Liver Pathobiology's Role in Hepatocellular Carcinoma

Transcript:

Ghassan K. Abou-Alfa, MD, MBA: Hello and thank you for joining this OncLive Peer Exchange® titled “Multimodality Management of Liver Cancer.” As we all know, treatment of hepatocellular carcinoma [HCC] has become increasingly complex with recent innovation in both locally advanced and metastatic disease. In this OncLive Peer Exchange® discussion, I am joined by a panel of multidisciplinary experts in hepatocellular carcinoma. Today we will provide a practical perspective on current approaches to treatment of liver cancer and will discuss the rationale for future combination therapies. I am Dr Ghassan Abou-Alfa. I’m from Memorial Sloan Kettering Cancer Center, professor at Weill Medical College, and also the chair of the NCI [National Cancer Institute] Hepatobiliary Task Force.

Participating today on our distinguished panel are: Dr Catherine Frenette, medical director of liver transplantation at Scripps Center for Organ Transplantation and director of the Liver and Hepatocellular Cancer Program at Scripps MD Anderson Cancer Center in San Diego, California; Dr Tim Greten, head of the gastrointestinal malignancy section, cochair of the Center of Excellence in Immunology, and co-director of the NCI CCR [Center for Cancer Research] Liver Cancer Program at the National Cancer Institute in Bethesda, Maryland; Dr Riccardo Lencioni, professor of radiology at the University of Pisa School of Medicine in Pisa, Italy, and honorary research professor of interventional oncology at the Miami Cancer Institute in Miami, Florida; and finally Dr Michael Morse, professor of medicine in the division of medical oncology and professor in the department of surgery at Duke Cancer Institute in Durham, North Carolina.

Thank you so much for joining us and let’s begin. I’m sure you all agree, this is been an extremely busy 3 years with a lot of advances in regard to the treatment of advanced hepatocellular carcinoma. And of course, one of the things we talk quite a bit about is the use of checkpoint inhibitors. But I’ll start with Tim. What’s the story between immunity and the liver to begin with?

Tim F. Greten, MD: Well, obviously we’ve been always very interested in immunity because one of the distinct features of HCC is that it is a disease that is associated with inflammation. Our patients usually have chronic inflammation induced by viral hepatitis. Even the ones with excessive use of alcohol have chronic inflammation or fatty liver disease, all leading to chronic inflammation, and then the chronic inflammation finally promotes tumor growth. So this interplay of inflammation and the immune system in cancer is something that we’ve been working on for many, many years.

Ghassan K. Abou-Alfa, MD, MBA: That’s extremely helpful. Catherine, you’ve been, as an expert in transplant, involved in inflammation and immunity way before even the oncologists came on board. Tell us your perspective as a transplant hepatologist.

Catherine Frenette, MD, FAST, AGAF: Liver transplant really is an interesting interplay of the liver and the immune system. And when a liver is transplanted, it actually brings a lot of lymphocytes and immune system cells along with it to the recipient. So the recipient ends up with almost a chimeric type immune system. And it just shows us how many immune system cells are living in the liver at any one point.

Ghassan K. Abou-Alfa, MD, MBA: Mike, we all say anti—PD-1 [anti–programmed cell death protein 1], anti–PD-L1 [anti–programmed death-ligand 1]. What’s anti–PD-1?

Michael A. Morse, MD, MHS, FACP: One of the major findings in immunotherapy that’s really driven the field is this observation that once immune cells, T-cells, get to the tumor, their function is shut down. And this appears to be a function of a molecule called PD-L1, which is deployed by really any cell that’s under attack by another immune cell to protect itself. So PD-L1 interacts with PD-1 on activated T-cells and causes functional demise of those T-cells.

Ghassan K. Abou-Alfa, MD, MBA: In other words, it’s as if the PD-1 is preventing the T-cells from touching the cancer cells, and as such, an anti—PD-1 or anti–PD-L1 will bring the T-cell closer to the tumor. Tim, back to you, we hear quite a bit about CTLA-4 [cytotoxic T-lymphocyte–associated protein 4]. What’s the connection there, and what does CTLA-4 do to begin with?

Tim F. Greten, MD: Let me explain this very simply. If you have an immune response, that’s basically a light switch to start the immune response, and the T-cells become activated. But you need to stop that. Once the infection is over, you want the T-cells to stop, and that’s basically this mechanism about immune checkpoint inhibitors. And CTLA-4 is one of these very early molecules that we have that the immune system has developed to stop the immune response, so that you don’t overreact. The problem is that in the context of cancer, there are different mechanisms that the cancer has developed such that this is actually completely blocked.

So what we try to do is awake the T-cells again so that they start functioning again. And then there’s this interplay between CTLA-4 and PD-1, one working a little bit earlier, one working a little bit later, interacting with different antigen-presenting cells, other cells in the environment, differently expressed on different subsets of T-cells, which makes the whole story more complicated. But I think the important thing to understand really is that this is a mechanism that the human body has developed to start an immune response and to stop it again, which actually is a good thing. It’s just in the context of cancer, we need to boost this again.

Transcript Edited for Clarity