‐modified CD19 CAR‐T cells. TIM3/CD28‐modified CD19 CAR‐T cells show stronger anti‐tumor ability and maintain excellent immunotherapy effects even at low effector‐target ratios and remote distances. TIM3/CD28 also strengthens the local targeting ability of TIM3/CD28‐modified CD19 CAR‐T. Importantly, TIM3/CD28‐modified CD19 CAR‐T exhibits more distinct Th1/Th2 long‐term persistent and potent killer subgroups, which is very helpful for personalized therapy. Overall, this study provides a valuable approach that can be widely implemented to analyze current CAR‐T combinations and evaluate the function of innovative CAR treatments in the future.

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Section: High-throughput Multiperformance Systematic Evaluation Platf...mentioning

confidence: 99%

Immune function assessing of TIM3/CD28‐modified CD19 CAR‐T cells and general CD19 CAR‐T cells through a high‐throughput single‐cell microarray platform

Wang,

Liu

et al. 2024

Interdisciplinary Medicine

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show abstract

“…Chimeric antigen receptor (CAR) –T cell exhaustion or senescence in vivo remains a major issue. Increased expression of immune checkpoint proteins, such as that of TIM-3 during CART19-28ζ cell exhaustion, results in a decrease in cytotoxicity [ 3 ]. Moreover, CART19-BBζ cells are more prone to developing a senescent phenotype compared to CART19-28ζ cells [ 4 ].…”

Section: Influence Of Car-t Cell Activation and Bite Functionmentioning

confidence: 99%

Targeting TIM-3 for hematological malignancy: latest updates from the 2022 ASH annual meeting

Tan

2023

Exp Hematol Oncol

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T cell immunoglobulin domain and mucin domain-3 (TIM-3) is an important immune checkpoint (IC) protein in cancer immunosuppression that is considered a novel target for immunotherapy. Moreover, TIM-3, an immuno-myeloid regulator, is highly expressed on the cells of several solid tumors and myeloid leukemia stem cells (LSCs). TIM-3 blockade was shown to have dual effects for directly inhibiting leukemia cells and restoring T cell activation. We summarize several of the latest reports on the role of TIM-3 in immunotherapy for hematological malignancies from the 2022 ASH Annual Meeting (ASH2022).

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Co-expression of IL-4/IL-15-based inverted cytokine receptor in CAR-T cells overcomes IL-4 signaling in immunosuppressive pancreatic tumor microenvironment

Zhou,

Farooq,

Ajmal

et al. 2023

Biomedicine & Pharmacotherapy

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Identification of IL-4 As a Key Regulator of CAR T-Cell Exhaustion Using Functional Genomics and Correlates of the Zuma-1 Clinical Trial

Cited by 3 publications

References 0 publications

Immune function assessing of TIM3/CD28‐modified CD19 CAR‐T cells and general CD19 CAR‐T cells through a high‐throughput single‐cell microarray platform

Immune function assessing of TIM3/CD28‐modified CD19 CAR‐T cells and general CD19 CAR‐T cells through a high‐throughput single‐cell microarray platform

Targeting TIM-3 for hematological malignancy: latest updates from the 2022 ASH annual meeting

Co-expression of IL-4/IL-15-based inverted cytokine receptor in CAR-T cells overcomes IL-4 signaling in immunosuppressive pancreatic tumor microenvironment

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