Novel vaccine targets tumor angiogenesis, then creates a secondary immune response

A novel DNA vaccine is being employed to kill cancer, not by attacking tumor cells, but by targeting the blood vessels that keep them alive. The vaccine also indirectly creates an immune response to the tumor itself, amplifying the attack by a phenomenon called epitope spreading.

Previous studies have targeted tumor angiogenesis (the formation of new blood vessels that feed the tumor cells). However, this approach can also interfere with normal processes involved in wound healing and development. A group of researchers from the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania in Philadelphia avoided this pitfall by designing a DNA vaccine that specifically targets tumor endothelial marker 1 (TEM1), a protein that is overexpressed in tumors and poorly expressed in normal tissues.

"We demonstrated that by targeting TEM1, our vaccine can decrease tumor vascularization, increase hypoxia of the tumor, and reduce tumor growth," said Andrea Facciabene, PhD, of Penn Medicine. "Our results confirm that we were directly targeting the tumor vasculature and also indirectly killing tumor cells through epitope spreading.”

The team injected mice with a DNA fusion vaccine called TEM1-TT, created by fusing TEM1 complementary DNA with a fragment of the tetanus toxoid (TT). In mouse models of three cancer types (breast, colon, and cervical), tumor formation was delayed or prevented in mice vaccinated with the TEM1-TT DNA vaccine.  Specifically, they found that the mouse tumors had suppressed growth, decreased tumor vessel formation, and increased infiltration of immune cells into tumors.

The researchers found that the DNA vaccine, after killing the endothelial cells that make up the tumor vessels (vasculature), also resulted in epitope spreading, meaning that the immune cells of the mice gathered pieces of dead tumor cells (due to hypoxia) to create a secondary immune response against the tumor itself. The vaccine induced specific T cells to fight the expression of other proteins in other tumor cells, in addition to TEM1, thus increasing its therapeutic efficacy.

The new DNA vaccine approach to fight cancer is showing great potential compared to previous studies that focused on tumor cells rather than the blood vessels that allow tumor cells to thrive. The results of this study were published in the Journal of Clinical Investigation (2014; doi:10.1172/JCI67382).

"Until now there have been a lot of clinical trials using DNA vaccines to target tumors themselves, but unfortunately the results have been disappointing," Facciabene noted. "This is a different approach which should heighten optimism for cancer vaccines in general."

The prevalence of TEM1 in a wide range of tumor types coupled with its scarcity in normal vessels makes it a suitable target both for a prophylactic defense against cancer and a complement to other therapies such as radiotherapy and chemotherapy.

"Using this vaccine simultaneously with radiation may eventually have a double synergy," Facciabene said. "Both treatments affect the tumor endothelium. Radiotherapy could help the phenomenon of epitope spreading induced by the TEM1-TT vaccine."

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