Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma

SIMPLE SUMMARY: Glioblastomas are incurable tumors of the central nervous system. Currently, treatment strategies combine neurosurgical intervention, radiation therapy, and chemotherapy. Yet, clinical experience shows that tumors acquire escape mechanisms. Furthermore, the tumor-associated microenvironment, including macrophages expressing the receptor CSF1R, promote and nourish tumor cells. The so-called PD1/PDL1 axis is a major reason why tumors can grow with a “magic hat”; i.e., unrecognized from the immune system. The aim of our study was to assess treatment strategies that target macrophages in the microenvironment by blocking CSF1R alone or in combination with PD1 blockade. Using an immune competent mouse model and an ex vivo microtumor model using freshly resected glioblastoma material, we observed prolonged survival of treated mice and an improved “attack” of the immune system. We conclude that targeting CSF1R is a promising strategy that should be explored in clinical trials, potentially in combination with PD1 blockade. ABSTRACT: Glioblastoma is an aggressive primary tumor of the central nervous system. Targeting the immunosuppressive glioblastoma-associated microenvironment is an interesting therapeutic approach. Tumor-associated macrophages represent an abundant population of tumor-infiltrating host cells with tumor-promoting features. The colony stimulating factor-1/ colony stimulating factor-1 receptor (CSF-1/CSF1R) axis plays an important role for macrophage differentiation and survival. We thus aimed at investigating the antiglioma activity of CSF1R inhibition alone or in combination with blockade of programmed death (PD) 1. We investigated combination treatments of anti-CSF1R alone or in combination with anti-PD1 antibodies in an orthotopic syngeneic glioma mouse model, evaluated post-treatment effects and assessed treatment-induced cytotoxicity in a coculture model of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) ex vivo. Anti-CSF1R monotherapy increased the latency until the onset of neurological symptoms. Combinations of anti-CSF1R and anti-PD1 antibodies led to longterm survivors in vivo. Furthermore, we observed treatment-induced cytotoxicity of combined anti-CSF1R and anti-PD1 treatment in the PDM/TILs cocultures ex vivo. Our results identify CSF1R as a promising therapeutic target for glioblastoma, potentially in combination with PD1 inhibition.