Work

284P TES-4207, a first-in-class antagonist of the immune checkpoint NR2F6, drives anti-tumor immunity and enhances efficacy of PD-1 blockade

Year: 2025

Type: article

Abstract: Background: CLDN18.2 is highly expressed in several types of cancer, including gastric, esophageal and pancreatic cancer, and expression is maintained in metastases.Recent clinical success with zolbetuximab has validated CLDN18.2 as a therapeutic target in gastric cancer.AZD5863 is an affinity-optimized, bispecific T cell engager targeting CLDN18.2 and CD3, currently under clinical evaluation (NCT06005493).This preclinical work investigates the effects of AZD5863 in combination with chemotherapy and/or rilvegostomig, a monovalent, Fc-reduced, bispecific antibody against PD-1 and TIGIT receptors.Methods: AZD5863 cytotoxicity was assessed in vitro using gastric and PDAC cell lines.Combinatorial activity was assessed with 5-FU/oxaliplatin, gemcitabine/paclitaxel, and rilvegostomig across multiple rounds of AZD5863 treatment.Cytokine secretion was measured by ELISA, and T cell phenotypes were analyzed using spectral flow cytometry.In vivo efficacy was assessed in C57BL/6-hCD3 mice bearing MC38-mCLDN18.2tumours.Results: Treatment of gastric or PDAC cell lines with chemotherapy upregulated CLDN18.2expression in vitro; combination increased AZD5863 potency.In repetitive stimulation assays, AZD5863-activated T cells maintained cytotoxicity for up to three weeks even with continuous exposure to 5-FU and oxaliplatin.AZD5863 treatment in vitro and in vivo induced T cell expression of activation, proliferation, and co-stimulatory markers, as well as PD-1 and TIGIT expression.In vitro, rilvegostomig enhanced AZD5863-induced expression of T cell activation markers, cytokine secretion, and cytotoxicity and partially rescued functional decline in repetitive T cell stimulation assays.In vivo, combination of AZD5863 with 5-FU and oxaliplatin and a murine surrogate of rilvegostomig resulted in superior tumor growth inhibition, compared with monotherapies.Conclusions: AZD5863 induces T cell activation, cytokine secretion, and tumor cell cytotoxicity in vitro, and in vivo.These effects are further potentiated in combination with clinically relevant chemotherapies or rilvegostomig.Legal entity responsible for the study: AstraZeneca.

Source: Immuno-Oncology Technology

DOI: 10.1016/j.iotech.2025.101483