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We sit down with health care executive Eugene Chan to explore the rising rates of liver cancer worldwide and the potential game-changer in its treatment: monoclonal antibodies. Join us as we delve into the factors contributing to liver cancer’s prevalence, the impact of vaccination, and the promising future of mAbs as a more precise and effective treatment approach. Discover the latest research on bi-specific antibodies and the ongoing efforts to improve outcomes for patients battling hepatocellular carcinoma (HCC).

Eugene Chan is a health care executive.

He discusses the KevinMD article, “Diversified treatments are needed to fight the increasing threat of liver cancer.”

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Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast, and get CME for this episode by clicking on the CME link in the show notes. Today we welcome back Eugene Chan. He’s a health care executive. Today’s KevinMD article is “Diversified treatments are needed to fight the increasing threat of liver cancer.” Eugene, welcome back to the show.

Eugene Chan: Thank you so much, Kevin, great to be back.

Kevin Pho: So for those who didn’t listen to your first episode together, just briefly share your story, journey.

Eugene Chan: So I’m a physician and basically also a health care executive. So I am one of the co-founders of a biotech company called Abpro, which is based here in the Boston area, and we basically develop monoclonal antibody as well as bispecific antibody approaches to treating cancer.

Kevin Pho: All right, so today we’re going to specifically talk about liver cancer. So before talking about your treatment approach, just give us the context and the scope of the issue of liver cancer today.

Eugene Chan: So liver cancer is an area where there’s been increasing cases that have been happening over basically the past several decades. Part of this is actually based on hepatitis in areas outside of the U.S. And then even within the U.S., just like colon cancer, there’s increasing younger as well as more individuals who have liver cancer. And that becomes concerning because now there needs to be newer approaches to be able to treat liver cancer, so that basically patients can get the benefits of the most medicines.

Kevin Pho: All right, so tell us some of the risk factors that one can have to develop liver cancer.

Eugene Chan: So smoking has always been one of the big ones. Smoking, alcoholic cirrhosis is the other one. So these are sort of lifestyle factors that you control.

But then there’s also virus infections like hepatitis, including things like hepatitis B and C. In the case of hep B, if you’re not vaccinated to hepatitis B, which here in the U.S. you are but outside the U.S. it’s less common, then basically you could be at a much higher risk for getting liver cancer.

And so some of these things, at least lifestyle factors, you can definitely control. So basically you can quit smoking and quit drinking, or do it in moderation, and you can decrease your risks of those items. And then even in the case of hep C, basically there’s now new therapies that allow you to essentially effectively cure hep C. So those things would also basically decrease your risk of obviously getting liver cancer.

But there’s also other factors that we don’t know about, and so there’s probably other viruses that basically impact how our body handles certain immune reactions. And these are all things that are new and will be discovered as we start understanding, similar to colon cancer, why there are increased cases in young people. We’re going to start understanding some of these factors hopefully soon, so that we can basically do better by them sooner.

Kevin Pho: So if someone gets diagnosed with hepatocellular carcinoma, what are the traditional treatment approaches today?

Eugene Chan: So the traditional approaches today range. So it depends if it’s a primary or secondary cancer of the liver. So what I mean by that is basically, primary is that’s where the cancer arose, right in the liver. In other cases it’s a metastasis straight to the liver. So it really kind of depends on the primary tumor site.

Right now there’s several different approaches. You have conventional chemotherapy. There’s actually small molecules which basically target certain pathways, including the VEGF receptor, which is a great way of doing it. There’s also immunotherapy, PD-1 monoclonal antibodies, which have also recently kind of shown up, which have demonstrated ability to basically prolong life. And then anti-VEGF inhibitors, also monoclonal antibodies, that are being used as well. And then those are in conjunction with the standard approaches, which includes things like surgical resection.

So it really kind of ultimately depends on the specific nature of the liver cancer, as well as the primary location of it, and also depends on the stage.

And right now, over the past five years, let’s call five to 10 years, there’s been advances definitely on the immunotherapy side. And even right now in the pipeline, there’s approaches like what we’re developing over at Abpro, which is now a bispecific approach to treating hepatocellular carcinoma through GPC3, which is now one of the markers on liver cancer. And then the bispecific approach, essentially the other half of it basically targets CD3, which basically brings your immune system to life and brings your white blood cells to basically go and fight cancer specifically.

And so that’s sort of what I see as the new horizon, both that as well as some of these cell-based therapies which are also being explored. The advantage of having a bispecific approach is that essentially you can do an infusion, you don’t have to basically take cells out of a person. And basically now it’s a much simpler, more scalable approach to being able to treat with more of a punch to the actual treatment. And so that’s the horizon of the new therapies that are going to be coming out, and I think there’s great promise in those approaches.

Kevin Pho: So there’s variation in terms of the five-year survival rate when it comes to liver cancer. Are there any factors that make hepatocellular carcinoma more prone to one approach versus another?

Eugene Chan: Yeah, so I think when we look at it from a drug ability standpoint, I think a lot of this actually tends to be kind of marker driven, or the specific clonality, if you want to speak in scientific terms, of the actual cell types that you’re actually looking at.

