A computational approach by St. Jude Children's Research Hospital scientists promises to make designing T cell-based immunotherapies that target two cancer-related antigens at the same time far easier and faster.
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While CAR-T cells have been successful in treating certain blood cancers, they have not been as effective in treating solid and brain tumors. One reason for this is that cancer cells do not uniformly express the same proteins. Thus, CAR-T cells targeting a single antigen may miss malignant cells that do not express that protein, leading to tumor recurrence and difficult-to-treat relapse. For this reason, scientists have attempted to create CARs that target two proteins at once. However, they encountered problems, including low CAR expression on the surface of T cells and suboptimal anti-cancer capacity. To address this, the researchers developed a computational method to screen many theoretical models of tandem CARs and rank the best candidates for further optimization and validation. The researchers generated and experimentally validated the highest-ranked tandem CAR candidates against selected targets, demonstrating that computationally optimized CARs overcame previous difficulties and performed better in treating animal models of cancer.