Abstract B196: Live attenuated oral Salmonella platform for effective targeting of multiple tumor-associated epitopes and PD-L1
Authors: Wieckowski Sébastien , Podola Lilli , Springer Marco , Kobl Iris , Smetak Heiko , Nugues Anne-Lucie , Slos Philippe , Adda Berkane Amine , Wei Ming , Breiner Klaus , Meichle Albrecht , Philipp Beckhove , Mansour Marc , Schroff Matthias , Lubenau Heinz 
Published: August 2018

Abstract
Significant progress has been achieved recently in cancer vaccines that aim at engaging or reengaging the tumor immunity, in particular in the rapidly growing field of personalized immunotherapy. Yet novel immunization solutions to deliver efficiently tumor-associated (neo)antigens to professional antigen-presenting cells, and to overcome the peripheral tolerance and the immunosuppressive tumor microenvironment that prevent the eradication of cancer in most patients, are urgently needed. VAXIMM is 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 antitumor 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 Typhimurium-based polyepitope oral vaccines in healthy animals. 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. Multiple oral administrations of VXM10 used at 1010 colony-forming units (CFU) were generally well tolerated, and neither sign of toxicity nor body weight loss were observed throughout the study. Oral administration of VXM10 produced a strong antitumor 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 anticancer effect. Moreover, 100% of long-term surviving mice resisted rechallenge 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. Immunogenicity and antibody response towards PD-L1 are being evaluated to dissect the exact mechanism of action of these novel vaccines. Finally, different polyepitope vaccines encoding dominant 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/6J mice via the oral route, with doses up to 1010 CFU, as measured in the spleen by flow cytometry using peptide-MHC class I pentamers. This study provides further evidence that VAXIMM’s oral T-cell vaccination platform can be employed to stimulate antitumor immunity against antigens of the immune checkpoint regulatory protein PD-L1, and also against T-cell antigens encoded by polyepitope constructs. These data pave the way for advancing the development of VXM10 and neoantigen-based vaccines into clinical development.
Citation Format: Sébastien Wieckowski, Lilli Podola, Marco Springer, Iris Kobl, Heiko Smetak, Anne-Lucie Nugues, Philippe Slos, Amine Adda Berkane, Ming Wei, Klaus Breiner, Albrecht Meichle, Beckhove Philipp, Marc Mansour, Matthias Schroff, Heinz Lubenau. Live attenuated oral Salmonella platform for effective targeting of multiple tumor-associated epitopes and PD-L1 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B196.