Background: Leukocyte Immunoglobulin-like receptor B2 [LILRB2; immunoglobulin-like transcript 4 (ILT4)] is an immunoinhibitory protein expressed on the surface of myeloid cells and is a therapeutic target of interest in immuno-oncology. Published data showed that antagonism of LILRB2 resulted in the repolarization of human macrophages from an M2 (suppressive) to M1 (pro-inflammatory) phenotype, and enhancement of anti-tumor immunity in a mouse model (Chen 2018). JTX-8064 is a novel humanized IgG4 monoclonal antagonist antibody that selectively binds LILRB2 and prevents it from binding its ligands, classical and non-classical MHC I molecules. By blocking the ability of LILRB2 to bind HLA-A/B and/or HLA-G, a marker of immunotolerance on cancer cells, JTX-8064 has been shown to enhance pro-inflammatory cytokine production in macrophages (Cohen 2019). Additionally, blocking HLA-A/B-LILRB2 binding with JTX-8064 may augment antigen presentation and has been shown to lead to enhanced T cell activation and IFNg production (McGrath 2021). Using an ex vivo tumor explant model, we observed an IFNg-associated pharmacodynamic response in tumor tissue treated with JTX-8064 and a PD-1 inhibitor (PD-1i) that was not observed with PD-1i alone. Biomarkers were identified that predicted this JTX-8064 driven response (Hashambhoy-Ramsay 2020). It is hypothesized that JTX-8064 is a novel macrophage immune checkpoint inhibitor that may overcome mechanisms of resistance to PD-1i in tumors not responsive to JTX-8064 or PD-1i alone. Methods: The primary objectives of this open-label, phase 1, first-in-human, multicenter trial are to determine the safety and tolerability, and the recommended phase 2 dose (RP2D) of JTX-8064 as a monotherapy and in combination with a PD-1i, JTX-4014 (a Jounce investigational agent) or pembrolizumab, in patients with advanced solid tumors (NCT04669899). The INNATE study will consist of 4 stages: 1) JTX-8064 monotherapy dose escalation, 2) JTX-8064 dose escalation in combination with a PD-1i, 3) JTX-8064 monotherapy in indication-specific expansion cohorts and 4) JTX-8064 in combination with a PD-1i in indication-specific expansion cohorts. Stages 1 and 2 will employ an innovative interval i3 + 3 design with Bayesian decision framework to guide dose escalation. Safety, pharmacokinetic and receptor occupancy data will be considered during dose escalation. INNATE will assess pharmacodynamic and potential predictive biomarkers of response, and the expansion cohorts will explore multiple patient populations, including PD-(L)1i sensitive and PD-(L)1i-resistant (primary or acquired) patients to address current unmet medical needs. Enrolment in INNATE began in January 2021. Clinical trial information: NCT04669899