My name is Tamara Taddy and I'm honored to welcome you to the 2023 Leon Schiff state-of-the-art lecture. Okay, I'm advancing too quickly, hold on. Okay, so this lecture honors Dr. Schiff, an esteemed pioneer in the field of hepatology and a founding member and the first president of the ASLD. He authored one of the foremost textbooks on liver disease, Schiff's Diseases of the Liver, a valuable resource for generations of hepatologists now in its 12th edition. Dr. Schiff received his medical degree from the University of Cincinnati where he also founded one of the first divisions of digestive diseases. He later joined the faculty of the University of Miami in 1970, teaching and mentoring budding hepatologists until his death in 1994. His legacy lives on in his son, Eugene, who founded the Schiff Center of Liver Diseases at the University of Miami, named after his father. Here you see their shared infectious enthusiasm for the field. His legacy also lives on in each member of the ASLD and our vision to prevent and cure liver disease. This year's lecture will be presented by Dr. Lewis Roberts. Dr. Roberts is the Peter and Frances Georgeson Professor in Gastroenterology Cancer Research at the Mayo Clinic Rochester. Dr. Roberts' work is focused on understanding the mechanisms by which liver and biliary cancers develop, grow, and spread. He has been a pioneer in liver cancer research, outreach, and guideline development across the globe. He has mentored a diverse group of over 200 individuals at all stages of training in his laboratory over the last 25 years. His global health work in Africa has focused on research, education, and training, and increasingly on implementing programs to reduce the burden of hepatobiliary cancers on the continent. One of the accomplishments of which he is most proud has been the co- or peer-mentoring with his wife, Rosebud Roberts, of their lives, children, and careers. Pictured here is Dr. Roberts in his element as a husband, father, physician-scientist, and mentor. He will be speaking on a personalized approach to HCC. Thanks very much, Dr. Taddei. I'm humbled to be invited to present this lecture and would like to thank ASLD and particularly Dr. Terrell and Dr. Kim and the Annual Meeting Committee for this honor. As I reflected on the vast amount of information we are learning about hepatocellular carcinoma and its treatment and the opportunities we have to individualize or personalize care, I thought it would be most appropriate to present three recent studies from our group that point towards how we might be able to implement personalized treatment of liver cancer at the molecular level. We all already practice a degree of personalized treatment as we characterize the physical characteristics of HTCs, their size, the number of nodules, whether or not there's vascular invasion, and whether or not there's metastasis. And we consult together in tumor boards then to determine the optimal treatment or combination of treatments for cure or tumor control. But to begin, I would like to briefly review the state of HCC care on a global scale. So liver cancer is the most lethal of the common cancers, with an estimated 92% of persons who are diagnosed globally dying within one year after diagnosis. In the United States, the country with perhaps the highest healthcare expenditure per capita, it is one of only a very few cancers that are projected to increase in incidence over the next several years. In the countries with highest incidence and mortality in Asia and Sub-Saharan Africa, while we are making progress in a few countries, particularly in Asia and also in Egypt and Rwanda and Africa, the estimates in most countries are for increasing rates of mortality over the next 20 to 30 years. In the US, there are states that if they were a country by themselves would be a high incidence country for liver cancer. So in one sense, if we were fighting a war against liver cancer globally, it would appear that our forces have been routed and we are in full retreat. However, this is happening at a time of unprecedented progress in the biomedical technologies needed to prevent and treat liver cancer. So how we can leverage these new technologies and knowledge in ways that are transformative to leverage them to achieve the best liver cancer control on a global scale is really a key question for us. And I believe that the greatest need is to leverage what we already know through population awareness, through health policy, and through implementation science. But it's also important that we continue advancing our understanding of biomedical science, tumor genomics, and immune microenvironment of liver cancers, so that we can actually have more effective treatments also for patients who are already presenting with advanced disease. And I think I'm particularly proud to say that ASLD is an active global leader in this space, that we are working to reduce the burden of liver disease, to eliminate viral hepatitis, to address the increased burden of metabolic associated liver disease, and to improve screening for early detection and care of patients with liver cancer globally. So this is what the map looks like globally, and you can see that