Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma

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.

A platform of patient-derived microtumors identifies therapeutic vulnerabilities in ovarian cancer

“…In line with the present study on OvCa PDM, our recent work on PDM established from human glioblastoma tissue specimen showed a good histopathological comparability of PDM with corresponding primary tumor tissue 60,61 and contained, among other components of the tumor stroma, tumor-associated macrophage populations, which are crucial for the response shown towards treatment with CSF1R and PD1 targeting antibodies 60 . The expansion of currently existing interactions with clinical centers will be of crucial importance for the further successful implementation of this test system in future applications of precision oncology.…”

Targeted Protein Profiling of In Vivo NIPP-Treated Tissues Using DigiWest Technology

“…NIPP effects were primarily based on the inhibitory impact on the cell cycle and cell growth factors. NIPP treatment effects need to be studied more frequently in vivo, or at least in patient-derived cell culture models such as organoids or patient-derived microtumors (PDMs) that mimic the in vivo situation much better [41]. DigiWest technology enables comprehensive protein profiling from very small and FFPE primary tissue biopsies.…”

The Colony Stimulating Factor-1 Receptor (CSF-1R)-Mediated Regulation of Microglia/Macrophages as a Target for Neurological Disorders (Glioma, Stroke)

“…cell ratios, indicative of an enhanced anti-tumour activity (70), leading to longer-term surviving animals. Interestingly, Ali and colleagues investigated different combinatorial therapies, considering CSF-1R, PD-1 and other targets, in glioblastoma and highlighted the importance of the therapy-induced timedependent changes in TME cells (86).…”