Xiong et al. investigated the impact of c-Kit signaling on CAR T cell therapy for solid tumors. CAR T cells expressing a mutated c-KIT (KITv) that constitutively activates cKIT via phosphorylated STAT exhibited enhanced antigen-dependent growth, CD28/IL-2 independent co-stimulation, and increased IFNγ production with enhanced cytotoxicity compared to controls. In multiple solid tumor models, KITvCAR T cells improved survival, functioned well in TGFβ-high and antigen-low models, and were susceptible to TKI therapy. KITvCAR T cells were additive with CD28 costimulation and exhibited comparable or better in vivo efficacy than second-generation CARs.
Contributed by Katherine Turner
ABSTRACT: The limited efficacy of chimeric antigen receptor (CAR) T cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. Herein, we use c-Kit signaling, a physiological pathway associated with stemness in hematopoietic progenitor cells (T cells lose expression of c-Kit during differentiation). CAR T cells with intracellular expression, but no cell-surface receptor expression, of the c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen activation-dependent proliferation and CD28- and interleukin-2-independent and interferon-γ-mediated co-stimulation, augmenting the cytotoxicity of first-generation CAR T cells. This translates to enhanced survival, including in transforming growth factor-β-rich and low-antigen-expressing solid tumor models. KITv CAR T cells have equivalent or better in vivo efficacy than second-generation CAR T cells and are susceptible to tyrosine kinase inhibitors (safety switch). When combined with CD28 co-stimulation, KITv co-stimulation functions as a third signal, enhancing efficacy and providing a potent approach to treat solid tumors.
Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer
Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. adusumip@mskcc.org. Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. adusumip@mskcc.org.
