IMMU-15. Local CAR-NK cell therapy in combination with systemic checkpoint inhibition induces anti-tumor responses even in distant tumor locations in an immunocompetent glioblastoma mouse model

Abstract BACKGROUND The glioblastoma (GB) tumor microenvironment (TME) is characterized by pronounced immunosuppression, with PD-L1 expression both on glioma cells and microglia, and exhaustion of infiltrating immune cells. We showed previously that a combination of local injection of HER2-specific NK-92/5.28.z CAR-NK cells and systemic anti-PD-1 checkpoint inhibition modulates the immunosuppressive TME to a more inflammatory phenotype. Here, we explored whether this combination can induce a therapeutic effect even against distant untreated tumors (“abscopal effect”). METHODS Subcutaneous GL261/HER2 tumors were implanted bilaterally in both flanks of C57BL/6 mice. Then tumor-bearing animals received combination therapy with systemic anti-PD-1 checkpoint inhibition and local CAR-NK cell therapy of only one tumor, while effects on the growth of both tumors and survival were determined. RESULTS Combination therapy resulted in strong synergistic effects, with tumor regression observed in both, ipsilateral (treated) and contralateral (locally untreated) tumors. Thereby, the immune reaction triggered by the treatment caused rejection of both tumors, leading to long-term survival of the mice. CONCLUSIONS The induction of an endogenous immune response by local therapy with HER2-specific CAR-NK cells in combination with systemic checkpoint inhibition is an essential step to achieve therapeutic efficacy. Thereby, tumor control can also be attained in areas not directly accessible for locally injected CAR-NK cells. Ongoing work aims to elucidate the underlying immunological mechanisms and further increase efficacy of this approach.