Comment on Zhou et al, page 2026
An innovative approach to the use of cancer vaccines targets the vascular endothelial growth factor receptor-2 (FLK-1), suppresses tumor-associated angiogenesis, and results in antitumor activity.
In a highly innovative approach to the suppression of tumor growth, Zhou and colleagues have developed an anticancer vaccine that targets the vascular endothelial growth factor receptor-2 (VEGF-R2, FLK-1), an important molecule expressed on tumor-associated endothelial cells.1 Angiogenesis is a rate-limiting step in the development of tumors of any appreciable size.2 Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases have been shown to play important roles in angiogenesis. VEGF-R2, also known as FLK-1, demonstrates expression restricted to endothelial cells and is up-regulated once these cells proliferate during angiogenesis in the tumor vasculature. Numerous approaches by many groups have been used to block FLK-1, including the use of monoclonal antibodies against VEGF and the use of synthetic receptor kinase inhibitors. In this issue of Blood, Zhou and colleagues demonstrate the broad depth to which vaccines can be used to attack tumors. Previous studies by this group have demonstrated that vaccines containing the entire FLK1 gene can suppress tumor growth.3 In the study reported here, however, they used an oral DNA minigene vaccine, using a Salmonella-based vector containing only a single cytotoxic T lymphocyte (CTL) epitope of FLK-1. The oral carrier system, consisting of a double attenuated strain of Salmonella typhimurium, delivers the DNA to secondary lymphoid organs for subsequent transcription, translation, and antigen processing.4,5 The advantage of using the minigene approach is that it creates a simpler and more defined vaccine and reduces the potential of cross-reactivity with normal tissues with the use of a vaccine containing the entire FLK1 gene. The vaccine was shown to generate FLK-1–specific CTLs (which were capable of killing peptide-pulsed targets and FLK-1–expressing endothelial cells), suppress angiogenesis in vivo, and protect mice from tumors of different origins.
The authors point out several advantages of targeting CD8+ T cells to proliferating endothelial cells in the tumor vasculature, rather than targeting the tumor cells themselves. These include the following: (1) endothelial cells are more stable than tumors and do not down-regulate major histocompatibility complex (MHC) class I molecules; (2) the therapeutic target is tumor-type independent, so numerous different types of tumor can be efficiently targeted; (3) immune suppression triggered by factors given off by tumor cells can theoretically be avoided; and (4) proliferating endothelial cells can be more readily targeted by lymphocytes arriving by the bloodstream and are thus not impaired by anatomic barriers.
In summary, the studies reported by Zhou et al illustrate a potentially exciting new dimension for the use of cancer vaccines and the use of antiangiogenic interventions. ▪