Highlights d TAM-expressed TREM2 is associated with T cell exhaustion and anti-PD-1 resistance d Effector-enhanced anti-TREM2 antibody treatment drives anti-tumor immunity d TAM abundance and suppression are reduced following anti-TREM2 therapy d Anti-TREM2 therapy potentiates T cell activation and response to anti-PD-1 treatment

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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.

Myeloid cells present in the tumor microenvironment can exist in immunosuppressive states that impede productive anti-tumor immunity. One strategy for targeting these immunosuppressive mechanisms is reprogramming of myeloid cells from immunosuppressive to immunostimulatory, resulting in the removal of the immune inhibition and unleashing of anti-tumor immunity. Triggering receptor expressed on myeloid cells-1 (TREM1) is an immunoglobulin superfamily cell surface receptor expressed primarily on neutrophils and subsets of monocytes and tissue macrophages. TREM1 signals through the association with DAP12 adaptor protein and mediates proinflammatory signaling, amplifies the host immune response to microbial pathogens, and has been implicated in the development of acute and chronic inflammatory diseases. TREM1 is also enriched in tumors, specifically on tumor-associated myeloid cells. To investigate the potential of TREM1 modulation as an anti-cancer therapeutic strategy, we developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody. We found that PY159 does not deplete TREM1-expressing cells, but rather acts as a TREM1 agonist. In vitro human blood assays showed that PY159 treatment upregulated activation markers on monocytes and stimulated neutrophil chemotaxis, as assayed by flow cytometry, transcriptional analysis, and in vitro migration assays. Furthermore, PY159 induced a selective set of proinflammatory cytokines and chemokines, which was dependent on PY159 afucosylation. We validated TREM1 expression in human tumors by single-cell RNAseq, immunohistochemistry, and flow cytometry, and found that it is expressed on myeloid populations, including tumor-associated neutrophils (TAN), tumor-associated macrophages (TAM), and monocytic myeloid-derived suppressive cells (mMDSC). We showed that PY159 can also induce proinflammatory cytokines and chemokines in dissociated human tumors in vitro, demonstrating that PY159 can reprogram tumor-associated myeloid cells. Finally, in vivo treatment of mice with a surrogate anti-mouse TREM1 antibody, PY159m, promoted anti-tumor efficacy in several syngeneic mouse tumor models, both as single-agent and in combination with checkpoint inhibitors, such as anti-PD-1 antibody. Together, these results demonstrate that therapeutic targeting of TREM1 with a TREM1 agonist antibody, PY159, promotes myeloid cell reprogramming and anti-tumor immunity. PY159 safety and tolerability have been demonstrated in non-human primates, and safety and efficacy of PY159 are currently being evaluated in first-in-human clinical trial (NCT04682431) including solid tumors that are resistant and refractory to standard of care therapies. Citation Format: Erin Mayes, Vladi Juric, Mikhail Binnewies, Pamela Canaday, Tian Lee, Subhadra Dash, Joshua L. Pollack, Joshua Rudolph, Vicky Huang, Xiaoyan Du, Nadine Jahchan, Asa J. Ramoth, Shilpa Mankikar, Manith Norng, Carlos Santamaria, Kevin P. Baker, Linda Liang. Therapeutic targeting of TREM1 with PY159 promotes myeloid cell reprogramming and unleashes anti-tumor immunity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P104.