Josep Llovet, MD, PhD discusses molecular drivers of hepatocellular carcinoma (HCC) and provides the latest in management of early- /intermediate -stage HCC; standards of care for advanced HCC, including molecular therapies and immunotherapies; and biomarkers of response to immunotherapies.
Hi, everyone. Good morning. Um, we're gonna get started today. I have the pleasure of introducing Doctor Lovett. Yosip M. Lovett is director of the liver cancer program and professor of medicine here at Mount Sinai. He is also professor of medicine, hepatic oncology at the University of Barcelona and professor of research in the liver unit at the Hospital Clinic of Barcelona. Doctor Lovett was the founder and former president of the International Liver Cancer Association. He has chaired and contributed to the development of more than 10 guidelines related to clinical management and clinical trial design in liver cancer. He has published more than 359 manuscripts in peer reviewed journals and more than 55 book chapters. Doctor Lovett has devoted his career to studying the pathogenesis and treatment of liver cancer and has received numerous awards including the American Association for Cancer Research, the Land and International Award in 2009. And the International Hans Hopper Award in 2012. Please join me in giving Dr. Lovett a warm welcome. Uh, thank you very much for this nice introduction. So I'm Joseph Blot. So I'm professor of medicine at the division of liver disease and co-director of liver cancer program at the TCI, and I'm gonna talk today about immunotherapies for the management of apacellular carcinoma. These are my disclosures. So this is the outline of my presentation. We'll talk about epidemiology, molecular drivers, and uh precision oncology in HCC management of early intermediate HCC, and then in advance, we'll talk about molecular and immune therapies and finally, biomarkers of response to immunotherapies. So, as you know, liver cancer is the 6th most common cancer globally and the 3rd cause of uh cancer-related death. In 2018 we had 850,000 new cases, but by this year 2025 we're expecting around 1 million cases, mostly in Southeast Asia and sub-Saharan Africa. In the US we have around 2 41,000 cases in Europe, 68,000, and liver cancer is currently the leading cause of death in cirrhotic patients that represent 1% of the human population. So we are lucky in a, in, in, in that, in the fact that we know most of the risk factors that are linking uh the, the, the actual um factor to the development of the disease. Uh number one is hepatitis B virus that accounts for around 50% of HCCs globally. There are around 400 million people infected with hepatitis B virus infection that integrates into the DNA and produces um uh overexpression of oncogenes and or down regulation of tumor suppressors. Um, the second, uh, cause still is hepatitis C virus infection. Also it's clearly decreasing with all the drugs, the DEAAs that, uh, uh, actually are able to solve the diseases 95% of the cases and cure the disease but still remains as a second cause globally. The third is alcohol that it's flat, so accounts for 15 to 20% of the cases. And it's underrepresented in most of the statistics. It's well described, for instance, in Central Europe, in rural areas, for instance, in France, accounts for 60% of HCCs. Then the fastest growing theology is MasLD. That as you know is associated with overweight that accounts for close to 50% of the population in the US and associated to diabetes and this is the fastest growing cause of of apacellar carcinoma. Then we have cofactors. cofactors means that there are factors that per se do not produce HCC but on top of the other factors that I have described, increase the likelihood of developing ACC. And this, the most important one is a flatoxin one is a toxin that produces a point mutation in B53 that on top of hepatitis B virus infection increases the incidence of HCC3 folds compared to the patient with hepatitis B virus infection. Well, let's talk a bit about molecular drivers and precision oncology. So this slides summarize the molecular pathogenesis of the disease in one shot, so you can see that 80% of HCCs develop in a patient with underlying cirrhosis and only 20%. Uh, developing patients with chronic hepatitis. Mostly those patients with mass of the or hepatitis B virus are more prone to have HCC developing non-cirriatic livers. Otherwise, most of the HCC is developing erratic livers, and then. There are some molecular aberrations called gatekeepers that do not suffice to develop the tumor, but open the gates for the increasing the proliferation and, and proliferative advantage to hepatocytes. And these gatekeepers that are Currently described for their promoter mutations, chromosomal gas and losses, and epigenetic changes. And then at one time point there is an accumulation of alterations, uh, mostly mutations. Uh, the most important ones are Turk, betacatenin, and P53, and this, there is a point where is the tumor initiated event and from here you have early, uh, and progress and advanced tumors and then additional genomic heats. Ocu mutations, DNA amplifications, the lesions, and, and DNA uh methylation of promoter regions. So in average, HCC has around 60 mutations per tumor as opposed to highly mutated tumors like melanoma or lung cancer or MSI colorectal cancer that may have 150 mutations, non-somatic mutations, um, uh. Uh, non-synchronic somatic mutations per tumor as opposed to liquid tumors or pediatric tumors that have an average of 10 mutations per tumor, but out of these 60, most of the mutations are passenger, only a few proportion are actually driver mutations. And unfortunately among the driver mutations, and this is a study we published in 2015 with Jessica Suman was the first study in the Western world, uh, assessing, uh, collection sequencing in 250 patients and the most prevalent mutations start betacaten in TP 53. one where