Progress and Promise in Advanced Pancreatic Cancer - Episode 10

Emerging Immunotherapy Data in Pancreatic Cancer

Transcript:Johanna Bendell, MD: Let’s think about outside of chemotherapy. We’ve got clinical trials that are going on right now. They’re looking at immunotherapy for patients with pancreatic cancer. And I’m not talking about the checkpoint inhibitors. I’m talking about vaccines. So let’s talk a little bit about immunotherapy for pancreatic cancer. Caio, tell us a little bit about what you know.

Caio Rocha Lima, MD: It is exciting, actually, because we are moving on to a different modality of treatment in pancreatic cancer. Historically, unfortunately, targeted agents have not been successful in this disease. In GI malignancies, colorectal cancer, even gastric cancer, we have targeted therapy that has proof of principle to improve survival. EGFR inhibitors, VEGF tyrosine kinase inhibitors and trying to target KRAS, all those things failed in pancreatic cancer. Now, we are realizing that maybe the strategy could be a little bit different, either targeting the stroma or making your immune system work for you again. Because we all believe that in the tumorigenesis, the immune system failed at some point and allowed the cancer to establish itself.

How can we bring the immune system to be our ally again? One of the strategies is we have a new vaccine called algenpantucel-L. There are actually pancreatic cells, panc1 and panc2, that have been genetically modified to express alpha-gal, and alpha-gal induces a type of reaction that we observe in xenographic transplant, so there’s a very high reaction. And the hope is that by activating the immune system again through that mechanism, the immune system will eventually corroborate and help the chemotherapy in destroying the cancer cells.

Algenpantucel-L has been started in the adjuvant setting. A phase II study has been published, where the results were appealing. Populations of lymph node—positive patients were very high, where historical controls suggest that the addition of algenpantucel-L to chemotherapy could improve outcome. And a phase III trial has recently been completed, and we are waiting for results of adding algenpantucel-L to gemcitabine, then a move to gemcitabine/nab-paclitaxel, or FOLFIRINOX to gemcitabine, or to gemcitabine alone. So we are going to have a randomized phase III trial that will answer that question for us in the adjuvant setting.

In the locally advanced situation, we also have a trial where they extrapolate from the phase III data. Actually, it was physicians’ choice of either gemcitabine/nab-paclitaxel or FOLFIRINOX, and then you add algenpantucel-L—there’s a strategy. Radiation could be part of the program as well, so you have all the modalities together and the patients would become resectable. They could go to surgery and continue on algenpantucel-L after surgery as well.

Johanna Bendell, MD: It is very exciting. So instead of using a checkpoint inhibitor to block how tumors are hiding from the immune system, we’re actually giving them the target to hit.

Caio Rocha Lima, MD: Absolutely.

Johanna Bendell, MD: Tom, what are you guys doing at the Farber? Thoughts on this?

Thomas A. Abrams MD: Well, it’s really an exciting technology. It’s a different way of using immune drugs. We’re used to using the checkpoint inhibitors in many of the other diseases that we treat. They don’t seem to be, at least as single agents, very effective in pancreatic cancer, perhaps because it’s the concept of a cold tumor. But if we can heat it up and bring activated T cells into the tumor, we can perhaps really harness the immune system. We have a lot of these kinds of clinical trials in the works and certainly we participated in phase II of the algenpantucel-L vaccine in the adjuvant setting. And we’re very excited by that drug.

Johanna Bendell, MD: George, we’ve got a double vaccine, too. It’s not just a vaccine, we’ve got a vaccine/vaccine.

George P. Kim, MD: This is work from Hopkins. So those guys, they’re pretty smart over there. They’ve got GVAX, which is two pancreatic cell lines overexpressing GM-CSF. They irradiate them, and so they get more antigen presentation, and they showed data in the adjuvant setting: survival about 25 months. Then they brought in another drug called CRS-207, which is actually mesothelin. This is based on the Listeria strain that’s attenuated. So they combined the two. They did it in second-line treatment, and they showed some meaningful survivals of about 10 months. They did a GVAX versus GVAX plus this Listeria construct and showed about a 10-month survival versus about four months in the GVAX arm.

The Hopkins guys, they’re leading the way, and everybody is excited about the checkpoint data that they showed in the MSI-9 colorectal cohorts. There’s about four patients there. The poster is presented today: three out of the four pancreatic cancer patients had responses. The overall survival for the entire non-colorectal cohort is about 21 months. So there is some room for checkpoint inhibitors, but, unfortunately, it’s not a lot of patients. It’s probably a minority, 10% of patients that had this mismatch-repair tumors.

Thomas A. Abrams MD: Both of these strategies, they sort of do lend themselves to potentially partnering with a checkpoint inhibitor, and maybe that’s really going to be a way to move it forward. I think there is a phase III trial in pancreas cancer with the GVAX CRS-207. Top-line data are going to be available sometime later this year.

Johanna Bendell, MD: Yeah, so this is the double hit where you get the immune system all activated and angry, and then you give the Listeria, and that activates it even more to attack the pancreas cancer. There are so many different ways we’re hitting it.

Transcript Edited for Clarity