Abstract 733: Modulating T cell immunity in tumors by targeting PD-L1 and neoantigens using a live attenuated oral <i>Salmonella</i> platform
Authors: Sébastien Wieckowski, Lilli Podola, Heiko Smetak, Anne-Lucie Nugues, Philippe Slos, Amine Adda Berkane, Ming Wei, Klaus Breiner, Albrecht Meichle, Philipp Beckhove, Marc Mansour, Heinz Lubenau
Journal: Cancer Research (2018)

Abstract Significant progresses have been achieved recently in cancer vaccines that aim at engaging or reengaging tumor directed T cells, in particular in the rapidly growing field of personalized immunotherapy. Yet novel immunization solutions to produce effective tumor-associated (neo)antigens T cell responses while simultaneously overcoming the immunosuppressive tumor microenvironment are urgently needed. We are developing a unique and versatile oral T-cell vaccination platform based on the FDA-approved live-attenuated Salmonella Typhi strain Ty21a vaccine Vivotif®, capable of delivering tumor-associated antigens encoded in DNA expression construct to the gut-associated lymphoid tissue, breaking immune tolerance and inducing anti-tumor immunity. This study summarizes the immunogenicity and antileukemia efficacy of VXM10 vaccines based on the live-attenuated Salmonella Typhimurium strain SL7207, transformed with a eukaryotic expression plasmid encoding the murine programmed death-ligand 1 (PD-L1) protein. It also describes for the first time the systemic immunogenicity of Salmonella based polyepitope oral vaccines, supporting the design of Salmonella based neoantigen vaccines. The antileukemia activity of VXM10 was evaluated in the FBL-3 disseminated model of leukemia, in which the tumor cells express high levels of PD-L1. Oral administration of VXM10 produced a strong anti-tumor effect in the FBL-3 leukemia model, with 100% of surviving animals 80 days after leukemia challenge in the highest dose groups. In contrast, administration of the empty vector control did not show any anti-cancer effect. Moreover, 100% of long-term surviving mice resisted re-challenge with FBL-3 cells, demonstrating that vaccination with VXM10 generated a potent memory T cell response against the leukemia. Importantly, full leukemia control was achieved in both prophylactic and therapeutic settings. The anti-tumor effect observed in these experiments was as strong as in previous experiments using a Salmonella Typhimurium transformed with a plasmid encoding Wilm's tumor 1 (WT1). The anti-tumor efficacy was accompanied by an increased systemic antibody response, and the activation of T cells directed against PD-L1 epitopes. Finally, different polyepitope vaccines encoding model epitopes from VEGFR2, Mesothelin, WT1, CEA, and Ovalbumin, induced a significant systemic immunogenicity for up to 6 out of 9 epitopes, 10 days after vaccination of healthy C57BL/6 mice via the oral route, as measured in the spleen by flow cytometry using peptide-MHC class I pentamers. These studies demonstrate that the Salmonella Ty21a platform can be used to generate anti PD-L1 antibody and T cell responses, as well as CD8-positive T cell responses against a majority of MHC class I epitopes of a polyepitope construct. We are now designing a clinical neo-antigen based vaccine that employs the concepts presented. Citation Format: Sébastien Wieckowski, Lilli Podola, Heiko Smetak, Anne-Lucie Nugues, Philippe Slos, Amine Adda Berkane, Ming Wei, Klaus Breiner, Albrecht Meichle, Philipp Beckhove, Marc Mansour, Heinz Lubenau. Modulating T cell immunity in tumors by targeting PD-L1 and neoantigens using a live attenuated oral Salmonella platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 733.