c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation.

Yuquan Xiong, Meriem Taleb, Kyohei Misawa, Zhaohua Hou, Srijita Banerjee, Alfredo Amador-Molina, David R Jones, Navin K Chintala, Prasad S Adusumilli

Nature cancer 2023 Jul

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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. © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Yuquan Xiong, Meriem Taleb, Kyohei Misawa, Zhaohua Hou, Srijita Banerjee, Alfredo Amador-Molina, David R Jones, Navin K Chintala, Prasad S Adusumilli. c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation. Nature cancer. 2023 Jul;4(7):1001-1015