Immune System Impact of VEGF Targeting Under the Microscope

Jane de Lartigue, PhD
Published: Tuesday, Apr 12, 2016
Robert S. Kerbel, PhD

Robert S. Kerbel, PhD

For more than 25 years, Robert S. Kerbel, PhD, a senior scientist at Sunnybrook Research Institute and a professor of Medical Biophysics at the University of Toronto, has been studying tumor angiogenesis and the impact of inhibiting the VEGF pathway as an anticancer strategy.

Although the FDA has approved 10 VEGF-targeting agents in a variety of tumor types, the strategy has proved problematic. In an interview with OncLive, Kerbel, who also formerly served as Canada Research Chair in Tumor Biology, Angiogenesis, and Antiangiogenic Therapy, discussed the evolving landscape of VEGF targeting and some of the unique challenges posed by the strategy.

OncLive: How has our understanding of the role of the VEGF pathway in cancer evolved in recent years?

Well, there are a number of things. One is that VEGF was first discovered in retrospect as a vascular permeability factor in the mid-1980s and since then it has been mainly evaluated and studied as an angiogenesis factor. Although VEGF is predominantly considered to be a factor that stimulates endothelial cells to grow, divide, and form blood vessels, it has other functions, and now it’s evolving to some extent into some other interesting therapeutic areas.

One that’s beginning to attract much more attention is its possible role in regulating aspects of the immune system. It’s sort of evolving to some extent from an angiogenesis factor to an immune-modulating factor. Whether that will fully pan out, we still don’t know yet. I think a lot will depend on what happens with ongoing clinical studies evaluating, for example, immune checkpoint inhibitors like ipilimumab and nivolumab, and so forth, with drugs like ramucirumab and bevacizumab and some of the antiangiogenic tyrosine kinase inhibitors.

How have these changing views affected the use of VEGF-targeting drugs in the clinic or research relating to them?

I think another interesting thing about inhibiting this pathway is we still don’t really know all that well how it works. By not really having a clear answer to that question, it’s more difficult to make progress.

There are a couple of different mysteries. First, one would predict that if angiogenesis is really an important and significant driver of tumor growth, progression, and metastasis, that if you treat patients with a single-agent antiangiogenic drug only, like bevacizumab, the results would actually be much better than they have been in certain types of cancer such as breast, colorectal, lung, and prostate.

Patients, regardless of what type of cancer they have, rarely get these antibody drugs as monotherapy. They are almost always administered upfront as part of a small cocktail, usually with standard chemotherapy. The prevailing wisdom is that this makes the chemotherapy part of the cocktail work better.

Well, then, that raises the question of how does that actually happen? The first successful reports of this in the clinic came more than 12 years ago and we still don’t know why this type of combination works better than chemotherapy alone—when it does. There are a number of different theories, but really none of them have been validated as being definitively correct in the clinic, and the preclinical data are conflicting.

Another area in which there’s been a great deal of interest, because of the efficacy results, is trying to figure out why the drugs work and then stop working. This is obviously a big problem in oncology with virtually any type of cancer therapy, though immunotherapy in some cases may be an exception.

With almost every type of targeted therapy or chemotherapy or radiation therapy, the story has been that initially sensitive tumors become resistant over time to these therapies and the same thing seems to be happening with drugs that target the VEGF pathway. So there has been a great deal of interest in trying to understand why that happens and then, by figuring out how it happens, trying to delay the onset of resistance or actually develop some strategies to treat resistant disease.

How has it informed the development of new VEGF pathway-targeting therapies?

I think most researchers and key opinion leaders, if they were told that Company X or Academic Lab Y is trying to develop another VEGF pathway– targeting drug, my suspicion would be that they would roll their eyes and say, “you’ve got to be kidding.” We have so many such drugs now that are approved, do we really need anything more?


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