O8.3 - Targeting tumor-associated macrophages in cancer patients

Abstract

ABSTRACT Macrophage infiltration has been identified as an independent poor prognostic factor in several cancer types. The major survival factor for these tumor-associated macrophages (TAM) is macrophage colony stimulating factor 1 (CSF1). Current clinical approaches to therapeutic targeting of macrophages in oncology range from blocking the recruitment of monocytes into tumors to inhibition of TAM survival and manipulation of the polarization of macrophage subtypes within the tumor. Inhibition of TAM survival/activation by targeting the CSF1/CSF1 receptor (CSF1R) axis may be particularly attractive as CSF1 is highly expressed by several tumor types and both the CSF1 expression and the intratumoral presence of CSF1R positive macrophages have been shown to correlate with poor survival in various solid and hematological malignancies. Furthermore, in preclinical models, blocking the CSF1R pathway activity has been shown to enhance/restore the activity of several clinically established treatment modalities and also T cell based immunotherapy. Currently, at least nine clinical stage programs developing CSF1/CSF1R inhibitors are underway. However, available clinical data on both safety and clinical activity is still very limited. Objective responses for single agent treatment have been reported in up to 83% of patients with diffuse type giant cell tumor (dt-GCT; also referred to as PVNS) for RG7155, an anti-CSF1R IgG1 monoclonal antibody [ 1 , 2 ]. PVNS is an orphan disease with high unmet medical need, characterized by an overexpression of CSF1 usually caused by a chromosomal translocation involving the CSF1gene. Thus, PVNS may serve as a “model disease” for agents interfering with the CSF1R and its ligands. Administration of RG7155 to PVNS patients also led to striking reductions of CSF1R + CD163+ macrophages in the tumor. TAM reduction was also observed in paired tumor samples of patients with various advanced solid malignancies, suggesting broad applicability of this therapeutic approach, in particular in combination with other immunotherapeutic approaches.