while in Asia and Africa we have the highest rates, the U.S. really has intermediate death rates, and in some states, like I said, we actually have rates that are equivalent to very high rates. So the first study I'd like to show is on the impact of pretreatment biomarkers on the patient outcomes, and particularly what we are learning about what those biomarkers tell us about the underlying cancer pathways that are involved in these cancers. I just have one slide that talks about the molecular epidemiology of liver cancer, and makes the point that, you know, lifestyle, which results in obesity, diabetes, and alcohol use is an important factor. Aflatoxin, arystiloxic acid, and dimethyl sulfate, which has recently been identified as being a key component or key cause of liver cancer in Mongolia, that these toxins are really important also in the development of liver cancer. And I just point you to the last bullet point down there, that having more than one risk factor multiplies your risk of developing liver cancer, and I think it's important to say the other, you know, the other bullets are just encouraging us to try to decrease the risk, but anything that you can do to reduce any one of the risks also then is potentially really important to do. And there's an example of hepatitis C, where we can see that sustained biological response results in substantial reduction in the rate of liver cancer. So another point I think is important to make is that if we find people who are at risk and enroll them in surveillance, we find cancers at earlier stages of the disease. And there's strong body of evidence that suggests that early-stage liver cancer is much, much easier to treat, is a much less aggressive tumor biologically, than late-stage liver cancer. So we should all be working as hard as we can to find liver cancers at an early stage, even as we are working and we'll be talking about things that we are doing to try to treat late-stage liver cancer. And so the cascade of care to control liver cancer starts with trying to prevent the causes, identify those at risk, detecting cancer early, treating it effectively, and then personalizing the treatments. And as I have a couple of slides that just highlight what different countries look like right now in the world. So the blue row is Japan. So if we look at the population at risk in Japan, they probably have identified 90% or more of the individuals at risk in the country. If we assume that everybody does early detection and effective treatment at about the same rates, then they actually are able to achieve a level of control which results in over 50% five-year survival of patients diagnosed with liver cancer in Japan. That middle row, the United States would be typical of. We've only identified about 30% of the people who are at risk for liver cancer in this country. So even if we do about the same as Japan in terms of early detection and effective treatment, the best we can do is about 17 to 20% five-year survival, which is about where we are right now. And then the lower row I would call is Ghana, my home country, where we have identified probably less than 5% of people at risk. And even if we were able to do early detection and effective treatment quite well, we would only be seeing really low digits five-year survival. Another point I'll make specifically about the United States then is that if you look at the lower three rows, even if we were to take early detection to 95% performance and be able to detect everyone that we knew was at risk, and we're able to take treatment to 95% effectiveness so that we were able to cure all the people that we had identified, if we do not work at identifying the people at risk, we still limit ourselves to perhaps 30% five-year survival. So really important that we find those individuals at risk. Okay, so let's go back to the first study that I'd like to describe. We were really driven to this because of the issue of tumor heterogeneity, because as we all know, liver cancers present very differently. So on the very far right, you can see a small liver cancer that was diagnosed during surveillance, only about two or three centimeters in size, eminently treatable for cure. Then you see the middle one, the patient who presents, this patient I think had very little in the way of liver fibrosis. They presented with symptoms, this large tumor, but a single tumor is what they present with, and that's still quite different from the third patient, who was actually a patient from Ghana who had hepatitis B and hepatitis C, an alpha-fetoprotein of about 200,000, and you can see this large sort of infiltrative tumor, multiple, multiple nodules throughout the liver. It's a very different phenotype, reflective of the underlying tumor biology. So what do biomarkers tell us about this tumor biology? And this is work that we did with Dr. Kyung-Soo Ahn, who's from Daegu in South Korea, and spent some time with us. And what we did was an adjunct study to the Cancer Genome Atlas study for hepatocellular carcinoma. And so we identified people within the Cancer Genome Atlas cohort for whom we had serum samples. Now these are all patients who have had surgical resection at their home