First-in-human mRNA CAR therapy: Correlative biomarker analysis from the MT-302 phase 1 study targeting TROP2 in patients with advanced epithelial tumors.

Abstract

2591 Background: Outcomes for patients with epithelial cancers, including breast, lung and gastrointestinal tumors, remain poor particularly in advanced stages. MT-302, an mRNA-based chimeric antigen receptor (CAR) therapy, seeks to address this unmet need by reprogramming myeloid cells in vivo to recognize and kill TROP2-expressing tumors, recruit immune cells into tumor and induce systemic anti-tumor responses. Its CAR construct combines an anti-TROP2 scFv with truncated CD89 and becomes functionally active only upon association with FcRγ-expressing myeloid cells, ensuring precise immune engagement. Delivered as an off-the-shelf, repeatable intravenous treatment without the need for preconditioning, MT-302 overcomes the logistical and technical challenges of traditional cell and CAR therapies. MT-302 is being evaluated in a Phase 1, multicenter, open-label dose-escalation study (NCT05969041) in adults with advanced epithelial cancers expressing TROP2. Here, we present a correlative biomarker analysis from the first-in-human MT-302 study. Methods: Tumor biopsies and peripheral blood samples were collected pre- and post-dose. Biomarkers were evaluated utilizing advanced technologies including immunohistochemistry (IHC), Xenium and Hyperion imaging, flow cytometry, Chromium single-cell sequencing, T cell receptor sequencing and Meso Scale Discovery (MSD). These methods assessed TROP2 expression on cancer cells, TROP2 CAR expression within immune cells, systemic pharmacodynamic effects, immune cell infiltration and tumor microenvironment changes. Results: Results showed robust TROP2 CAR expression in circulating myeloid cells within hours of dosing. In tumor biopsies, CAR-positive myeloid cells co-localized with TROP2-expressing cancer cells. Post-dose tumor biopsies exhibited an increase in antigen presentation markers and pro-inflammatory signaling compared to baseline. MT-302 elicited systemic interferon-driven chemokine responses and reprogrammed the tumor immune microenvironment, promoting effector T cell recruitment. T cell receptor sequencing confirmed the emergence of novel T cell clones, consistent with adaptive immunity activation. Baseline IHC confirmed high TROP2 expression in enrolled patients, correlating with pharmacodynamic activity and immune reprogramming. Conclusions: This Phase 1 study provides the first evidence of successful delivery of mRNA-CAR therapy in humans. These biomarker findings demonstrate that MT-302 selectively engages myeloid cells and induces robust innate and adaptive anti-tumor pharmacodynamic responses, providing support for further investigation of MT-302’s potential as a transformative treatment for patients with TROP2-expressing epithelial cancers. Clinical trial information: NCT05969041 .