CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency
Year: 2026
Type: article
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.
Source: Nature Cancer
Authors: 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
Institutions: University Children's Hospital Tübingen, University of Tübingen, Universitätsklinikum Tübingen, Columbia University Irving Medical Center, Memorial Sloan Kettering Cancer Center, First Affiliated Hospital Zhejiang University, Zhejiang University, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7119001174