institutions, so are generally patients with early-stage disease. But we identified of the 91 or so of them that had serum available, we did the three commonest biomarkers that are used for detection of liver cancer, the AFP, then the AFP L3 isoform, and the DCP or desgamma carboxyprothrombin. And you can see that of the 91, 26 of these patients had normal levels of all three biomarkers. And then we had a lot of overlap between AFP and AFP L3. And so for those individuals who had either high AFP or high AFP L3, there were 26 of them, and those individuals we put in a separate category. Then we had 13 that had high DCP alone, and we had 21 that had elevation of all three biomarkers. So these are again all people with early-stage disease. And then we looked at what information we had on patient outcomes. And it's remarkable, the 26 people who had normal levels of all three biomarkers had a hundred percent 10-year survival after resection. On the other hand, the 21 people that had all three biomarkers elevated achieved only a median survival of just about 30 months. So all went to surgery for cure. Biology, as reflected by these biomarkers, made a huge difference in their outcomes. And I think as we can all imagine, and you can see, you know, for those who have AFP or AFP L3 alone elevated or DCP alone elevated, they were intermediate. All did quite well, you know, five-year survival above 80 percent. But I think this tells us something. And what we found as we looked at the genomics was that you could actually find genes that were upregulated or downregulated in each of the different subgroups, and you could associate them with specific oncogenic signaling pathways. So that for each of these subclasses of tumors, we could actually identify particular oncogenic pathways that are associated with these tumors. So in summary, blood-based biomarkers predict outcome of patients after surgery. We are already using them clinically. You know, many liver cancer transplant guidelines now exclude patients with markedly elevated AFP due to the high risk of post-transplant recurrence that's been identified. And these biomarkers are now known to be associated with activation of specific oncogenic pathways. Lots of work going on in this field, and the idea that biomarkers could potentially predict response to specific therapies. So the next thing I'd like us to think about is a little bit of a thought exercise with some data. And it's the idea that the goal of personalized treatment is to normalize exceptional response. Every one of my patients wants to have an exceptional response. And so my goal is not to have an average response for people. What I'm trying to do for them is to maintain a series of exceptional responses to whatever therapy I give them. And Professor Kudo and his colleagues, Dr. Arao and others, published this paper. So seraphinib was first approved for treatment of HTC in about 2008. And this paper was published in 2013 in hepatology. And they made the point that patients that were responders to seraphinib, that a subset of them had amplification of the FGF3, FGF4 locus on chromosome 11, that these patients often actually presented with multiple lung metastases, but were responders to seraphinib. And this is data from Professor Kudo, and where he shows the fish assay. And you can see the FGF3 amplification, the bright red dots in the tumors, all of those are spots where in the genome there's an amplification signal for FGF3 locus. And you can see down there the patient that has an exceptional response, a large tumor, shrunken with no enhancement. So when we did the Cancer Genome Atlas Project, which was finished just about 2017, we actually went back to see, within the Cancer Genome Atlas Project, what proportion of the HCCs that were studied had amplification of this locus? And we found that it's actually about 4%, where FGF3, FGF4, and FGF19 are all in sort of a row on chromosome 11. So about 4% in the Cancer Genome Atlas elevator. The challenge with the Cancer Genome Atlas, of course, was that, as I was telling you, these were all patients that were resected. And we do not have information on whether they subsequently had treatment with serafinib. So in a sense, we had this information, but not much else. And so the next thing we did then was waiting, fast forwarding several years. We took a cohort of 260 patients at Mayo Clinic, diagnosed between 2012 and 2018. They received either surgical treatment by resection or transplant, or liver biopsies that were performed for intermediate or advanced stage disease. And they had formalin-fixed paraffin-embedded tissue available. So we sent the samples for sequencing and targeted mutational and copy number analysis, and did an analysis to assess our proportion of FGF locus amplification and the impact on the outcomes. So of the 260, 18, so about 6.9% had amplification at this FGF3, 4, 19 locus. And it turned out that four of the 18, over the course of their treatment, had been treated with serafinib. And this is the data from one of those patients, actually, that I took care of for several years. And I'll just expand it here. And you can see here, highlighted in yellow, at chromosome 11, where you