CD28 Co-Stimulus Achieves Superior CAR T Cell Effector Function against Solid Tumors Than 4-1BB Co-Stimulus

Spacer or co-stimulatory components in chimeric antigen receptor (CAR) design influence CAR T cell effector function. Few preclinical mouse models optimally support candidate pre-selection for clinical development. Here we use a model which murine cells can be exploited with human tumor xenografts. This mouse-in-mouse approach avoids limitations caused by species-specific factors crucial survival, trafficking and We compared trafficking, expansion control expressing different construct designs targeting two antigens (L1CAM HER2), structurally identical except spacer (long short) (4-1BB CD28) domains to evaluated. Using monoclonal, murine-derived L1CAM-specific Rag-/- mice harboring established xenografted tumors from neuroblastoma line revealed clear superiority using CD28 co-stimulation. L1CAM-targeting short spacer-CD28/? expanded the most at site induced initial regression. Treating patient-derived xenografts confirmed of co-stimulus. was also demonstrated HER2-specific (targeting ovarian carcinoma xenografts). Our findings encourage incorporating signaling into adoptive treatment solid tumors.