Abstract
BACKGROUND
Glioblastoma (GB) is the most common and aggressive primary brain tumor with limited efficacy of standard therapy. The GB tumor microenvironment (TME) is characterized by pronounced immunosuppression, with PD-L1 expression on glioma cells and exhaustion of infiltrating immune cells. We have previously shown that combination of NK-92/5.28.z CAR-NK cells and anti-PD-1 checkpoint inhibition modulates the immunosuppressive TME to a more anti-tumorigenic phenotype. Hence, we explored if the combination of CAR-NK cells and anti-PD-1 induces a therapeutic effect even in distant untreated tumor locations (“abscopal effect”).
MATERIAL AND METHODS
Subcutaneous GL261/HER2 tumors were implanted bilaterally in both flanks of C57BL/6 mice. Mice received combination therapy with systemic anti-PD-1 checkpoint inhibition and local CAR-NK cell treatment of only one tumor, while effects on growth of both tumors and survival were determined.
RESULTS
Combination therapy resulted in strong synergistic effects, with tumor regression observed in both equilateral (treated) and contralateral (locally untreated) tumors. Moreover, complete rejection of both tumors with long-term survival was achieved in these mice.
CONCLUSION
The activation of an endogenous immune response by HER2-specific CAR-NK cells in combination with checkpoint inhibition is important for therapeutic efficacy, providing tumor control in areas not accessible for CAR-NK cells. Ongoing work aims at elucidating the underlying immunological mechanisms and further increasing efficiency of this approach.