A tumour without a blood supply — like flora and fauna in a valley that is deprived of its source of water — is unlikely to survive, and this makes inhibiting angiogenesis an attractive antitumour strategy. Andreas Niethammer and colleagues now report a novel antitumour approach by inhibiting the growth of endothelial cells in the tumour vasculature using an oral DNA vaccine.

The authors first constructed a DNA vaccine encoding mouse Vegf receptor 2 (Flk1) carried by an attenuated bacterium, Salmonella typhimurium. They showed that when mice were challenged with melanoma, colon carcinoma or non-small-cell lung cancer cells 2 weeks after receiving the last of three vaccinations with the Flk1 vaccine, development of subcutaneous tumour growth was suppressed. Even 10 months after their last vaccination, mice still had greatly reduced tumour growth compared with controls that were vaccinated with an empty vector. The experimental animals that were challenged with lung carcinoma also had a marked decrease in the development of spontaneous lung metastases, and vaccinated mice that were challenged with a lethal dose of CT-26 colon carcinoma cells survived four times longer than mice that were vaccinated with an empty vector.

The problem with this model is that the tumour challenge was given after vaccination, which is not representative of what would happen in a therapeutic setting. So Niethammer et al. injected mice with CT-26 cells 10 days before giving the Flk1 vaccine, when they already had established lung metastases. All of the treated mice survived and growth of the established metastases was greatly reduced — all of the control mice died.

So, the Flk1 vaccine has an impressive impact on tumour-cell growth, but what is the mechanism of cell kill? Anti-angiogenesis effects of the Flk1 vaccine that were independent of tumour cells were shown in a Matrigel assay — vascularization was markedly reduced in Matrigel plugs of mice that were immunized with the Flk1 vaccine versus the empty control vaccine. The authors hypothesized that the vaccine triggered a T-cell-mediated immune response against proliferating endothelial cells, as Flk1 is often overexpressed on these cells in the tumour vasculature. They observed a marked upregulation of several T-cell activation markers when splenocytes were incubated with cells expressing Flk1, and showed that in vivo depletion of CD8+ T cells, before challenging the vaccinated mice with CT-26 tumour cells, resulted in severe impairment of the antitumour response, with extensive tumour growth and development of metastases.

This novel strategy of inhibiting the tumour blood supply might overcome problems that limit the effectiveness of therapies that target the tumour cell per se, such as genetic instability and heterogeneity of tumours cells, and using a DNA vaccine overcomes the usual lack of stimulation of an immune reponse by tumour cells.