Phase I study of patients with non-muscle invasive bladder cancer (NMIBC) treated with vesigenurtacel-L (HS-410) after Bacillus Calmette-Guérin (BCG)

Abstract

Background: Vesigenurtacel-L (HS-410), consists of an allogeneic bladder cancer cell line, selected for high expression of a series of tumor antigens that are known to be shared by a high proportion of bladder tumors. The cell line secretes gp96-Ig, a modified heat shock protein which delivers cell-derived antigens to MHC-I via the cross-presentation pathway, leading to preferential activation of CD8+ cytotoxic T cells. Vesigenurtacel-L was evaluated in a Phase I trial after treatment with standard of care induction BCG for safety and immune response. Methods: Ten patients with non-muscle invasive bladder cancer who had undergone TURBT, were judged to be at an increased risk for recurrence, and were either BCG naïve or had completed previous BCG treatment >12 months prior to the most recent TURBT were treated with induction BCG as standard of care and enrolled in the trial. Patients received up to 15 doses of monotherapy vesigenurtacel-L at a dose of 106 cells per dose, weekly for 12 weeks followed by 3 monthly doses. Baseline tumor tissue and any follow up biopsies were evaluated by immunohistochemistry for tumor infiltrating lymphocytes and expression of PD-L1. Results: Vesigenurtacel-L was well tolerated with no treatment-related Grade 3/4 adverse events. The most common adverse events were lowgrade injection site reactions consistent with delayed type hypersensitivity. Peripheral blood mononuclear cells were evaluated by flow cytometry for detection of circulating leukocyte subsets, regulatory T cells, myeloid derived suppressor cells, activated T cells and expression of immune checkpoint molecules on T cells. Additionally, analyses from pre- and post- (Figure presented) treatment tissue specimens in a subset of patients including antigen expression, evaluation of tumor-infiltrating lymphocytes, PD-L1 expression and T cell receptor sequencing will be reported, and their extrapolation to an emerging definition of responder phenotype discussed. For example, tissue analysis indicates an increase in CD8+ T cells in the bladder after treatment, consistent with the mechanism of action derived from preclinical models, and this change appears be correlated to clinical outcome.