Biomarker study of BND-22 in combination with cemiplimab in solid tumors.

Abstract

TPS2676 Background: Immune checkpoint inhibitors benefit only a subset of patients, indicating a need to identify other therapeutic targets and understand the role of tumor microenvironment in shaping immune response. Immunoglobulin-like transcript-2 (ILT2) is an inhibitory receptor expressed on monocytes, dendritic cells, NK cells, and subset of T cells. ILT2 binds multiple MHC class-I molecules, with highest affinity for HLA-G, which is frequently overexpressed in solid tumors. Engagement of HLA-G/ILT2 pathway inhibits key immune functions, including cytotoxicity, cytokine production, antigen presentation, phagocytosis and proliferation. ILT2 expression can be upregulated following anti PD-1 therapy, suggesting a mechanism of resistance to checkpoint blockade. Inhibition of this pathway could potentially promote antitumor immune responses. BND-22, a first-in-class humanized IgG4 mAb, selectively binds to ILT2 on NK/T cells/macrophages, blocking its interaction with HLA-G. In preclinical studies and in a phase I trial, BND-22 alone and in combination with a PD-1 inhibitor demonstrated enhanced anti-tumor activity. The study revealed a dose-dependent activation in immune markers. Building on this finding, we initiated a phase II biomarker study (NCT06651593) of BND-22 in combination with cemiplimab, a recombinant human IgG4/kappa anti–PD-1 mAb, to further understand immune biology and explore the tumor microenvironment. Methods: The study has 2 patient cohorts: Cohort 1: patients with cholangiocarcinoma, who have had prior immunotherapy and Cohort 2: patients with microsatellite stable colorectal cancer and ovarian cancer who are anti–PD-1/PD-L1 naïve. Approximately 40 patients will be enrolled (10 per indication and an additional 10 to the best performing indication). The dose of BND-22 is 10 mg/kg IV on Day 1 every 3 weeks (Q3W), based on the dose escalation trial (NCT04717375). The dose of cemiplimab is the FDA-approved dose of 350 mg IV on Day 1 Q3W, starting at C2D1. Each cycle = 21 days. The combination will be administered for a max of 24 months in the absence of progression or until progression, unacceptable toxicity, death, withdrawal of consent, or discontinuation. Biopsy tissues and peripheral blood samples for biomarker analyses will be collected at baseline, on treatment, and at progression (for patients with CR, PR, or SD≥6 months). The primary objective is 1) to identify biomarkers related to mechanism of action and predictors of response, resistance, and survival 2) evaluate the association between the biomarkers and outcomes. The secondary objective is to evaluate efficacy, safety, and tolerability of this combination; identify imaging characteristics predictive of response and toxicity; and, evaluate TCR beta variable polymorphism and its relationship with immune-related adverse events. Enrollment is ongoing; 2 patients in Cohort 1 and 10 patients in Cohort 2 have been treated. Clinical trial information: NCT06651593 .