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News and Views
Nature Medicine 8, 1352 - 1353 (2002)
doi:10.1038/nm1202-1352
Vessel maneuvers: Vaccine targets tumor vasculature
Michael S. O'Reilly
Departments of Radiation Oncology and Cancer Biology University of Texas M.D. Anderson Cancer Center Houston, Texas, USA moreilly@mdanderson.org
A new oral vaccine targets a receptor in newly forming blood cells and thwarts angiogenesis in mouse models of cancer (pages 1369−1375).
Since its inception over three decades ago, the field of angiogenesis has made significant progress and has led to an improved understanding of physiological and pathophysiological conditions1. However, a number of obstacles remain before the anti-tumor effects of anti-angiogenic therapy in mice2 can be translated to clinical practice. In this issue, Niethammer et al. have devised a strategy that overcomes some limitations of anti-angiogenic and conventional cancer therapies3. Their approach may hasten the translation of anti-angiogenic therapy into the clinic.
The authors designed an oral DNA vaccine that selectively targets a receptor for vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), which is preferentially found in tumor vasculature. Their studies demonstrate that immunotherapy directed against proliferating endothelial cells can be used to selectively target malignancy (Fig. 1). In a series of elegant studies, the authors demonstrate that their vaccine can be used to treat pre-existing malignancy and to prevent the formation of cancer in animal models without obvious short-term toxicity or resistance to therapy. The current studies were limited to tumors growing in mice, but they serve to clearly demonstrate the feasibility of using oral DNA vaccines as a means to effectively target tumor vasculature.
Figure 1. A DNA vaccine against VEGF receptor 2 targets tumor vasculature.
After vaccination, CD8+ T cells attack VEGFR2-overexpressing endothelial cells of the neovasculature, leading to vascular collapse. Normal endothelial cells not overexpressing VEGFR2 are spared.
Full Figure and legend (54K)
VEGF acts as both an angiogenic factor and endothelial-cell survival factor4, and multiple strategies have been devised to block its effect upon the vasculature5. Most commonly, small molecules that target the function of the VEGF receptor or antibodies to VEGF and its receptors are used to block the effects of VEGF. A drawback of these agents is the need for prolonged and frequent administration of high doses. The vaccine designed by Niethammer et al. overcomes these limitations. The vaccine evoked a durable T cell−mediated immune response against endothelial cells at sites of active angiogenesis, followed by collapse of the tumor vasculature.
Because the normal vasculature is quiescent, the anti-vascular effects of the vaccine occurred within the tumor and not within normal organs or tissues. However, toxicity may result from strategies that target VEGF and its receptors, and clinical trials have been associated with complications6 possibly due to the role of VEGF in maintaining the vascular integrity. Further targeting a single pro-angiogenic molecule such as VEGF might be associated with eventual resistance to therapy7 as tumor cells increase their production of other pro-angiogenic molecules8. Strategies that target the VEGF receptor must therefore be combined with other anti-angiogenic and biological agents and with conventional modalities, and patients must be monitored closely for evidence of vascular damage.
Does a DNA vaccine against VEGF receptor 2 represent the long-awaited magic bullet for the treatment of cancer? Absolutely not. Moreover, hopes for a single agent that will eradicate all malignancies belong within the realm of fantasy. However, angiogenesis is involved in most pathological conditions and a better understanding of the process provides for an improved understanding of malignancy. Stimulators of angiogenesis are currently in clinical trials for cardiovascular disease and offer the potential for the revascularization of organs whose functions are compromised by impaired circulation. Inhibitors of neovascularization can in turn be used to treat a variety of disease states, although the focus of most clinical trials of these agents have been on cancer and, more recently, ocular diseases. Although the anti-angiogenic effects of interferon- have been lifesaving in treating hemangioma and giant-cell tumors in children9, the use of anti-angiogenic agents as monotherapy in treating patients with advanced cancer have not yet shown significant efficacy. The limitations of anti-angiogenic monotherapy in this setting were in fact predicted by preclinical studies with the angiogenesis inhibitors endostatin and angiostatin10.
Great progress has been achieved in the field of angiogenesis11, yet significant effort is still required. It has become apparent that anti-angiogenic monotherapy is inadequate for the treatment of advanced malignancy and that combined modality therapy is necessary. It will be critical to integrate any anti-angiogenic strategy into existing and emerging treatment strategies for cancer. Although eradication of cancer is obviously preferable, it seems more realistic to approach malignancy as a chronic but treatable disease. To do this, strategies that include the prolonged administration of multiple angiogenesis inhibitors with other biological agents during and after conventional modalities will be required. The translation of anti-angiogenic and antivascular therapies into the clinic is now inevitable. However, only by continued study and improved understanding will this occur rapidly so that anti-angiogenic agents can achieve their full potential.
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