unfortunately undruggable mutations and this is very important. This is by chance and it's very important because this is the main reason why you do not have at this point precision oncology in ACC because the mutations, the most important mutations are undruggable so the ones that are druggable are these long tail. Of 5% of mutations at BRAF and all this stuff that are very difficult to target in the setting of a clinical trial. So you are very familiar about a precision oncology, the oncogenic addiction loops, the BCR AVL fusion, it was described in the 60s and imagine it was approved 40 years later. ER2 amplification in breast cancer. Trastuzumab was approved 13 years later. Then you have BRAF mutations in melanoma, uh, and 8 years later Benmrafeni was approved. And now we have the example of a fusions in non small cell lung cancer and crysotiny in a very short period of time was developed and approved. And this is because of the path of accelerate approval in oncology by FDA. Uh, for instance, this is the, an, an example that epitomizes what's accelerate approval. 1500 patients were screened. Uh, only 3% of the patients with non-small cell lung cancer have a fusions, so 82 were included actually in the phase two proof of concept study. And then they have a signal of efficacy published that in New England, got accelerate approval because of the 6 month progression free of 72% as opposed to 20. 7% in historic controls and then they had accelerated approval pending the phase three confirmatory study when you enrich and they enrich the trial for a fusions and they randomize the patient's chrysotomy versus the chemotherapy and uh 0.49 was the haa region. So this is the final uh slide for introduction. So in terms of mutational landscape, this is a study running memorial 10,000 patients and they screen with the platform impact uh uh 500 mutations to understand what exactly uh is the percentage of patients that are able to receive precision oncology in an academic center and the answer is 30. 7%. So out of the 10,000 patients, 37% as a result of doing the analysis of the genome receive a personalized medicine, but this ranges from Gs that you have up to 80% cholangiocarcinoma 45%, but HCC in the bottom just 5% because barely we have actionable mutations in HCC. Luckily enough, we know the molecular classification, the molecular classification in HCC our group was the first, we published that. Doctor Daniel Lacia reported that in gastroenterology in 2017 and then We, uh, uh, have recently updated the classification and in short we have 35% of inflamed tumors or hot tumors and 65% of non-inflamed or cold tumors among which 20% of those are immune excluded or in other tumors is they are called immune desert. So we assume for understanding the pathogenesis of what's going on and the immune types of cells that are enriching immune heart tumors that the immune heart tumors are more prone to respond to immunotherapist. Let's see if this is the case. So, let's talk a bit about the management and how immunotherapies are now modulating the, the management of the disease. This is the BCLC classification. We classify its in 5 stages. Mostly early stages are single tumors or 3 less than 3, and they achieve with resection transplant and local ablation 5 year survival rate of or median survival of 60 months. So in early tumors, 60 month median survival and. In terms of resection, there are two approaches. The Western approach that is what we're doing here, that we are more conservative. We are only selecting patients with well preserved liver function, and absence of mild port hypertension, and undergoing resection, the mortality rate pererative mortality rate is 0.5% with very low risk of the compensation 5%. But there is the Asian approach that is much more aggressive approach where uh they are operating tumors that are larger or multinodular and they are able to remove 3 segments out of the 8 segments of the liver and this leads to up to 30% risk of the compensation and. 5 and 9% of mortality and here you have a series of more than 2000 resections and in green you have those patients in which resection was indicated actually the treat the the tumor was removed and the 5 year survival rate is about 70% at 5 years. In blue candidates for a section in which the tumor was not removed, they received another therapy. They, the survival was significantly lower and finally in red, those patients that actually were not candidates for resection, but they actually receive resection will be more the uh uh Asian approach according to um Asian guidelines and the 5 years survival was around 35%. So what is the role of immunotherapy in this setting? There are two approaches, and one approach is the adjuvan immunotherapy that is the more conventional approach where the surgeon removed the tumor, then, uh, the treatment is applied afterwards. And then there is an activation of few different T cells and fewer and less diverse T cells search for cancer cells. This is the actual approach. Then the new A1 plus Auban is the, let's say the novel approach that is, is gaining um more momentum at this point. Why? Because when you have the tumor is when you have all the bulk of antigens there. Presented and therefore, it is the ideal place to uh deploy the, the immunotherapies prior resection. Then it gets the the cells get activated many different T cells, then the tumor is removed and then many more and more diverse T cells search for cancer. cells. So and then after the resection you keep giving adjuvant therapy. So what study epitomizes the beauty of the new adjuvan adjuvan compared to adjuvan alone? Melanoma in this New England paper lead by Tony Rivas in UCLA. So they compare new Ajuan pembrolizumab. Plus adjuvant pembroli map compared to only adjuvan alone, but it's 12 month treatment to resection and 10, or resection and 12 afterwards, and there is a significant difference in terms of the primary point that