Therapeutic effects of anti‐GM2 CAR‐T cells expressing IL‐7 and CCL19 for GM2‐positive solid cancer in xenograft model
Takahiro Sasaki, Yukimi Sakoda, Keishi Adachi, Yoshihiro Tokunaga, Koji Tamada
Abstract
BACKGROUND: While chimeric antigen receptor (CAR)-T cell therapy has demonstrated excellent efficacy in hematopoietic malignancies, its clinical application in solid cancers has yet to be achieved. One of the reasons for such hurdle is a lack of suitable CAR targets in solid cancers. METHODS: GM2 is one of the gangliosides, a group of glycosphingolipids with sialic acid in the glycan, and overexpressed in various types of solid cancers. In this study, by using interleukin (IL)-7 and chemokine (C-C motif) ligand 19 (CCL19)-producing human CAR-T system which we previously developed, a possibility of GM2 as a solid tumor target for CAR-T cell therapy was explored in a mouse model with human small-cell lung cancer. RESULTS: Treatment with anti-GM2 IL-7/CCL19-producing CAR-T cells induced complete tumor regression along with an abundant T cell infiltration into the solid tumor tissue and long-term memory responses, without any detectable adverse events. In addition, as measures to control cytokine-release syndrome and neurotoxicity which could occur in association with clinical use of CAR-T cells, we incorporated Herpes simplex virus-thymidine kinase (HSV-TK), a suicide system to trigger apoptosis by administration of ganciclovir (GCV). HSV-TK-expressing anti-GM2 IL-7/CCL19-producing human CAR-T cells were efficiently eliminated by GCV administration in vivo. CONCLUSIONS: Our study revealed the promising therapeutic efficacy of anti-GM2 IL-7/CCL19-producing human CAR-T cells with an enhanced safety for clinical application in the treatment of patients with GM2-positive solid cancers.