have these three genes, there are five copies of each of the genes. So there's clear increase or gain of expression at this locus. And this is the imaging for this patient. She had initially had a surgical resection when she presented with an HTC. She subsequently developed dysplenic metastasis. And she was sent to me when she had an AFP almost 60,000. Now, I started her on serafinib. And two months later, her AFP was 10. And you can see that lesion had shrunken significantly and was no longer enhancing. At four months, her AFP was down to 3.3. This woman lived on serafinib for over five years. And I'm sorry to say, eventually, she passed away because she tripped on a rug and fell and broke her hip. So she actually didn't die of HTC. So looking at these patients, then, we asked the question, for those patients who had FGF amplification and were treated with serafinib, what was the outcome compared to individuals who did not have amplification? And you can see here that those individuals with amplification who were treated with serafinib did substantially better than patients without amplification who were treated with serafinib. And so, in a sense, they are the exceptional responders. Median survival, 4.7 years, compared to less than a year for the ones who were treated with serafinib. And this is from time of serafinib initiation. So to summarize here, it's possible to identify biomarkers of exceptional response to systemic multikinase inhibitor therapy. Now, Professor Kudo, in his initial report, summarized his results by saying, you know, this might be a good idea sometime for us to actually do this assay and treat patients with serafinib who have amplification at this locus. But I'm not sure whether 2% is a high enough proportion for us to do this. But then, look, we are finding now it's somewhere between 2% and 7%, maybe around 4% that have this amplification, depending on the cohort. By comparison, one of my close friends, Dr. Alex Adjaye, treats patients with lung cancer. 4% to 5% of them have ALK fusions. He sequences every one of those patients with lung cancer so he can find the 4% to 5% to treat with the ALK inhibitor. NTREC inhibitors are approved for all patients now by the FDA with NTREC fusions, regardless of tumor type. If you take all solid tumors, only 0.3% to 0.4% of solid tumors have an NTREC fusion. So is there a good rationale, then, for us to biopsy and do genomics of all of our HCC patients, particularly those with metastasis, perhaps, to see if they have FGF3-419 locus amplification, given what our colleagues in other cancers are doing? OK. So the last project I'd like to describe to you is one where we are trying to see if we can maximize the benefit of immune-based therapies by using new combinations. And this study was actually first written by Dr. Judong Yang, who I'm sure many of you know. Judong, when he was a fellow at Mayo, actually wrote the study. We sent it off to the FDA. And by the time we got it back from the FDA, he had left. And so Lionel Kankofongkwa, who is one of the medical oncologists, is currently running the study. And it's in collaboration with Sean Park, who is a radiation oncologist, and Yi Lin, who runs the cell therapy group at Mayo. And Al Dietz was running the cell therapy laboratory at the time. The problem here is immunotherapy is transforming the lives of cancer patients who respond, the ones who respond. Despite a lot of success stories, most patients with liver cancer do not respond to single-agent or even double-agent immune checkpoint inhibition. And there's this idea that immunologically cold tumors have a low number of effector T cells in the tumor microenvironment. And that results in resistance to immune checkpoint. So this, I think, is a rationale for trying to use immunotherapy combinations, that we are averaging only 10% to 30% long-term response. Can we convert non-responders to responders, rescue patients who progress on immunotherapy, then overcome the secondary resistance, or deepen the responses that do occur? And maybe part of it is we can do this through harnessing tumor biology to support immunotherapy with monoclonal antibodies, and maybe a combination with small molecule inhibitors. And the question, of course, is can we integrate them with historical treatment modalities, such as chemotherapy and radiation, as well? So this cancer immunity cycle really starts with the idea that tumor cells release tumor antigens, that these tumor antigens are presented by dendritic cells. We have antigen presentation. Dendritic cells then go to lymph nodes, where they educate the immune system and cause the production of T cells that can traffic back to the tumors, infiltrate the tumors, and recognize the cancer cells and destroy the cancer cells. So that's the cancer immunity cycle. And there's multiple sites right now at which we are trying to address or target cancer immunity. So what's the role of radiotherapy? What we've observed is that cancer cells generally, or many of them, avoid immune stimulation when they die by dying in ways that avoid detection by the immune system. So they take part in what's called non-immunogenic cell death. And there's some evidence that radiation