Expert Discusses Research Using Ceramide Liposome Particles With Immunotherapy to Treat HCC

Kevin Staveley-O’Carroll, MD, PhD

After years of limited treatment options for patients with hepatocellular carcinoma (HCC), the treatment paradigm is now shifting as more agents become available. Now that multiple lines of therapy have been established, the focus is on how to best integrate these treatments, explained Kevin Staveley-O’Carroll, MD, PhD.

During the 2018 SITC Annual Meeting, O’Carroll discussed immunotherapy in HCC, including a mouse model he has developed with colleagues at the University of Missouri to further investigate immunotherapy for these patients. One of the most promising strategies they have seen with their research is using ceramide liposome particles with immunotherapy.

“Our most recent data used in our realistic model of HCC in mice was used in conjunction with immunotherapy. That gave us very good response…in future clinical trials, we want to use those two together, and that’s data that came directly out of our mouse model,” O’Carroll said.

In an interview withTargeted Oncology, O’Carroll, chair and cancer center director at the University of Missouri, discussed how the field of HCC has advanced over the last few years and how his mouse model is being used to further investigate immunotherapy treatment options.

TARGETED ONCOLOGY:Can you begin by providing me with some background on your trial investigating immunotherapy in HCC?

Staveley-O’Carroll:Well it’s an exciting time in immunotherapy for HCC. For years, we have had very, very limited treatment options. I’m a surgeon, and the thing that made me want to research HCC was our inability to treat it. There’s a lot of liver tumors that I can remove and really offer people a good chance of cure, but HCC is not one of them because it occurs in diseased livers. Almost all cases of HCC occur in livers that are cirrhotic. It’s this cirrhotic necrosis and regeneration that predisposes these cancers. They’re all in unhealthy livers that can’t be cured readily with surgery.

The liver also has a very peculiar biology. We know this from liver transplant. You can transplant a liver from one person to another and use much less immunosuppression than it takes with other organs. In fact, if you transplant 1 liver along with a kidney it helps protect the other organs. The liver is a tolerogenic organ. It has a very specific immune response that goes on in it. It might have to do with protecting us from the gut, bacteria, the food, and the antigens that we are exposed to, but the liver is something that has a very peculiar immunology. There is a potential to study the immune response to liver cancer, but it’s going to be complicated because the liver has such an unusual immunology.

Despite all of that, we’ve recently made some progress. We’ve had sorafenib now since 2008, a targeted kinase inhibitor that shows efficacy. The efficacy seems to be improving. Initially, it seemed to extend people’s lives by 3 months only, but it was approved just for that because there was nothing else that worked at all. Now it seems to be extending people’s lives more.

In the second-line, we have developed other targeted kinase inhibitors like regorafenib. Now, if you have first-line sorafenib followed by second-line regorafenib, you can get survival over 2 years. We’re definitely making improvements there with targeted kinase inhibitors. Meanwhile, immunotherapy seems to work somewhat. Nivolumab in the first- and second-line had a response rate of 20%, and now it’s being compared to sorafenib in clinical trials in the first-line.

We also have a lot of other therapies that we use that are sometimes not curative but are somewhat effective. We can ablate liver tumors, we can put probes in and burn them with radiofrequency ablation or microwave ablation. We can destroy them by cutting off the blood supply, with a transarterial chemoembolization. Now we can even cut off the blood supply and leave Y-90-emitting spheres.

We have a lot of different potential therapies, and what we are going to have to do is figure out how to best integrate them. It seems like if you integrate targeted kinase therapies with local ablative therapies, it will release all of that dead tumor and then it might give you the opportunity to have more effective immunotherapy. We have developed a lot of different lines of therapy, but now the challenge is going to be how to integrate them.

What we have done in our lab is to develop a mouse model liver cancer that really recapitulates what happens in human beings. We’ve got a spontaneously arising cancer that occurs in the background of fibrosis and cirrhosis. We are able to follow the immune response to the tumor antigens in HCC. We’ve experimented with chemotherapy and immunotherapy together. We have a very promising new result where we take ceramide liposome particles and use that with immunotherapy to destroy HCC. That’s what the focus of my study is on.

TARGETED ONCOLOGY:What’s your ultimate goal with this research?

Staveley-O’Carroll:To cure HCC, eventually, but right now our goal is to understand HCC and the immune response to it. Some things that are very interesting are how the immune response in the liver changes in response to changes in the gut microbiome. That’s very important in all cancers, but it’s particularly important in liver cancer because the very first filter that all the gut microbiome goes through in the human body is the liver. The liver is fed by the portal vein which drains the intestine directly into the liver, so all food antigens or bacterial antigens in the gut will travel to the gut first. There’s going to be a very complex immuno-biology in between the liver and the gut microbiome that we are going to have to figure out.

TARGETED ONCOLOGY:Are there any key trials ongoing for integrating these therapies?

Staveley-O’Carroll:There are. The integration ones are going to be complex, and there are not that many. We have first-line trials and second-line trials. Most of the integration trials are just small trials. Right now, we are well positioned to look at integrating targeted kinase inhibition with immunotherapy, with local ablative therapy, with gut microbiome modification, but as we look to do those trials, we are going to need some guidance. That’s why I think the mouse model that recapitulates what happens in humans is very, very important because it’s easy to do those studies in mice to get some ideas of what’s most effective. When you have that many combinations, you have so many groups of people that it would be impossible to do a good trial, so we need more guidance before we move to the human trials in some instances.

TARGETED ONCOLOGY:What data has come out of the mouse model that you are most excited about?

Staveley-O’Carroll:The thing we are most excited about is we have just had this success with ceramide liposome particles. We showed in a gut paper back in 2010 that killed HCC directly, and based on that and other results, that agent, that ceramide liposome particle, has been brought to clinical trials in humans. It’s just passed phase I clinical trials that have shown it’s safe in humans. Our most recent data used in our realistic model of HCC in mice was used in conjunction with immunotherapy. That gave us very good response. We’re very excited about moving that forward into the clinic because immunotherapies have been proved for people, and now the ceramide liposome particle has been shown to be safe in clinical trials. In future clinical trials, we want to use those two together, and that’s data that came directly out of our mouse model.

TARGETED ONCOLOGY:What have been the biggest challenges in developing the mouse model?

Staveley-O’Carroll:It was very difficult to establish a realistic mouse model for HCC because HCC always occurs in diseased livers, so a lot of models won’t recapitulate that diseased liver. In the past, liver disease in this country has been largely caused by hepatitis C and alcoholic cirrhosis. We’re getting better therapies and we’re getting a handle on that disease, but in the future, nonalcoholic fatty liver disease is really going to be a problem.

We’ve worked hard to get a realistic model in which we can have spontaneous cancers that develop in the background of nonalcoholic fatty liver disease. That’s going to be important for the immune response, that’s going to be important for the interaction with the gut microbiome. It’s very important when you’re studying HCC to study it in a liver that recapitulates the inflammatory process that happens in human beings, because almost all of HCC in human beings occurs in the setting of the diseased liver.