And so basically in the case of what we’re developing with GPC3, essentially you’re looking at high expressors of this particular cell surface marker, which is going to be vastly higher in the case of certain types of HCC and not others.

And so it’s almost like, I think the most similar to it would be taking the breast cancer kind of analogy, HER2 expressing cancers versus not, or estrogen receptor positive or progesterone receptor positive kind of types of cancers. In the case of liver cancer it’s the same thing. So basically there’s going to be a higher expressing GPC3 type liver cancer versus others. You do have to kind of check it beforehand before you administer a therapy. But once you have specific markers, then basically now you have a little bit of a more tailored approach in terms of choosing which one it’s going to basically look for.

And also depends on stage. So basically if it’s more advanced, different therapies will be better than others at certain stages. And so particularly some of the PD-1 antibodies, generally you’ll want to basically engage that a little bit later as opposed to straight off the bat. And then some of this is also used in conjunction with more conventional chemotherapy type approaches, where not just one therapy is effective but now you’re targeting more than one pathway to basically get that response that you want.

Kevin Pho: So just give us a primer for new drug development. Where are we specifically with the bispecific antibody approach in the drug pipeline, and what needs to be done for it to move forward?

Eugene Chan: So there’s been now a precedent of bispecific antibodies being able to target effectively. So it’s not just for liver cancer but for other therapies, both what we’re working on over at Abpro as well as for other types of cancers.

Generally for these bispecific approaches, they’ve been focused on liquid tumors. So basically your leukemias and your lymphomas, things that are a little bit more easily, let’s call it, druggable, because it’s more easily accessible to a bispecific type antibody approach.

Now, targeting liver is a little bit different, because now it’s essentially classified as a solid tumor. Even though your liver is very vascular, you still need penetration of the bispecific antibody into that tumor site in order to get maximal response.

Fortunately, for the bispecific type of approaches, you’re actually relying on activation of T cells. So the T cells now will go find and basically squeeze through the cracks, essentially. That’s the way we think about it, between the vascularity in the solid tumor, and then be able to essentially target most of the tumor sites in the solid type tumor.

So that’s a huge distinction between the pharmacodynamics between, let’s say, conventional, let’s say even small molecule chemotherapy drugs, where it’s actually harder to penetrate deep inside the tumor. Here in this case you’re kind of relying on a cell to kind of squeeze through the cracks. They’ve got special receptors where, once it’s activated, it actually is able to have that kind of homing technique.

And right now you’re seeing these bispecific approaches, they’re in phase one, phase two, or pre-IND. And based on what we know out there, I think now there’s at least like eight approved therapies using this bispecific kind of T cell activation approach. And I think pharmaceutical companies are gravitating towards that, because it’s just a much easier way of administering essentially cell-based therapy without the hassles of that ex vivo kind of cell modification approach, as we’ve seen with CAR T therapies.

Kevin Pho: So assuming everything goes well with clinical trials, how long do you expect it will take before we see a bispecific antibody approach specifically for hepatocellular carcinoma?

Eugene Chan: So generally these trials are reasonably long, because I think one of the big concerns that the FDA has is safety, right? You are activating T cells, and T cells do have cytokine release. So you do want to have a reliable dose escalation during the phase one.

And so once you get past phase one it becomes a little bit easier, because now you’re going in there at a reliable one or two kind of remaining doses. And then at that point, basically soup to nuts, phase one to phase three, probably around a five-year cycle. So we’re seeing some of these things in the two-year mark. For ours in particular, we’re probably in the four to five-year mark for ourselves.

But the phase ones tend to be longer, the phase twos tend to be a little bit shorter, and then the phase threes, you’re kind of back to looking at a little bit more lengthy trial. But you’re really kind of looking for, what kind of mortality benefit does this give? And also there’s noninferiority of these particular agents compared to conventional methods.

So in a lot of cases you’re basically using this drug on people that have failed other therapies, like the VEGF inhibitors or whatever it might be. And so it’s actually a harder population that you’re basically going after. And basically if you demonstrate efficacy against these harder to treat patients, that’s where the value in these bispecific approaches is, because they have a different mechanism of action, they pack way more punch than some of these other conventional therapies. That’s where we anticipate that there’s going to be a reasonable mortality benefit to these drugs.

Kevin Pho: We’re talking to Eugene Chan. He’s a health care executive. Today’s KevinMD article is “Diversified treatments are needed to fight the increasing threat of liver cancer.” Eugene, let’s end with some of your take-home messages to the KevinMD audience.

Eugene Chan: So basically I think what we’re looking at is, liver cancer is something that is becoming increasingly concerning, in terms of just the amount and the rate by which it’s increasing.

And right now we’re seeing conventional therapies, basically they’re prolonging life but it’s not enough. And so that’s where new therapies like bispecific antibody approaches, T cell engagers, are going to become increasingly more important, to basically try to bump up that patient benefit. Which right now we’re seeing these great therapies that are out there, but still a lot more needs to be done. And so basically, be on the lookout for some of these new therapies in the future.

Kevin Pho: Eugene, thank you so much for sharing your perspective and insight, and thanks again for coming back on the show.

Eugene Chan: Great, thank you so much.