P04.21 Combination therapy of CAR-NK cells and anti-PD-1 antibody displays potent efficacy against late-stage Glioblastoma and induces protective antitumor immunity

Abstract

Background

Checkpoint inhibitors as well as adoptive cell therapy hold great promise for cancer treatment and promising treatment responses have already been demonstrated in different cancer indications. Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Standard therapy prolongs life expectancy only by months. Analysis of the GBM tumor microenvironment (TME) indicates elevated suppressive leukocyte infiltration. While the surrounding brain is HER2-negative, GBM tumors are frequently HER2-positive, suggesting HER2 as a promising target for adoptive immunotherapy. Indeed, previous results show efficacy of CAR-NK cells (NK-92/5.28.z) targeted to HER2 in mouse glioma models at early stages of tumor development.

Materials and Methods

The murine glioma cell line GL261 was transfected with HER2. Tumor cells were implanted subcutaneously into C57BL/6 mice and treated either with HER2-specific NK-92/5.28.z, parental NK-92 cells, or in combination with anti-PD-1. Effects on tumor growth and survival were determined, and lymphocyte infiltration and immunosuppressive TME were characterized by flow cytometry.

Results

Combined treatment with NK-92/5.28.z cells and anti-PD-1 resulted in tumor regression and long-term survival of late-stage tumor bearing mice. Analysis of TME showed enhanced cytotoxic lymphocyte infiltration after treatment.

Conclusion

These data demonstrate enhanced efficacy of a combination of NK-92/5.28.z cells with checkpoint inhibitors in advanced tumors. Checkpoint inhibition possibly induces a cytotoxic rather than immunosuppressive TME, leading to a primed immune system. Thus, combination therapy may be a promising treatment goal for a clinical phase I/II study.