Chimeric antigen receptor (CAR) T cell therapy has revolutionised the treatment paradigm of haematological cancers but remains largely ineffective in solid cancers. Understanding the difference in anti-cancer responses in blood cancers and solid cancers will contribute to the development of a valid CAR T cell therapy in solid cancers. In this study, we generated new CARs having the same backbone structure and directly compared these CAR T cell efficacies in blood and solid cancers.
The CD19-CAR and Her2-CAR T cells generated from the same donors demonstrated very similar profiles in their CD8: CD4 ratio, CAR transduction rate, T cell memory phenotype, exhaustion markers and the speed of expansion in vitro. Both CAR T cells are highly effective in killing their target cancer cells and secrete IFN-g in vitro. Consistent with other preclinical and clinical reports, in NSG mice, while CD19-CAR T cells were highly effective in suppressing CD19+ NALM6 acute lymphoblastic leukemia (ALL) progression, Her2-CAR T cells failed to inhibit the growth of MDA-MB-468-Her2+ breast cancers.
To dissect the tumour- and CAR-related factors in the in vivo models, we enforced MDA-MB-468-Her2+ breast cancer cells to express CD19 and the CD19+ NALM6 leukemia cells to express Her2. Our data showed that CD19-CAR T cells were efficient in suppressing all the CD19+ cancers in vivo including both the blood and solid cancers, while Her2-CAR T cells failed to suppress all the Her2+ cancers. Together, our study demonstrated that antigen selection is critical for CAR T cell treatment. Our current study focuses on developing novel strategies to force tumour cells to express CD19 in vivo and developing new CARs and reagents to redirect CD19-CAR T cells to kill CD19- cancers.