Building a better CAR: emerging high-throughput in vitro tools for CAR selection and optimization

Engineered cell-based therapies show great promise as potential cancer cures, particularly regarding chimeric antigen receptor T cell (CAR-T) treatment of B-cell leukemia. While anti-CD19 CAR-T therapies demonstrate strong clinical responses in hematological malignancies, only a subset of patients show durable remission and trials targeting solid tumor antigens exhibit less encouraging results. The lack of wider CAR-T success likely results from the complexity of this therapeutic modality whereby many factors including the antigen binding domain characteristics (i.e. affinity, avidity), CAR-T phenotype, and micro-environment within individual tumors/tumor-types impact its efficacy. Hence, the extensive toolbox generated and utilized to optimize CAR-T for leukemia may not be applicable to the development of CAR-T against other tumor types. Here, we outline the available in vitro techniques for designing, assessing, and optimizing CAR ectodomains in anticipation that leveraging them will accelerate pre-clinical CAR-T development. These strategies exploit advancements in molecular biology, genetic engineering, biotechnology and high-throughput analysis to manipulate and examine T-cell characteristics learned from decades of cellular immunology research.

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