Small cell lung cancer (SCLC) tumors resist checkpoint blockade immunotherapy by disabling the machinery of antigen presentation that would otherwise betray their presence to T cells, whose receptors bind only to antigens presented by MHC molecules on sick and cancerous cells. So chimeric antigen-receptor (CAR)-T cells, which detect cancer antigens using an antibody fragment that requires no such presentation, could be a viable alternative for SCLC immunotherapy. The trouble here is that only a couple of CAR targets have been identified for this cancer, and those are mainly expressed in neuroendocrine SCLCs. Researchers co-led by Ludwig Stanford’s Crystal Mackall reported in Cell Reports Medicine in January that SCLC and thoracic SMARCA4-deficient undifferentiated tumors (UTs)—which clinically mimic SCLC—both express another antigen, B7-H3/CD276, that can be targeted for CAR-T therapy. SCLC cells unfortunately express this antigen parsimoniously. SMARCA4-deficient UTs, on the other hand, express it at high levels. They, however, resist CAR-T therapy by secreting TGF-β. Cell culture and animal studies demonstrated that both mechanisms of resistance can be overcome by engineering the CAR-T cells to co-express c-Jun. When knocked in to the CAR-T cell genome using CRISPR-Cas9 editing, c-Jun enhances CAR-T activity by inducing the expression of type I/II cytokines and preventing CAR-T cell exhaustion. The researchers also showed that their manufacturing method is suitable for clinical applications.
c-JUN enhances CRISPR knockin anti-B7-H3 CAR T cell function in small cell lung cancer and thoracic SMARCA4-deficient undifferentiated tumors
Cell Reports Medicine, 2026 January 20