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Chimeric Antigen Receptor (CAR) T cell therapy has shown curative potential for B cell malignancies and is expected to treat other hematological malignancies and solid tumors. However, the main obstacle to its extension to solid tumors remains the challenge of specific tumor recognition. Although chimeric antigen receptors (CARs) targeting tumor-associated antigens can be modified, many of these antigens, especially solid tumors, are often expressed at lower levels in other normal tissues, leading to cases of toxic cross-reactivity. The application of CAR-T cells in solid tumors is limited by the difficulty of identifying a single target antigen that can fully distinguish tumors from normal tissues to avoid toxicity. However, the current methods of engineering CAR-T cells only focus on the recognition of a single target antigen. If we think that solid tumors express an array of antigens, it is possible to improve specificity by identifying combinatorial antigen signatures.
At Creative Biolabs, we perform a comprehensive in silico screen to identify multiple antigen signatures that can improve tumor discrimination through CAR-T cells, which are engineered to integrate multiple antigens through Boolean logic (such as AND and NOT) enter. We constructed and tested several potential AND-gated T cells for different cancers. It was verified that the addition of a second or third antigen using AND or NOT gating can significantly improve CAR-T cell performance.
For each cancer type (N=33), the standardized RNA-seq expression data was combined with the RNA-seq data of 34 normal tissues. Then evaluate the potential of all potential transmembrane antigen pairs in the expression space to isolate samples of a given tumor type from all normal samples. The shaded boxes highlight the specific steps of the pipeline, first representing the presentation data, then the scoring method, and the toy example highlights how to calculate the evaluation metrics.
Fig.1 Computational pipeline for identifying antigen pairs with improved tumor discrimination.
Fig.2 Novel antigens identified that form high-performing pairs with numerous current clinically targeted CAR antigens.
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