AI-in-the-loop in vivo screening and preclinical development of CRISPR-boosted CAR T cells for solid tumor therapy

Objectif

CAR T cell therapy constitutes a medical breakthrough and proof-of-concept for genetically engineered cells as therapeutics. But little progress has been made for solid tumors. We will tackle this challenge by building upon powerful experimental and computational methods developed in my ERC Starting & Consolidator grants.

In Aim 1, we make CAR T cells fitter and better able to withstand the hostile microenvironment of solid tumors through AI-guided in vivo screens in immunocompetent mice, based on our newly developed high-content CAR T cell screening and optimization platform (Datlinger 2025 Nature, in press).

In Aim 2, we make CAR T cell killing specific to the tumor microenvironment, including “two-factor authentication” with AI-designed enhancers controlling CAR activity; this addresses the dearth of tumor-specific antigens and dose-limiting on-target, off-tumor toxicity in solid cancers.

In Aim 3, we adapt the most promising discoveries to human CAR T cells and validate in xenograft models, in anticipation of future clinical testing and following the example of our CRISPR-boosted CAR T cells for leukemia, which we are currently preparing for first-in-human clinical trials with our clinical collaborators.

To combine breadth with coherence, we will focus on molecularly defined subgroups of HER2-positive tumors for three of the most common solid cancers (colon, lung, breast).

This project profits from my long-standing expertise in AI-accelerated biomedical discovery. We integrate high-content screening with multimodal language models (Schaefer 2025 Nature Biotechnology, in press) to optimize CAR T cells and employ AI enhancer design to activate target cell killing only inside tumors.

In conclusion, the Solid-CART project tackles a hard challenge of cancer therapy with innovative methods. It is highly timely as commercial investment into cell therapies has collapsed and academic medicine is stepping up to ensure that new cell therapies reach patients.