P06.06.B PD-1 CHECKPOINT INHIBITION IN CONJUNCTION WITH NK-92/5.28.Z CELLS IS EFFECTIVE IN AN ADVANCED-STAGE GLIOBLASTOMA MOUSE MODEL AND INDUCES A CD4-ENRICHED T CELL RESPONSE

Abstract

Abstract INTRODUCTION Checkpoint inhibition in combination with adoptive cell therapy holds promise for cancer immunotherapy, and encouraging treatment responses have already been demonstrated for certain tumor types. Glioblastoma (GB) is the most common and aggressive primary brain tumor with limited efficacy of standard therapy. Analysis of the GB tumor immune microenvironment (TIME) has shown prominent immunosuppressive features, including upregulation of exhaustion markers on tumor and infiltrating immune cells. While the surrounding brain is HER2-negative, GB tumors are frequently HER2-positive, suggesting HER2 as a promising target for adoptive immunotherapy. Previous results from mouse glioma models showed efficacy of off-the-shelf NK-92/5.28.z CAR-NK cells targeted against HER2 as monotherapy in early stage tumors. RESULTS Combined treatment with NK-92/5.28.z cells and anti-PD-1 checkpoint blockade resulted in strong synergistic effects, with tumor regression and long-term survival observed even in advanced-stage tumor bearing mice. Analysis of tumor tissues using highplex methods (highplex multicolor flow cytometry, bulk RNAseq and multicolor IHC) revealed changes in lymphocyte infiltration and an altered TIME upon combination treatment with NK-92/5.28.z and anti-PD-1 checkpoint therapy. Specifically, infiltrating lymphocytes displayed an activated phenotype with predominance of CD4 cells and reduction of regulatory T cells. CONCLUSION Our data demonstrate that efficacy of HER2-specific NK-92/5.28.z cells can be enhanced by combination with checkpoint blockade. The combination therapy reverted the immunosuppressive TIME, resulting in successful treatment even of advanced othotopic tumors refractory to CAR-NK monotherapy. We are currently translating this concept into early clinical testing by including a respective patient cohort in our ongoing CAR2BRAIN phase I clinical trial (NCT03383978).