PY159, TREM1 and “re-tuning” the tumor microenvironment (TME) through targeted reprogramming of immunosuppressive myeloid cells
Pionyr Immunotherapeutics is developing PY159 for the treatment of advanced solid tumors refractory to or relapsed with the current standard of care (SOC). PY159 is a humanized monoclonal antibody (mAb) that specifically binds Triggering receptor expressed on myeloid cells 1 (TREM1) and acts as an agonist mAb by crosslinking TREM1 and inducing downstream signaling through the TREM1/DNAX Activating Protein of 12kDa (DAP12) complex. Pionyr’s PY159 program has been cleared by the FDA for initiation of Phase 1 clinical trials.
Why target immunosuppressive myeloid derived immune cells?
Clinically, high levels of tumor-associated myeloid infiltrate correlate with poor patient prognosis across multiple solid tumor indications and are likely sources of CPI resistance (Awad et al. 2018; Bingle et al. 2002).
Given the immunosuppressive function of tumor-associated myeloid cells, including monocytic myeloid derived suppressor cells (mMDSC), tumor associated neutrophils (TANs), and tumor associated macrophages (TAMs), re-programing these cells within the tumor microenvironment (TME) to become pro-inflammatory is expected to have a major impact on stimulating anti-tumor immunity (Guerriero et al. 2017; Jahchan et al. 2019; Raggi and Bosco 2020).
Reprogramming of immunosuppressive myeloid cells in combination with removing the “immunosuppressive brake” on T-cells via treatment with checkpoint inhibitors, is a potentially synergistic all-immune therapy strategy for solid tumor treatment.
TREM1 expression on TAMs, TANs and immunosuppressive monocytes
TREM1 is an immunoglobulin (Ig) superfamily transmembrane protein constitutively expressed on the cell surface of peripheral blood monocytes and neutrophils, and further upregulated by Toll-like receptor (TLR) ligands (Bouchon et al. 2000; Bouchon et al. 2001; Mabbott et al. 2013). Targeting TREM1 offers a promising therapeutic opportunity for patients with checkpoint inhibitor (CPI)-hypo-responsive or -resistant tumors as the receptor is expressed on the three myeloid immuno-suppressive cell populations (i.e., mMDSC, TANs, and TANs) and activation of TREM1 is known to amplify immune responses (Bouchon et al. 2000; Bouchon et al. 2001). Shown above, TREM1 is specifically expressed in TAM and monocytes from single cell immune profiling of stage III-C ovarian cancer.
TREM1 is expressed within the TME and is associated with poorer outcomes
As with TREM2, the level of expression of TREM1 has been shown to be higher in cancerous tissues vs normal tissues, likely due to the presence of TREM1 positive myeloid cells infiltrating cancerous tissue. TREM1 levels have also been shown to correlate with poorer patient outcomes across multiple solid tumor types. Shown here as an example is breast cancer where high levels of TREM1 have been shown to correlate with a lower probability of patient survival.
PY159 Mechanism of Action
PY159’s mechanism-of-action (MOA) involves the activation of TREM1 signaling to repolarize suppressive tumor-associated myeloid populations, including mMDSCs, TANs, and TAMs, to induce a proinflammatory phenotype in the tumor microenvironment (TME), which promotes anti-tumor immunity
PY159 demonstrates single agent and combinatorial efficacy in preclinical models
Therapeutic administration of PY159 alone or in combination with CPIs resulted in complete regressions of tumors in multiple mouse syngeneic subcutaneous and orthotopic tumor models. In the mice cured of tumors, Pionyr confirmed long-term immunity by reimplanting the same tumor cell lines and finding no tumor growth after a month of treatment-free period.