Abstract C104: Therapeutic targeting of TREM2+ tumor-associated macrophages as a means of overcoming checkpoint inhibitor resistance
Authors: Binnewies Mikhail , Abushawish Marwan , Lee Tian , Le Tiep , Pollack Joshua L. , Lu Erick , Chen Amanda , Mehta Ranna , Jahchan Nadine , Huang Vicky , Du Xiaoyan , Dash Subhadra , Norng Manith , Pal Aritra , Baker Kevin P. , Sriram Venkataraman 
Published: March 2020

Abstract
Tumor-associated macrophages (TAMs) are a major sources of innate checkpoint inhibitor (CPI) resistance, as they subvert anti-tumor immunity through immunosuppression and supporting tumor growth. In patients, high levels of TAMs predict poor prognosis across multiple solid tumor indications. Therefore, therapeutic targeting of TAMs by impacting their survival and/or modulating their suppressive function is a promising strategy to augment response rates in solid tumor indications, as well as overcome resistance to CPI therapies. We and others have identified the transmembrane protein triggering receptor expressed on myeloid cells-2 (TREM2) as a highly enriched TAM target. TREM2 is comprised of one IgV domain but lacks any known intracellular signaling motifs. However, TREM2 associates with TYRO protein tyrosine kinase-binding protein (TYROBP), which contains an intracellular immunoreceptor tyrosine-baased activation motif (ITAM), allowing for TREM2/TYROBP-mediated signaling to occur. Screening of human tumor tissue microarrays for TREM2 protein demonstrated that TREM2+ TAMs were present in multiple human solid tumors and correlated with disease severity in some indications. Furthermore, in a variety of tumor types, TREM2 mRNA expression negatively correlated with patient survival. To target TAMs, we developed an anti-TREM2 monoclonal antibody (mAb), termed PY314m, that demonstrated compelling anti-tumor activity either as single agent in CPI-sensitive syngeneic tumor models or in combination with anti-PD-1 in CPI-resistant mouse syngeneic tumor models. Mechanistically, PY314m reduced a subset of TAMs, namely the MHCIILow ArginaseHigh M2-like TAMs, expanded MHCIIHigh M1-like TAMs, and induced both innate and adaptive pro-inflammatory cytokine production. By depleting M2-like TAMs and inducing expansion of M1-like TAMs, PY314m treatment removes and modulates multiple immunosuppressive mechanisms. The combination treatment of PY314m and anti-PD-1 mAb produced long-term immunological memory as evidenced by the resistance to tumor rechallenge in mice cured of their tumors. Collectively these findings suggest that anti-TREM2 mAb therapy could be used to overcome CPI resistance in humans. To this end, we developed a humanized version of PY314m termed PY314, which was well-tolerated and showed good pharmacokinetic properties in pilot, repeat dose non-GLP studies in non-human primates. Our ongoing efforts are aimed at better defining CPI-resistant patient populations that will maximally benefit from PY314 therapy.
Citation Format: Mikhail Binnewies, Marwan Abushawish, Tian Lee, Tiep Le, Joshua L. Pollack, Erick Lu, Amanda Chen, Ranna Mehta, Nadine Jahchan, Vicky Huang, Xiaoyan Du, Subhadra Dash, Manith Norng, Aritra Pal, Kevin P. Baker, Venkataraman Sriram. Therapeutic targeting of TREM2+ tumor-associated macrophages as a means of overcoming checkpoint inhibitor resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C104. doi:10.1158/1535-7163.TARG-19-C104