Oncotarget

Research Papers:

Induction and characterization of anti-tumor endothelium immunity elicited by ValloVax therapeutic cancer vaccine

Samuel C. Wagner, Thomas E. Ichim _, Vladimir Bogin, Wei-Ping Min, Francisco Silva, Amit N. Patel and Santosh Kesari

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Oncotarget. 2017; 8:28595-28613. https://doi.org/10.18632/oncotarget.15563

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Abstract

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

Correspondence to:

Thomas E. Ichim, email: thomas.ichim@gmail.com

Keywords: angiogenesis, ValloVax

Received: November 15, 2016     Accepted: January 24, 2017     Published: February 21, 2017

ABSTRACT

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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