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BACKGROUND Checkpoint inhibitors as well as adoptive cell therapy hold great promise for cancer treatment and encouraging treatment responses have already been demonstrated in different cancer indications. Glioblastoma (GB) is the most common and aggressive primary brain tumor. Standard therapy has very limited efficacy in the majority of patients. Analysis of the GB tumor microenvironment (TME) has shown prominent immunosuppressive features including expression of PD-L1 on tumor cells and increased frequency of FOX-P3 positive regulatory T cells. While the surrounding brain is HER2-negative, GB tumors are frequently HER2-positive, suggesting HER2 as a promising target for adoptive immunotherapy. MATERIALS AND METHODS The murine glioma cell line GL261 was transfected with HER2. Tumor cells were orthotopically implanted into C57BL/6 mice and treated either with HER2-specific NK-92/5.28.z cells alone or in combination with an anti-PD-1 antibody. Effects on tumor growth and survival were determined, lymphocyte infiltration and immunosuppressive TME were characterized. RESULTS Combined treatment with NK-92/5.28.z cells and anti-PD-1 antibody resulted in synergistic tumor regression and long-term survival of advanced-stage tumor bearing mice. Analysis of TME showed enhanced cytotoxic lymphocyte infiltration and altered profiles of exhaustion markers in tumor and immune cells. CONCLUSION These data demonstrate that efficacy of NK-92/5.28.z cells can be enhanced by co-therapy with checkpoint inhibitors, resulting in successful treatment of advanced tumors refractory to mono-therapy. Furthermore, this combination therapy induces a cytotoxic rather than immunosuppressive TME, leading to a primed immune system. To address this question in a clinical setting, we are planning a phase I clinical study (CAR2BRAIN-CHECK).

neuro-oncology

P12.04 Synergistic effects of combination therapy of CAR-NK cells and anti-PD-1 antibody result in high efficacy against advanced stage orthotopic glioblastoma grafts in a syngeneic mouse model and induce protective anti-tumor immunity in vivo