Immunotherapy in Pancreatic Cancer

Transcript:Tanios Bekaii-Saab, MD: Unfortunately, in pancreas cancer, immune therapy is not making the same strides that we’ve seen with other cancers. PD-1 inhibitors have mostly shown very little activity. In fact, the only place where there has been activity are those tumors that are MSI-high, which is less than a couple percent in pancreas cancer. In the rest of pancreas cancer, PD-1 had almost no evidence of activity or, at least, for now, we don’t see much evidence of activity. In terms of the vaccine strategies, there were two major strategies being looked at in clinical trials. With algenpantucel-L in the early setting and with standard chemotherapy in the adjuvant setting, unfortunately, we heard that the IMPRESS study failed to meet its primary endpoint. And so, algenpantucel-L did not seem to add benefit to an adjuvant strategy.

CRS-207 plus GVAX was an interesting dual vaccine strategy that essentially looked promising in the early stage of the development. But, unfortunately, again, the study that looked at the combination of the two did not show any added benefit. So, there were two failed studies with vaccines and very little promise from other immunotherapeutic regimens. And the problem is likely, and remains likely to be the same, because we have that barrier that holds up all the immune suppressive cells in proximity to the tumor and excludes all the good cells—the T cells, the cytotoxic T cells, and NK cells—outside the tumor. That may explain why a lot of these immunotherapeutic strategies are not working in pancreas cancer. There’s a caveat to that. If we can find a way to break that barrier or to enhance the immunogenic potential of these tumors, we may actually be able to revisit these immune therapy strategies and attack pancreas cancer. But, at this point of time, it does not seem that an immune-therapy-only strategy is going to be successful in pancreas cancer.

Philip A. Philip, MD: My patients with pancreatic cancer constantly ask me about immunotherapies. They read the internet, and then you have a meeting like ASCO, especially over the last couple of years where immunotherapy is a major component of advances that are presented, and patients easily know about it. They are asking me constantly about, “Can we get an immunotherapy treatment?” Unfortunately, immunotherapies have not really made any advances in this disease. Pancreatic cancer tumors are notoriously unable to really take advantage from the immunotherapy, as we know it today; the one which is used, for example, in other cancers. And the reason for that is that for immunotherapy to work, it needs a number of things. One of them is that it needs certain immune cells, we call them T cells, to be available around the cancer cell, to be able to destroy the cancer cells when they are stimulated to do so. But, if you don’t have those cells in sufficient numbers outside of the cancer cells or next to the cancer cells, we cannot really utilize, for example, immune checkpoint inhibitors, like PD-1 inhibitors that are currently being tested successfully in a number of cancers. But, these checkpoint inhibitors, they require T cells. And the T cells are not present in any abundance in the tumor cells, unlike melanoma where it has a lot of T cells infiltrating. We’re not giving up. We’re not saying that immunotherapy is not going to work in this disease. What we’re saying is that, on the one hand, we have to understand more

how to make it work better. So, we want to have a better handle on the biology. That’s being vigorously investigated. And, on the other hand, we need to be able to bring in cocktails of drugs, because one drug is not going to do it. An immune checkpoint PD-1 inhibitor is not going to do it, so we need other strategies to work together. And there is evidence that that will be possible, but when, I don’t know. That will take us some time putting those drugs together. Obviously, we need clinical trials. And one thing which we really always have to remind our colleagues in the community is that patients who are newly diagnosed with pancreatic cancer should always be considered for clinical trials. And there are clinical trials in different classes of agents, and also, increasingly, in patients who are now being referred for immunotherapy. But, we don’t have a standard treatment immunotherapy. We think that we’re still a ways from having a treatment that is really going to be good. But, at this point in time, there is active effort to really understand the immunotherapy problem in this disease and to try to put a treatment strategy, which I can tell you is going to be a combination of the drugs, not one drug.

Targeting the Notch pathway in preclinical experimental models is something which is certainly of interest. And why? Because it’s also involved in the stem-cell biology. Stem cell is unimportant because when we give chemotherapy to patients, we kill cancer cells. We think that one of the reasons why we fail is because those stem cells are hiding. They’re not being destroyed by chemotherapy, and they are resulting in the progression of the cancer or the recurrence of the cancer. Therefore, any approach that can damage those stem cells and kill them may help us to improve the outcome of our chemotherapy we use. So, there are agents that are targeting the Notch pathway, but at this point in time, they’re still experimental. We don’t have really any indication that they’re going to be drugs that are going to show benefit in patients who we are treating for their pancreatic cancer.

Transcript Edited for Clarity