c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation Journal Article
| Authors: | Xiong, Y.; Taleb, M.; Misawa, K.; Hou, Z.; Banerjee, S.; Amador-Molina, A.; Jones, D. R.; Chintala, N. K.; Adusumilli, P. S. |
| Article Title: | c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation |
| 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. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | genetics; t lymphocyte; t-lymphocytes; metabolism; interleukin 2; cell line, tumor; protein tyrosine kinase; tumor cell line; receptor protein-tyrosine kinases; adoptive immunotherapy; immunotherapy, adoptive; cd28 antigen; interleukin-2; cd28 antigens |
| Journal Title: | Nature Cancer |
| Volume: | 4 |
| Issue: | 7 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2023-07-01 |
| Start Page: | 1001 |
| End Page: | 1015 |
| Language: | English |
| DOI: | 10.1038/s43018-023-00573-4 |
| PUBMED: | 37336986 |
| PROVIDER: | scopus |
| PMCID: | PMC10765546 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Prasad Adusumilli -- Source: Scopus |
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