therapy can upregulate expression of genes that contain immunogenic mutations and synergize with new antigen vaccination to improve tumor control. So one of the key questions we had in this project was, can we use radiation therapy to enhance new antigen expression in tumors? And then what about dendritic cell therapy? Dendritic cells are concentrated at the center of the immunological universe. They sample the environment. They sense pathogens. They traffic from the periphery to lymph node. They present antigens and shape the adaptive immune response. And they also inhibit unwanted responses and can activate necessary responses. And so we developed this protocol, which I'll describe here. We start with the patient, the tumor, and the liver. And actually, before we do radiation therapy, we do apheresis. So we take the patient's own white cells, and we purify them. And the idea is that we're going to purify those cells. We're going to mature them into dendritic cells. And we're going to inject them back into this milieu of irradiated tumor cells that are exposing these new antigens. And so hopefully, that leads to activation of the dendritic cells. They traffic to lymph nodes. They stimulate cytotoxic T cells and other effector cells, which come back to the tumor and destroy it. And so this is our study schema. We start out, the first cycle is apheresis first. And then patients get the radiation therapy. So apheresis, we make monocytes. We get immature dendritic cells. We mature them. That's a secret sauce in the cell therapy lab. And then they make these mature dendritic cells that are active. So patients get radiation therapy for one to three weeks. And then they begin to get cycles. In the first three cycles, they get monthly injections of 60 million dendritic cells into the tumor bed. In addition, we inject pneumococcal vaccine to broadly stimulate as an adjuvant. And then they go into another four cycles in which they get monthly DC injections and then go into an event monitoring phase. So what we found in the early part of this pilot study was that we had enrolled, at this time, eight patients, five with HTC3 with intraparticulangic carcinoma. The maximal dose of 60 million cells appeared to be well-tolerated without autoimmunity or grade three or higher adverse events. Five patients had completed the protocol. The objection response rate was about 60%, with three partial responses, one progressive disease, and one stable disease, including a partial response that I'll show you, I think, next, of this patient who had intraparticulangic carcinoma, was treated with radiation and the injections. We see, of course, by month four a beginning of reduction in tumor size. She's all the way out to month 36. You can see almost hardly any tumor that can be seen in the liver. This other patient had a very large hepatocellular carcinoma, was treated again with radiation and in dendritic cell injections. And you can see, by month nine, loss of enhancement and shrinkage of a tumor to about a 10-centimeter lesion with no enhancement. And we are beginning to do some ancillary studies to try to better understand what's really happening as we do this protocol. What does the radiation therapy do? What does the addition of the dendritic cell injections do? And those are complicated studies that I don't completely understand. But the next question in our minds, then, was it seems as though this regimen is safe. We have pretty good evidence that we can use, for example, TARGET, VEGF, and PD-L1 with atezolizumab and bevacizumab for substantial improvements in outcome in patients with HTC. So what if we designed a phase 2 study and expanded it to add atezolizumab and bevacizumab to the regimen? And that's really what we've done. And I know we're kind of running out of time, so I'm going to move fast here. We are now accruing a phase 2 HTC cohort using, again, the external beam radiation therapy, injection with the autologous dendritic cells, but then adding in atezolizumab and bevacizumab to see if we can further boost the immune response. So we are targeting, again, immunity from multiple directions to see if that will help with patient outcomes. And I'll skip this and that and basically conclude that these novel combinatorial strategies we're trying to use to sensitize hepatomas to checkpoint inhibition. And we hope that innovative trial designs such as this one that incorporates the cancer immunity cycle in a multi-pronged approach can bring the promise of immunotherapy to more patients. So key takeaways, combined external beam radiation, prevna, immune adjuvant, and intraperituminal dendritic cell injection is well tolerated in intrahepatic cholangiocarcinoma in HCC. We've moved to a phase 2 study in HCC incorporating standard of care atezolizumab, bevacizumab. And we're actually planning a phase 2 expansion of the cholangiocarcinoma cohort as well, incorporating immune checkpoint inhibition there as well. I'd like to acknowledge our funders for this work. And thanks very much for your attention. Thank you, Dr. Roberts.

hepatology pioneer

individualized care

biomarkers

global burden

early detection

immune-based therapies

innovative treatment approaches