Identifying Antigen Combinations To Improve CAR-T Tumor Discrimination

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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.

Pipeline for Identifying Antigen Combinations that Improve Tumor Discrimination

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.

Computational pipeline for identifying antigen pairs with improved tumor discrimination

Fig.1 Computational pipeline for identifying antigen pairs with improved tumor discrimination.

Highlights of Our Service

Dual antigens and antigen triplets AND or NOT logic gates can improve the tumor recognition ability of CAR-T cells.
All transmembrane antigen combination pairs and triples are computationally screened.
Combinatorial antigens that outperform current clinical CAR-T cells are predicted.
Adding antigens improves precision at the cost of recall; 2-3 is optimal.
Dual / Triple Antigen Combinations CAR Design and Construction Services.

Fig.2 Novel antigens identified that form high-performing pairs with numerous current clinically targeted CAR antigens.

For more detailed information, please feel free to contact us or directly sent us an inquiry.

Reference

Dannenfelser, R., et al. (2020). Discriminatory Power of Combinatorial Antigen Recognition in Cancer T Cell Therapies. Cell Systems.

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