Novel CAR-T cell designs to address the challenges of solid tumor therapy

Although treating solid tumors remains disappointingly elusive, the potential of cell-based therapeutics surpasses other modalities suggesting a path forward using cell-based therapies. First, the successful development and fine tuning of Chimeric Antigen Receptors (CARs) are presented to illustrate how highly optimized CARs can be developed de novo.

Using the well-characterized HLA-A*02/HPV-E626-38 complex as an example, several novel CARs were created. Following iterative on-target screening and extensive counter-screening, the CARs made from these scFvs displayed sensitivity and selectivity roughly on par with high-performing patient-derived T-cell receptors (TCRs). Next, in vitro comparisons—antigen sensitivity, selectivity, influence of co-stimulation, checkpoint control, cytokine sensitivity, and antigen-dependent exhaustion—of CARs to clinically relevant TCRs across 5 pMHC targets were conducted, suggesting minimal differences between the two receptor classes as potential therapeutics and that the engineered-T cell modality offers a broad design space for innovation.