Researchers at Yale University have come up with a new take on an old problem: how to cut off blood supply to a tumour. Previously, it was believed that we might be able to eradicate cancer by preventing tumour angiogenesis--a theory that worked well in animal models, but had disappointing results in humans. The new twist on the method developed by Hu and Garen is to destroy tumours by killing the blood vessels that supply them, rather than trying to prevent their development in the first place.
The researchers developed an immunoconjugate molecule (icon), composed of a mutated mouse factor VII (mfVII) targeting domain and the Fc effector domain of an IgG1 Ig (mfVII/Fc icon), and tested its efficacy in mouse models of human and mouse prostate cancer, and human melanoma. Mice were injected subcutaneously with a human prostatic tumour line, forming a skin tumour that produces a high blood titer of prostate-specific antigen and metastasizes to bone. The icon was encoded in a viral vector that was injected directly into the tumour. Tumour cells infected with the vector synthesize more of the icon molecule and secrete it into the blood where it binds to mouse tissue factor expressed on endothelial cells lining the lumen of the tumour vasculature and to human tissue factor on the tumour cells. One part of the icon then activates an immune attack against any cell that is capable of binding it--which means that the immune attack is only directed against cells that show 'tumour' characteristics. Injection with icon resulted in long-term regression of the injected human prostatic tumour, and also of the uninjected tumour (a model for a metastasis), without any toxicity to the mouse. The same results were obtained for the mouse model of human melanoma.
The researchers are hoping to begin clinical trials in humans next spring, although they caution that it is far too early to predict how well the technique will work in humans.
- Hu Z and Garen A. Targeting tissue factor on tumor vascular endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer. Proc. Natl. Acad. Sci. USA, 10.1073/pnas.201420298.
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