Journal of Clinical Oncology and Cancer Research

CRISPR screening of CAR T Cells and cancer stem cells reveals critical dependencies for cell-based therapies

18^th International Conference on CANCER AND CANCER THERAPY
June 13-14, 2022 | Webinar

Dongrui Wang

City of Hope Medical Center, USA

Posters & Accepted Abstracts : J Clin Oncol Cancer Res

Abstract:

Glioblastoma (GBM) contains self renewing GBM stem cells (GSCs) potentially amenable to immunologic targeting, but chimeric antigen receptor (CAR) T cell therapy has demonstrated limited clinical responses in GBM. Here, we interrogated molecular determinants of CAR-mediated GBM killing through whole-genome CRISPR screens in both CAR T cells and patient-derived GSCs. Screening of CAR T cells identified dependencies for effector functions, including Transducin-like enhancer protein 4 (TLE4) and IKAROS Family Zinc Finger 2 (IKZF2). Targeted knockout of these genes enhanced CAR antitumor efficacy. Bulk and single cell-RNA sequencing of edited CAR T cells revealed transcriptional profiles of superior effector function and inhibited exhaustion responses. Reciprocal screening of GSCs identified genes essential for susceptibility to CARmediated killing, including RELA and NPLOC4, the knockout of which altered tumor-immune signaling and increased responsiveness of CAR therapy. Overall, CRISPR screening of CAR T cells and GSCs discovered avenues for enhancing CAR therapeutic efficacy against GBM, with the potential to be extended to other solid tumors.

PDF HTML