Abstract 2940: Comprehensive biomarker program demonstrates proof of mechanism and modulation of the tumor microenvironment due to RG7155, a novel therapeutic antibody targeting tumor associated macrophages
Authors: Bröske Ann-Marie , Klaman Irina , Ratnayake Jayantha , Meneses-Lorente Georgina , Smart Kevin , Cassier Phiippe , Gomez-Roca Carlos , Tourneau Christophe L. , Italiano Antoine , Delord Jean-Pierre , Blay Jean-Yves , Ries Carola , Ruettinger Dominik , Cannarile Michael 
Published: May 2015

Abstract
The tumor microenvironment (TME) is a dynamic, highly complex network consisting of a variety of stromal cell types which support tumorigenesis. Myeloid derived cells probably represent the most abundant cell lineage in the TME, including tumor associated macrophages (TAMs). TAMs have been identified as an independent poor prognostic factor in several cancer types. RG7155 is a novel humanized monoclonal antibody targeting colony stimulating factor-1 receptor (CSF-1R). In vitro, RG7155 treatment results in cell death of CSF1-differentiated CD163+ M2-like macrophages.
The associated mode of action and clinical proof of principle was evaluated in a first-in-man phase 1 study in patients with pigmented villonodular synovitis (PVNS), a neoplastic disorder characterized by CSF1 overexpression, as well as in patients with other advanced solid tumor entities. The associated biomarker program involves mandatory paired pre- and on-treatment biopsies of tumor and surrogate skin tissue as well as pharmacodynamic marker assessment in circulating blood. Biomarker analysis in tumor and skin includes multiplex IHC assays to assess tumor associated macrophages (CD163/CD68/CSF1R), T cells (CD4/CD8), tumor proliferation (Ki67) and vascularization (CD31). Tissue analysis is complemented by systematic peripheral blood sampling allowing flow cytometric analysis of circulating white blood cells (CD45/CD3/CD4/CD8/CD19/CD56/CD14/CD16/MHCII) and profiling of cytokines and growth factors.
Here, we report the initial biomarker data from representative patients from the ongoing Phase 1 study. RG7155 induced a profound reduction of TAMs both in PVNS and various solid malignancies of up to 95% vs. baseline. We also observed depletion of macrophages in the skin which therefore may qualify as a surrogate tissue for mechanistic response. In peripheral blood RG7155 induced sustained modulation of CSF-1 (increase) and alternatively activated monocytes (decrease) was detected. Furthermore, preliminary data indicates a trend for overall increase of CD8/CD4 T cell ratio in the TME following RG7155 treatment, thus a secondary effect of TAM depletion causing intratumoral T cell modulation and tumor microenvironment re-education.
Taken together, the individual biomarker program accompanying the first-in-man phase 1 study of RG7155 is demonstrating proof of mechanism and identified surrogate tissue as well as circulating markers to support optimal biological dose and regimen selection for future studies.
Citation Format: Ann-Marie Bröske, Irina Klaman, Jayantha Ratnayake, Georgina Meneses-Lorente, Kevin Smart, Phiippe Cassier, Carlos Gomez-Roca, Christophe Le Tourneau, Antoine Italiano, Jean-Pierre Delord, Jean-Yves Blay, Carola Ries, Dominik Ruettinger, Michael Cannarile. Comprehensive biomarker program demonstrates proof of mechanism and modulation of the tumor microenvironment due to RG7155, a novel therapeutic antibody targeting tumor associated macrophages. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2940. doi:10.1158/1538-7445.AM2014-2940