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<p>Chimeric antigen receptor T cells (CAR T cells) with T stem (T<sub>SCM</sub>) cell-like phenotypic characteristics promote sustained antitumor effects. We performed an unbiased and automated high-throughput screen of a kinase-focused compound set to identify kinase inhibitors (KIs) that preserve human T<sub>SCM</sub> cell-like CAR T cells. We identified three KIs, UNC10225387B, UNC10225263A and UNC10112761A, that combined in vitro increased the frequency of CD45RA<sup>+</sup>CCR7<sup>+</sup>TCF1<sup>hi</sup> T<sub>SCM</sub> cell-like CAR T cells from both healthy donors and patients with cancer. KI-treated CAR T cells showed enhanced antitumor effects both in vitro and in vivo in mouse tumor models. The KI cocktail maintains T<sub>SCM</sub> cell-like phenotype preferentially in CAR T cells originating from naive T cells and causes transcriptomic changes without arresting T cell activation or modulating the chromatin organization. Specific kinases, ITK, ADCK3, MAP3K4 and CDK13, targeted by the KI cocktail in a dose-dependent manner are directly associated with the preservation of T<sub>SCM</sub> cell-like CAR T cells. Knockdown of these kinases individually or in combination enriches for T<sub>SCM</sub> cell-like CAR T cells, but only CAR T cells generated in the presence of the KI cocktail show robust expansion and differentiation on stimulation with tumor cells. Overall, transient pharmacological inhibition of strategically targeted kinases maintains stem-like features in CAR T cells and improves their antitumor activity.</p>

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A multi-kinase inhibitor screen identifies inhibitors preserving stem-cell-like chimeric antigen receptor T cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月8日

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  • Feifei Song,
  • Ourania Tsahouridis,
  • Simone Stucchi,
  • Tara Walhart,
  • Sophie Mendell,
  • P. Brian Hardy,
  • Matthew Axtman,
  • Shiva K. R. Guduru,
  • Thomas S. K. Gilbert,
  • Lee M. Graves,
  • Laura E. Herring,
  • Barbara Savoldo,
  • Xingcong Ma,
  • Mark Woodcock,
  • Justin J. Milner,
  • Anastasia Ivanova,
  • Kenneth H. Pearce,
  • Yang Xu,
  • Gianpietro Dotti

摘要

Chimeric antigen receptor T cells (CAR T cells) with T stem (TSCM) cell-like phenotypic characteristics promote sustained antitumor effects. We performed an unbiased and automated high-throughput screen of a kinase-focused compound set to identify kinase inhibitors (KIs) that preserve human TSCM cell-like CAR T cells. We identified three KIs, UNC10225387B, UNC10225263A and UNC10112761A, that combined in vitro increased the frequency of CD45RA+CCR7+TCF1hi TSCM cell-like CAR T cells from both healthy donors and patients with cancer. KI-treated CAR T cells showed enhanced antitumor effects both in vitro and in vivo in mouse tumor models. The KI cocktail maintains TSCM cell-like phenotype preferentially in CAR T cells originating from naive T cells and causes transcriptomic changes without arresting T cell activation or modulating the chromatin organization. Specific kinases, ITK, ADCK3, MAP3K4 and CDK13, targeted by the KI cocktail in a dose-dependent manner are directly associated with the preservation of TSCM cell-like CAR T cells. Knockdown of these kinases individually or in combination enriches for TSCM cell-like CAR T cells, but only CAR T cells generated in the presence of the KI cocktail show robust expansion and differentiation on stimulation with tumor cells. Overall, transient pharmacological inhibition of strategically targeted kinases maintains stem-like features in CAR T cells and improves their antitumor activity.