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bioRxiv · 10.1101/2023.10.02.560460

IDR-induced CAR condensation improves the cytotoxicity of CAR-Ts against low-antigen cancers

Zhang, X.·Xiao, Q.·Zeng, L.·Hashmi, F.·Su, X.
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Abstract

Chimeric antigen receptor (CAR)-T cell-based therapies demonstrate remarkable efficacy for the treatment of otherwise intractable cancers, particularly B-cell malignancies. However, existing FDA-approved CAR-Ts are limited by low antigen sensitivity, rendering their insufficient targeting to low antigen-expressing cancers. To improve the antigen sensitivity of CAR-Ts, we engineered CARs targeting CD19, CD22, and HER2 by including intrinsically disordered regions (IDRs) that promote signaling condensation. The "IDR CARs" triggered enhanced membrane-proximal signaling in the CAR-T synapse, which led to an increased release of cytotoxic factors, a higher killing activity towards low antigen-expressing cancer cells in vitro, and an improved anti-tumor efficacy in vivo. No elevated tonic signaling was observed in IDR CAR-Ts. Together, we demonstrated IDRs as a new tool set to enhance CAR-T cytotoxicity and to broaden CAR-Ts application to low antigen-expressing cancers.

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Zhang, X., Xiao, Q., Zeng, L., Hashmi, F., Su, X.. 2023-10-03. IDR-induced CAR condensation improves the cytotoxicity of CAR-Ts against low-antigen cancers. https://doi.org/10.1101/2023.10.02.560460

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