Chimeric antigen receptor T cell (CAR-T) therapies have revolutionized cancer treatment, with six CAR-T products currently in clinical use1–4. Despite their success, high resistance rates due to antigen escape remain a major challenge5,6. In silico design of de novo binders (DNBs) has the potential to accelerate the development of new binding domains for CAR-T, possibly enabling personalized therapies for cancer resistance7,8. Here, we show that DNBs can be used for CAR-T, targeting clinically relevant cancer antigens. Using a DNB against the epidermal growth factor receptor (EGFR), we demonstrate comparable cytotoxicity, cytokine secretion, long-term proliferation, and lysis of primary patient-derived cancer organoids with single-chain variable fragment (scFv)-based and DNB-based CAR-T cells. Moreover, we use generative artificial intelligence (AI) guided binder design with RFdiffusion9 to target the B cell maturation antigen (BCMA), a key antigen in multiple myeloma treatment10–17. We confirmed the activity of our AI-designed BCMA CAR-T in short- and long-term effector readouts, including a xenograft mouse model of multiple myeloma. Notably, our AI-guided CAR-T approach also successfully targets a mutated BCMA protein variant resistant to the clinically used bispecific antibody teclistamab. In sum, we demonstrate a proof-of-concept for engineering new, bespoke cellular immunotherapies targeting cancer resistance with the help of generative AI. This approach may further accelerate the development of new CAR-T therapies addressing cancer resistance.Competing Interest StatementJ.G. is a paid consultant for Poseida Therapeutics, a company developing various gene and cell therapies, and has financial interests in the company. J.G. is a member of the gene editing committees of ASGCT and ESGCT. A.S. is a paid consultant for TQ Therapeutics, a company developing gene and cell therapies. M.R. has received payments or honoraria for lectures, presentations, and participation in speakers\textquoteright bureaus from Celgene, Falk, Servier, and Roche. F.B. received honoraria and/or travel/accommodation expenses from BMS, AbbVie, and Janssen. M.M., D.A., J.G., and A.S. are co-inventors on a patent application filed by TUM on engineering DNB-based CAR-T therapies.
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Chimeric antigen receptor T cell (CAR-T) therapies have revolutionized cancer treatment, with six CAR-T products currently in clinical use1–4. Despite their success, high resistance rates due to antigen escape remain a major challenge5,6. In silico design of de novo binders (DNBs) has the potential to accelerate the development of new binding domains for CAR-T, possibly enabling personalized therapies for cancer resistance7,8. Here, we show that DNBs can be used for CAR-T, targeting clinically r...
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