Efficacy of pLADD, a personalized immunotherapy strategy targeting tumor-specific neoantigens using live attenuated Listeria monocytogenes
Weiwen Deng, Thomas E Hudson, Victor Lira, William G Hanson, Edward E Lemmens, Justin Skoble, Peter Lauer, Chan Whiting, Meredith Leong, Thomas W. Dubensky Jr.,
Aduro Biotech, Inc.
Clinical successes of checkpoint inhibitors, dendritic cell therapies, and adoptive T cell transfers highlight the importance of tumor-specific neoantigens as critical targets for effective immunotherapy. Advances in genome sequencing and predictive epitope binding algorithms provide an unprecedented opportunity to develop highly personalized immunotherapeutics. We are advancing personalized therapy (pLADD) based on the live, attenuated double-deleted Listeria monocytogenes (LADD) platform, which has been administered safely to over 350 cancer patients, and resulting in promising responses in particular malignancies. To test the efficacy of pLADD targeting tumor-specific neoantigens, mutated epitopes unique from germ-line sequences identified in the mouse colorectal cancer cell line, MC38, were expressed as a synthetic neoantigen protein from LADD. Administration of pLADD-MC38 in mice induced CD8+ T cell responses against encoded neoepitopes, but responses against native sequences were not detected. Treatment with pLADD-MC38 also induced significant changes in the TME, including enhanced CD8+ T cell effector function and recruitment of critical antigen presenting cells. An immunotherapy regimen combining pLADD-MC38 with PD-1 immune checkpoint blockade significantly enhanced antitumor efficacy, which correlated with sustained antigen-specific responses. Based on these results, established clinical safety, and an emerging efficacy profile for the LADD platform, pLADD is an attractive approach to target multiple tumor-specific neoantigens, and also takes advantage of rapid construction, manufacture, and release of personalized vaccine strains. A clinical trial to evaluate the safety and immunogenicity of pLADD is expected to start in 2017, and a summary of the design of this Phase 1 study will be presented.
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