Overcoming ovarian cancer resistance and evasion to CAR-T cell therapy by harnessing allogeneic CAR-NKT cells

Ovarian cancer (OC) poses a significant challenge for conventional chimeric antigen receptor-engineered T (CAR-T) cell therapy, due to frequent recurrence linked to tumor heterogeneity, platinum resistance, immune evasion, and an immunosuppressive tumor microenvironment (TME). Here, we analyze primary OC patient samples and identify a unique opportunity for allogeneic CAR-NKT (AlloCAR-NKT) cells to concurrently attack OC tumor cells and their TME. Leveraging stem cell gene engineering and a clinically guided culture method, we achieve robust generation of AlloCAR-NKT cells at high yield and purity. Compared to conventional CAR-T cells, AlloCAR-NKT cells demonstrate superior anti-OC efficacy, showcasing multiple OC-targeting mechanisms, focused tumor homing, and pronounced TME modulation. AlloCAR-NKT cells also exhibit a high safety profile with reduced cytokine release syndrome. Additionally, these cells do not induce graft-versus-host disease and resist host immune-cell-mediated allorejection. These findings underscore the unique efficacy and safety advantages, as well as the off-the-shelf potential of AlloCAR-NKT cell therapy for OC. Major funding was provided by the California Institute for Regenerative Medicine (CIRM).