Abstract 1405: Vesigenurtacel-L stimulates tumor infiltration of unique polyclonal T cell clones in non-muscle invasive bladder cancer patients

Abstract

Abstract Non-muscle invasive bladder cancer affects approximately 50,000 Americans each year, requires chronic medical management with a combination of surgical resection and intravesical BCG instillations for treatment. While BCG improves recurrence-free survival in this population, there remains a significant unmet medical need for therapeutics in patients who have a particularly high risk of recurrence and/or progression to muscle-invasive disease. Vesigenurtacel-L is an allogeneic, cell based, vaccine engineered to secrete the heat shock protein, gp96-Ig, which facilitates cross-presentation of cell-derived antigens on MHC I to activate CD8+ T cell responses across MHC barriers. We recently reported that in patients treated with Vesigenurtacel-L in a Phase I clinical trial, a minimum of 15 antigens were shared between the vaccine and individual patient tumors. Although no patient received a complete course of maintenance BCG, 70% of patients remained recurrence free beyond 12 months. Baseline biopsies were collected from all patients, and serial biopsies for several patients when clinically indicated. Analysis of these tissues by RNA Sequencing revealed that recurring patient tumors expressed higher levels of B7-H4, GITR and KIR3 at baseline, while non-recurring patient tumors expressed an immune profile consistent with an interferon defense signature. In addition, patients with progressive elimination of residual disease in repeat biopsies showed increased levels of CD3, CD8, IL-23A and OX40. Deep sequencing of peripheral blood T cells and total tumor DNA for T cell receptors was performed at baseline and at several post-treatment time points. These data demonstrated polyclonal expansion of TCR clones that were either absent, or present at low frequencies at baseline in the peripheral blood. Remarkably, approximately 40% of these clones could also be found expanded within the tumor. These data correlate positively with the absolute increase in tumor infiltrating lymphocyte percentages observed by immunohistochemistry. ELISPOT assays were performed to demonstrate the specificity of expanded T cell clones toward shared tumor antigens, since the antigens in both the patients tumors and Vesigenurtacel-L were known. These data provide exciting clinical evidence of patient benefit derived from an allogeneic immunotherapy vaccine and compelling evidence for a vaccine therapy converting ‘cold’ tumor to (predominantly CD8+) TIL-rich tumors, with a corresponding analysis of the antigenic determinants of the response. Citation Format: Taylor H. Schreiber, George Fromm, Xin Xu, Eric Yusko, Brandon Early, Melissa Price. Vesigenurtacel-L stimulates tumor infiltration of unique polyclonal T cell clones in non-muscle invasive bladder cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1405.