Abstract LB071: Tuning the tumor myeloid microenvironment (TME) by targeting TREM2+ tumor-associated macrophages to overcome resistance to immune checkpoint inhibitors

Abstract

The tumor microenvironment (TME) often contains high levels of suppressive myeloid cells that may contribute to innate checkpoint inhibitor (CPI) resistance. Pionyr's Myeloid Tuning approach involves altering the composition and/or the function of myeloid cells in the TME. To this end, therapeutic targeting of tumor-associated macrophages (TAMs) is a promising strategy to increase CPI response rates in solid tumor indications, as well as to overcome resistance to CPI therapies. Pionyr and others identified the transmembrane protein triggering receptor expressed on myeloid cells-2 (TREM2) as a highly enriched TAMs target. Furthermore, TREM2 mRNA expression negatively correlates with patient survival in a variety of tumor types, supporting the involvement of TAMs in tumor progression. Pionyr developed a lead anti-TREM2 monoclonal antibody (mAb), termed PY314, as well as a murinized version of PY314, termed PY314m. PY314m demonstrated significant anti-tumor activity either as single agent in CPI-sensitive syngeneic tumor models or in combination with anti-PD-1 in CPI-resistant syngeneic tumor models. Mechanistically, PY314m reduced the pro-tumorigenic MHC class II-low, M2-like TAMs, induced pro-inflammatory cytokine production, significant increased CD8+ T cell infiltration into the TME. These findings suggest that PY314 therapy could be used to overcome CPI resistance in humans. To select patients most likely to benefit from PY314 therapy, Pionyr developed a qualitative IHC assay that detects TREM2 expression levels in formalin-fixed, paraffin-embedded human tumor tissues. Screening for TREM2 expression in tumor tissues demonstrated that TREM2+ TAMs were present in multiple solid tumor indications and their number increased with disease grade in a selected set of indications. Ongoing efforts are aimed at better understanding localization of TREM2+ TAMs within the TME, and spatial relationship of the TREM2+ TAMs to other immune cells present in the TME. The TREM2 IHC assay will be used to test our hypothesis that patients with tumors with high level of TREM2+ TAMs are most likely to benefit from PY314 treatment. Citation Format: Nadine S. Jahchan, Mikhail Binnewies, Joshua L. Pollack, Ranna Mehta, Subhadra Dash, Christine Tun, Erick Lu, Xiaoyan Du, Kevin P. Baker, Len Reyno, Venkataraman Sriram. Tuning the tumor myeloid microenvironment (TME) by targeting TREM2+ tumor-associated macrophages to overcome resistance to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB071.

Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy

“…Finally, the level of TREM2 presence within TAMs has been positively correlated with tumor staging, including the degree of nodal metastases. Similar inverse trends of TREM2 expression and overall survival have been documented with gastric, hepatic, colorectal, ovarian and breast cancers [ 411 , 413 , 414 ]. Other studies utilizing TREM2 −/− mice and TREM2 inhibitors for sarcoma, colorectal, and breast cancer models have demonstrated that TREM2 deficiency leads to improved antigen presentation from TREM2 −/− macrophages compared to wild type, along with improved CD8 + TIL presence and PD-1 expression, suggesting that TREM2 inhibition may be synergistic with ICI therapy [ 411 ].…”

“…PY314, a humanized monoclonal antibody against TREM2, was among the first to reach clinical trials, with a phase I study (NCT04691375) currently underway comparing PY314 therapy with or without pembrolizumab in patients with advanced solid tumors. While clinical data are currently ongoing, preclinical studies involving PY314 have demonstrated that this anti-TREM2 therapy can provide anti-tumor activity in certain breast cancer models (EMT6) while improving the immune landscape of the TME through increasing the presence of CD8 + TILs, NK cells, and MHC-II-expressing TAMs [ 413 ]. When combined with anti-PD-L1, PY314 further amplifies these immune cell changes, as seen via flow cytometry and IHC staining.…”

The emerging role of triggering receptor expressed on myeloid cell-2 in malignant tumor

“…Preclinical studies of PY314 have shown antitumor effects of anti-TREM2 therapy in breast cancer. This may be because PY314 reduces the infiltration of pro-tumorigenic M2 phenotype macrophages, while increasing the infiltration of CD8 + T cells, NK cells and M1 phenotype macrophages [ 71 ]. Numerous interventions are possible to block TREM2 and its related signaling pathway, such as blocking the extracellular domain with a specific monoclonal antibody (mAb), deleting TREM2 ligands that conditionally existed in the tumor or directly inhibiting TREM2 downstream molecules involved in a related signaling pathway.…”