The overarching aim of cancer vaccines is to induce robust tumor-specific, cytotoxic T cell responses that eliminate neoplastic cells, amplify and broaden the anti-tumor immune response, and promote the formation of memory T cells that will ensure durable remissions. Listeria monocytogenes (Lm) is a potent inducer of innate and adaptive immune responses. Its natural tendency to infect mononuclear antigen-presenting cells (APC) and its unique biology that enables it to deliver engineered tumor-associated antigens into the MHC I and II processing pathways make it a potent biological vector able to prime both CD4 and CD8 T cell responses. In addition, this facultative anaerobe exerts direct effects on the tumor microenvironment reducing regulatory T cells and myeloid derived suppressor cells (MDSC), enabling appropriately primed tumor-specific T cell responses to exert therapeutic anti-tumor effects. Lm has been shown to directly infect MDSC which traffic to the tumor and deposit the bacteria there, promoting additional direct anti-tumor effects. Multiple human clinical trials are underway using recombinant Lm-based vaccines targeting tumor-associated antigens such as HER2/neu, prostate specific antigen (PSA) and Human Papillomavirus oncoprotein E7 (HPV-E7) either alone or in combination with other immunomodulatory agents including chemotherapy, radiation therapy and checkpoint inhibitors with promising results. To overcome the inherent difficulties in breaking immune tolerance against self-proteins, the Lm platform is now being evaluated as an off-the-shelf vaccine to target hot spot mutations such as V600E B-Raf which is highly expressed in human melanoma and canine urothelial carcinoma. Furthermore, in personalized approaches, where the patient’s tumor is sequenced and non-synonymous mutations identified, genetic constructs that encode putative neo-antigens can be engineered to be expressed by Lm, generating a personalized, multi-targeted, vaccine approach that aims to circumvent tumor antigen escape. In this lecture, we will address the use of recombinant Lm technology, the results that have been achieved with it in dogs with osteosarcoma and urothelial carcinoma and future combination approaches that can be employed to further enhance therapeutic efficacy.
Upon completion, participant will be able to describe the key mechanisms of action by which recombinant Listeria vaccines induce innate and adaptive immune responses
Upon completion, participant will be able to describe the different types of Listeria vaccines being used in current clinical trials
Upon completion, participant will be able to describe the effects of a recombinant HER2/neu Listeria vaccine in canine osteosarcoma