Therapeutic efficacy of IL-7/CCL19-expressing CAR-T cells in intractable solid tumor models of glioblastoma and pancreatic cancer.

Cancer immunotherapy using immune checkpoint inhibitors and its combination with other anti-cancer therapies have emerged as a new standard of care, due to the encouraging therapeutic effects in various solid cancers. Nonetheless, glioblastoma and pancreatic cancer remain resistant to immunotherapy and represent intractable cancers with the poorest prognosis. We investigated therapeutic effects of next-generation CAR-T cells producing IL-7 and CCL19 (7×19 CAR-T) in these intractable cancers. Cytotoxic activities and therapeutic effects of 7×19 CAR-T were evaluated in vitro and in vivo, in a model using epidermal growth factor receptor variant III (EGFRvIII)-positive glioblastoma and anti-EGFRvIII CAR-T generated from healthy donor PBMC, or a model using human epidermal growth factor receptor 2 (HER2)-positive pancreatic cancer organoid and anti-HER2 CAR-T generated from the same patient's PBMC. Anti-EGFRvIII 7×19 CAR-T exhibited cytotoxic activity specific to EGFRvIII-positive tumor, induced complete rejection of glioblastoma with massive T cell infiltration and tumor cell death in the tumor tissues, and consequently prolonged mouse survival. Anti-HER2 7×19 CAR-T demonstrated a potent cytotoxic activity against autologous HER2-positive pancreatic cancer organoid and induced complete rejection of autologous tumor along with prolonged mouse survival. Our results suggest that 7×19 CAR-T could become a therapeutic option for glioblastoma and pancreatic cancer. To the best of our knowledge, this study is the first to demonstrate the therapeutic efficacy of next-generation CAR-T in an autologous model using patient-derived tumor organoid and CAR-T generated from the same patient's PBMC, in which unwanted allogeneic immune responses are fully excluded.