Induction and characterization of anti-tumor endothelium immunity elicited by ValloVax therapeutic cancer vaccine
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Samuel C. Wagner1,*, Thomas E. Ichim1,*, Vladimir Bogin1, Wei-Ping Min2, Francisco Silva3, Amit N. Patel3, Santosh Kesari4
1Batu Biologics, Inc. San Diego, CA, USA
2Department of Immunology, University of Western Ontario, London, Ontario, Canada
3Department of Surgery, University of Miami School of Medicine, Miami, FL, USA
4John Wayne Cancer Institute and Pacific Neuroscience Institute, Santa Monica, CA, USA
*These authors have contributed equally to this work
Thomas E. Ichim, email: [email protected]
Keywords: angiogenesis, ValloVax
Received: November 15, 2016 Accepted: January 24, 2017 Published: February 21, 2017
ValloVax is a placental endothelium derived vaccine which induces tissue-nonspecific antitumor immunity by blocking tumor angiogesis. To elucidate mechanisms of action, we showed that production of ValloVax, which involves treating placental endothelial cells with IFN-gamma, results in upregulation of HLA and costimulatory molecules. It was shown that in mixed lymphocyte reaction, ValloVax induces Type I cytokines and allo-proliferative responses. Plasma from ValloVax immunized mice was capable of killing in vitro tumor-like endothelium but not control endothelium. Using defined antigens associated with tumor endothelial cells, specific molecular entities were identified as being targeted by ValloVax induced antibodies. Binding of predominantly IgG antibodies to ValloVax cells was confirmed by flow cytometry. Further suggesting direct killing of tumor endothelial cells was expression of TUNEL positive cells, as well as, reduction in tumor oxygenation. Supporting a role for antibody mediated responses, cell depletion experiments suggested a predominant role of B cells in maintaining an intact anti-tumor endothelial response. Adoptive transfer experiments suggested that infusion of CD3+ T cells from immunized mice was sufficient to transfer tumor protection. Generation of memory T cells selective to tumor endothelial specific markers was observed. Functional confirmation of memory responses was observed in tumor rechallenge experiments. Furthermore, we observed that both PD-1 or CTLA-4 blockade augmented antitumor effects of ValloVax. These data suggest a T cell induced B cell mediated anti-tumor endothelial response and set the framework clinical trials through elucidation of mechanism of action.
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