Robert Sikorski

Abstract 1599: Antibody-based inhibition of CSF-1R as a component of combination immunotherapy in preclinical models

The colony stimulating factor 1 receptor (CSF-1R) signaling pathway promotes tumor progression via the recruitment, differentiation, and survival of immuno-suppressive tumor-associated macrophages (TAMs). FivePrime has developed cabiralizumab (FPA008), an IgG4 antibody against CSF-1R that blocks the ability of both CSF-1 and IL-34 to bind and activate this receptor, thereby modulating the immune response to tumorigenesis. In order to investigate the impact of CSF-1R signaling inhibition in preclinical models, we generated a surrogate antibody, cmFPA008, which targets mouse CSF-1R and demonstrates equivalent affinity and ligand-blocking ability as FPA008. Utilizing a combination of flow cytometry and immunofluorescence analyses, we have identified alterations in the tumor microenvironment that occur upon CSF-1R inhibition, including significant reduction of immunosuppressive TAMs and an increase in tumor PD-L1 expression. Interestingly, we observe a transient increase in CD8+ T cell number and activation upon TAM depletion, followed by a subsequent increase in MDSC populations that corresponds with reduction of the CD8+ T cell numbers. Moreover, we have used murine syngeneic tumor models to examine the anti-tumor impact of CSF-1R inhibition in combination with other immuno-oncology agents. Our results show that, when added to PD-1/PD-L1 blockade, cmFPA008 can significantly enhance anti-tumor efficacy. We are currently exploring the effects of combining cmFPA008-induced TAM depletion with additional immuno-oncology agents, including T cell agonists. Our preclinical results demonstrate that inhibition of the CSF-1R pathway can combine with various immuno-oncology agents with distinct mechanisms of action. FivePrime has initiated a clinical trial in collaboration with Bristol-Myers Squibb (BMS) to investigate the use of cabiralizumab in combination with nivolumab (anti-PD-1, OPDIVO®) in six different tumor types. Citation Format: David I. Bellovin, Nebiyu Wondyfraw, Barbara Sennino, Quinn Walker, Susan Johnson, Anita Levin, Emma Masteller, Susannah D. Barbee, Robert Sikorski, Tom Brennan. Antibody-based inhibition of CSF-1R as a component of combination immunotherapy in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1599. doi:10.1158/1538-7445.AM2017-1599