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<p>Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (CAR) therapies. Here we performed a CAR-adapted base-editing screen of <i>PIK3CD</i>, a key regulator of T cell function, metabolism and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. We found that point mutations with differing effects on phosphatidylinositol-3-kinase delta (PI3Kδ) signaling activity were advantageous in distinct CAR contexts: The PI3Kδ-activating substitution E81K enhanced proliferation, metabolic fitness and effector function of 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3Kδ-attenuating substitution L32P improved T cell memory formation and functionality of 28z CAR T cells. Together, our approach of rational optimization of activation-dependent signaling through targeted allelic reprogramming (ROADSTAR) illustrates the importance of CAR design-specific fine-tuning of intrinsic T cell signaling and demonstrates the potential of base editing for next-generation cellular therapies.</p>

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CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月6日

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  • Philip Bucher,
  • Nadine Brückner,
  • Jule Kortendieck,
  • Melanie Grimm,
  • Jan T. Schleicher,
  • Karlotta Bartels,
  • Steffen Hardy,
  • Martina Rausch,
  • Hannah Wurzer,
  • Meike Thiemann,
  • Celina May,
  • Mara Mitstorfer,
  • Dennis Letzgus,
  • Julia Quach,
  • Carolin Schneider,
  • Denis A. Ispan,
  • Irene Gonzalez-Menendez,
  • Nayan Jain,
  • Yu-Jui Ho,
  • Jiangqing Chen,
  • Francisco J. Sánchez-Rivera,
  • Jie Sun,
  • Leticia Quintanilla-Martinez,
  • Christoph Trautwein,
  • Bettina Weigelin,
  • Manfred Claassen,
  • Michel Sadelain,
  • Judith Feucht,
  • Josef Leibold

摘要

Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (CAR) therapies. Here we performed a CAR-adapted base-editing screen of PIK3CD, a key regulator of T cell function, metabolism and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. We found that point mutations with differing effects on phosphatidylinositol-3-kinase delta (PI3Kδ) signaling activity were advantageous in distinct CAR contexts: The PI3Kδ-activating substitution E81K enhanced proliferation, metabolic fitness and effector function of 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3Kδ-attenuating substitution L32P improved T cell memory formation and functionality of 28z CAR T cells. Together, our approach of rational optimization of activation-dependent signaling through targeted allelic reprogramming (ROADSTAR) illustrates the importance of CAR design-specific fine-tuning of intrinsic T cell signaling and demonstrates the potential of base editing for next-generation cellular therapies.