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.
Highlights
Numerous approaches have been developed in attempts to selectively block tumor angiogenesis or induce collapse of tumor-associated blood vessels
This is a fundamental point because numerous antigens found on tumor endothelial cells are found on non-malignant cells, for example VEGFR is known to be associated with hematopoietic stem cell self-renewal
Superior activity of ValloVax was observed as compared to inhibition of VEGFR2 inhibition, suggesting the possible potency of active immunization towards a plurality of tumor endothelium associated antigens as compared to passive antibody transfer against one tumor vasculature associated antigen
Summary
Numerous approaches have been developed in attempts to selectively block tumor angiogenesis or induce collapse of tumor-associated blood vessels. We recently reviewed numerous works in which immunization to proliferating endothelial cells, whether syngeneic, allogeneic or xenogeneic results in selectivity of killing of tumors without damage to non-malignant tissues [1]. This is a fundamental point because numerous antigens found on tumor endothelial cells are found on non-malignant cells, for example VEGFR is known to be associated with hematopoietic stem cell self-renewal. This is supported by clinical data in which immunization with HUVEC cells multiple times did not result in hematopoietic or other toxicities
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