These results underscore an essential requirement for successful CAR T, namely, a high frequency of early memory CAR T cells. non-responders to CD19 CAR T therapy among CLL patients 18. More striking, the presence of an early memory T-cell population in the pre-manufacturing leukapheresis product predicted, with 100% accuracy, responders vs. Importantly, sustained remission of chronic lymphocytic leukemia (CLL) and large B-cell lymphoma (LBCL) has been associated with elevated frequency of CD19 CAR T cells with memory-like characteristics 18, 19. Moreover, stem-like memory T cells (T SCM) have been shown to play a critical role in mediating early anti-leukemic responses and long-term immune surveillance against leukemia relapse in patients for up to 3 years 17.
The percentage of CAR T cells with a central memory phenotype (T CM) is highly concordant with longer-term in vivo persistence and favorable clinical outcomes in neuroblastoma 16. The cumulative effects of these alterations enhance myeloid cell and dendritic cell (DC) activity, reverse immunosuppressive TME conditions, and prime endogenous T cells to reject tumor cells with CAR-directed antigen loss 15. These include, but are not limited to, altering an array of tumor-specific CAR T cells to express (i) the p40 IL-23 subunit to promote proliferation and survival 9, (ii) the dominant-negative TGF-β and adenosine receptor to promote proliferation 10, 11, (iii) the IL-8 receptor, CXCR1 or CXCR2, to enhance migration and persistence in the TME 12, (iv) the anti-PD-L1 antibody, PD-1 dominant-negative receptor, or PD-1–knockout alteration to block PD-1/PD-L1 signaling in CAR T cells 13, 14, and (v) immunostimulatory RNA RN7SL1 to activate RIG-I/MDA5 signaling and promote expansion and effector-memory differentiation of CAR T cells. Significant efforts have been made to genetically engineer modified CAR T cells to promote more effective treatments for solid tumors. In addition, intrinsic target antigen heterogeneity and/or antigen loss due to selective pressure by targeted therapies 5, 6 also contribute to the resistance of solid tumors to CAR T 7, 8. These include insufficient infiltration, expansion, persistence, and effector function, resulting in the ultimate exhaustion of adoptively transferred CAR T cells and an immunosuppressive tumor microenvironment (TME) 4. Many factors contribute to the poor efficacy of CAR T for solid tumors. In contrast, results from clinical trials of CAR T for solid tumors have been disappointing 2, 3. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.Ĭhimeric antigen receptor T-cell therapy (CAR T) has achieved unprecedented success as a novel immunotherapy with curative potential for certain hematologic cancers 1. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion.
CAR SHOWS ON DISCOVERY PLUS PLUS
The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR).
Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Nature Communications volume 14, Article number: 5727 ( 2023) Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment
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