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

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.

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Publication Details

Journal
Nature Cancer
Published
2026-01-06
DOI
https://doi.org/10.1038/s43018-025-01099-7
Citations
1
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
24.20
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article

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

Celina May, Priv.Doz.Dr. Leticia Quintanilla-Martinez, Denis Andrei Ispan, Manfred Claassen et al.
1 citations
Nature Cancer
CAR-T cell therapy research
24.20
article

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

Celina May, Priv.Doz.Dr. Leticia Quintanilla-Martinez, Denis Andrei Ispan, Manfred Claassen, Judith Feucht, Carolin Schneider, Meike Thiemann, Hannah Wurzer, Christoph Trautwein, Mara Mitstorfer, Michel Sadelain, Katrin Bartels, Yu-Jui Ho, Jan Schleicher, Nadine Brückner, Irene González-Menéndez, Jiangqing Chen, Mary Rausch, Philip Bucher, Josef Leibold, Nayan Jain, Melanie Grimm, Jule Kortendieck, Steffen Hardy, Francisco J. Sánchez-Rivera, Dennis Letzgus, Jie Sun, Julia Quach, Bettina Weigelin
article en
1 citations

Abstract

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.

Nature CancerVol. 7(2)
Siemens (Germany) (DE), Memorial Sloan Kettering Cancer Center (US), Columbia University Irving Medical Center (US), Universitätsklinikum Tübingen (DE), Research Institute for Work, Technology and Culture (DE), University Children's Hospital Tübingen (DE), First Affiliated Hospital Zhejiang University (CN), Massachusetts Institute of Technology (US), Zhejiang University (CN), Columbia University (US), University of Tübingen (DE)
Openalex Percentile: Top 3%
CAR-T cell therapy research
24.20
DOIOpen Access PDFOpenAlex
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