IL-12 restores the sequential cytotoxic capacities of anti-GD2 CAR-T and CAR-iNKT cells against glioblastoma

Glioblastoma (GBM) is a fast-progressing and deadly brain tumor. Chimeric antigen receptor (CAR)-based cellular therapies, such as CAR-T cells targeting GD2, have shown some effectiveness, but their long-term success is questionable. To understand why tumors resist these treatments, researchers studied how GBM cells evade CAR-T and CAR-iNKT cells in the lab.

They exposed the CAR effector cells to GD2+ GBM cells in a stepwise manner, and found that while the CAR cells initially killed the tumor cells, their anti-tumor abilities waned after repeated exposures.

Several tumor escape strategies were identified. These included decreased CAR production, slower cell division, less release of granzyme and perforin, reduced GD2 expression on the tumor cells, and an imbalance favoring HLA-E/NKG2A inhibitory pathways over MICA-B/NKG2D activation pathways on both tumor and immune cells. Attempts to improve the CAR cells' persistence by increasing their numbers or adding IL-15 and IL-7 helped somewhat, but did not fully restore their effectiveness.

However, adding IL-12 proved successful in optimizing the tumor-killing capacity of the CAR-T and CAR-iNKT cells. This was achieved through increased CAR effector cell proliferation, higher CAR surface expression, more IFN-y production, and a more balanced HLA-E/NKG2A versus MICA-B/NKG2D pathway. The study concludes that while GD2.CAR-T and GD2.CAR-iNKT cells can target GBM, they are vulnerable to repeated antigen exposure, which IL-12 can counteract.

The researchers suggest further development of IL-12-boosted CAR-T or CAR-iNKT cells and more investigation into the roles of HLA-E and MICA-B pathways in immunotherapy against GBM.