Combined Targeting Against VEGF and PD-1 in Bladder Cancer

Transcript:Mark A. Socinski, MD: I want to ask Jared about atezolizumab in the POPLAR, BIRCH studies in a moment, but I want to go back to John and just get your perspective on the role of bevacizumab as an antiangiogenic agent, and how that may enhance an immune effect.

John V. Heymach, MD, PhD: We’ve been studying antiangiogenic drugs now for a couple decades. I trained with Judah Folkman, who was one of the pioneers in this area. And our focus was always exclusively on these blood vessels, these endothelial cells, and things that make endothelial cells grow. But it turns out that there’s enormous cross-talk between the things that make blood vessels grow and things that stimulate the immune system. So, the target we go after the most for antiangiogenic therapy is VEGF, but VEGF is actually known to be an immunosuppressive factor. It plays a role in dendritic cells, and it drives an immunosuppressive environment. This always raised the question, is it possible that some of the benefit we were seeing from drugs like bevacizumab wasn’t always from an antiangiogenic effect, but possibly from altering the immune microenvironment and stimulating the immune system?

In melanoma, for example, BRAF inhibitors modulate the immune environment. Part of the way they do that is when you inhibit BRAF, it lowers VEGF levels. So, work from Patrick Hwu and his group has shown this. The notion of bringing together bevacizumab and atezolizumab, or VEGF inhibitors and immunotherapy, I think is a very appealing one. And there’s one other reason it’s appealing. We know that with VEGF inhibitors, tumors become resistant to them eventually. And our group and others have looked at what goes up when tumors become resistant to VEGF inhibitors, and at the top of the list have been cytokines and other factors that drive myeloid-derived suppressor cells and other immune cells. So, in other words, immune infiltration may be one of the things that leads tumors to be resistant to VEGF inhibitors. Blocking VEGF may help the immune system, and blocking the immune system may help VEGF and avoid resistance there. The combinations, I think, are wonderful to study.

Mark A. Socinski, MD: Do you see a difference in the monoclonal antibody approach, bevacizumab, ramucirumab, or others versus the TKI approach?

John V. Heymach, MD, PhD: Yes. It’s a really fascinating question because the TKIs, of course, have the spectrum that they’re usually inhibiting more than one target. And sunitinib is a great example of a drug that’s fairly dirty. And, we’ve had arguments for a long time, is it a negative thing to hit a lot of targets, in which case you call it dirty, or is it a good thing and you call it multi-targeted? It’s a matter of whose perspective it is here. Now, it turns out that a lot of these other targets play a role in the immune system. So, sunitinib, for example, hits the CSF1 (colony stimulating factor 1) receptor, which helps regulate myeloid cells. It helps the kit receptor and the PDGF (platelet-derived growth factor) receptors, which both play a role in myeloid development. It’s been known for some time that when you take drugs like sunitinib, you get a drop in myeloid cells, and that this may provide benefit as well. This will be a really interesting field to see how it plays out. I think some TKIs will be better than just VEGF alone in targeting, but they’re also more difficult to tolerate, and we see this with sunitinib. Sunitinib is not easily tolerated by a lot of solid tumor patients, especially if you’re giving it continuously. So, wait and see. I think that TKIs could end up being more effective, but bevacizumab is a cleaner drug and certainly a logical starting place.

Mark A. Socinski, MD: The TKI paradigm is being tested with avelumab in renal cell.


Dean F. Bajorin, MD: Right, it’s being tested with . And yes, for exactly the same reason. But if you take a look at bevacizumab, it’s better tolerated so it’s easier to go together. They play better in the sandbox, so to speak. Following on this, there are a lot of things we don’t know about the drugs we’ve been giving for years. It’s remarkable how little we may know. Gemcitabine is effective against MDSCs (myeloid-derived suppressor cells), and we’re just learning that now. I treat germ cell tumors, and we know that you can have primary tumors that regress if they’re infiltrated with lymphocytes and we give them chemotherapy to cure it. But one of the things we see is thymic hyperplasia after chemotherapy. It is very, very common. So, I think there may be a lot of interactions that we simply don’t know, but actually may be great strategies as we move forward and we look at combining therapies.

Transcript Edited for Clarity

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