Journal
NEURO-ONCOLOGY
Volume -, Issue -, Pages -Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/noad108
Keywords
adoptive immune cell transfer; BST2; CAR T cell; glioma; immunotherapy
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In this study, CD317 was identified as a novel target antigen for CAR T cell therapy against glioblastoma. CD317-CAR T cells showed strong anti-tumor activity in vitro and in vivo, demonstrating the potential of CD317-CAR T cell therapy for glioblastoma treatment. Further evaluation and translation of this immunotherapeutic strategy into clinical neuro-oncology is warranted.
Background Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors. Methods CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models. Results We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals. Conclusions These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology.
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