was recurrence with survival. So this, this was a uh uh uh uh uh um change in the view of what we have to do. And are we doing this in HCC? Yes, and one of the pioneers is the group here in Sinai. With uh Tom Marron, Scott, uh um uh Myron Swartz and Miriam Mehra, they developed new adjuvant therapies. This is the case of semiliap a single Asian, and just to give two months of single Asian prior section. Uh, tumor necrosis, about 50% was achieved in 35% of the patients and then they study what was happening in, in, in this Nature Medicine paper and actually, of course, they defined that the whole tumors were responding. But also an important message that is a proportion of hot tumors that are that not responding to single Asian checkpoint inhibitors and and I will develop that concept later on because that it is very important to understand why hot tumors are not responding. So then what is this is new Auban we are not there in HCC phase two studies. What about Ajuan well. We had, uh, for 30 years, 40 randomized controlled trials, all negative, and in 2023 there was the first trial positive with Atsolizuma plus bevacizuma versus active surveillance after resection on local ablation, and this therapy was given for one year. So and as you can see here, has a ratio 0.72 for the recurrence survival p value. 0.012 the trial was stopped, was claimed. This is a positive trial published in Lancet and adopted in guidelines. Unfortunately, later on, it, it turns out that the follow up of the data. Indicate that the hazard ratio moved from 0.72 to 0.9 and the p value was negative. So how come a positive trial can become negative and we have been studied that with some guys on my team here. Um, and, and we identify that the, it, it's due because the non-proportional hazards, and if you are interested in that, we will talk about this later on. So actually, we do not have adjuvant therapy in the setting of HCC. Transplant very briefly because this is the same picture as 30 years ago. Milan criteria boom, single tumor less than 53 less than 3 outstanding outcome, hundreds of studies retrospectives respective fantastic indication. What about if we push a bit the envelope beyond Milan criteria? Well, there are a lot of different uh sizes and a number of tumors. So the bottom line is that expanding slightly, the Milan criteria you still achieve median survival 5 to 7 years, but you are increasing, you are increasing the recurring rates to 20 to 40%. And the recurrence in transplant doesn't happen as in resection that happens in the liver. In transplant, 50 to 60% of the recurrences are outside the liver. So by default these recurrences are systemic. So therefore should be treated with systemic therapies as opposed to after resection, most of the recurrences occur in the liver so can be treated locally. Well, here we were leading one of the, I would say the best studies lead by Parisa Travisson from the Transplant Institute. She put together 2500. Cases of liver transplant for HCC and we were analyzing the three scenarios. One scenario is the one, the classical one. OK, Millan criteria, single tumor or 3 less than 3, undergoing transplant, boom, 10 year survival 61%, outstanding. What about downstaging that has been debated a lot. If you get down stage the tumor, so it's beyond Milan and as, as a result of operational therapies goes within Milan, the 5, the 10 year survival is 52%, which is pretty amazing. Conversely, if you are unable to downstage the tumor, then the survival goes down to 39% and recurrent rate 47%. So then in this scenario is more questionable. What about Immunotherapy is in this regard because liver transplant, because you are giving immunosuppressant is regarded as a contraindication for liver transplantation. But in Sinai we are pioneering the new adjuvant therapy in the waiting list of transplant and here I'm presenting the 1st 17 cases we recently reported that is a very, very is that like a small, small pilot study, but this is the first one reporting a TeOE in the waiting list of liver transplant. And just to mention. That if you are performing local regional therapies, you have partial response, 62% complete response, 13%. Look, when you are adding a test of E in those patients, then the complete response reaches up to 60% and then this mimics what happens in the pathological report that is a complete response close to 47%. So as a result of that, now we will be starting a phase two study using. Tear, so why 90 because this is the standard of care, either tear or taste plus a test of in the waiting list in a pilot study with 40 patients. Well, now the treatment is local ablation. The standard is radio frequency microwave with a level one strong recommendation from SLD, but in this institution we have been working with radiation segmentectomy. And it, it got level 3, evidence because there are no randomized controlled trial there's a strong recommendation because the complete responses achieved with a radiation segmentectomy ranges between 65 and 85% which are very high complete responses and the difference between the panel in the left and the panel in the right is that radio frequency microwave. are very good for 2 or less than 2, but once the size gets less than 3, once the size gets beyond 3 centimeters, then the percentage of effectiveness that decrease a lot. Conversely, with radiation segmentectomy and at the bottom with SVRT combined with taste in this case, it's very effective in tumors above 4 centimeters. Well, let's move to intermediate HCC OK. For 20 years, key mobilization has been the standard of care, but last month, two randomized control trials were reported combining taste with immunotherapies, and I'm gonna walk you through that. OK, you have the conventional taste. The drug eluting beat taste that you are embolizing the tumors with uh uh beats that are loaded with chemotherapy and have a slow release of high dose of chemotherapy within the tumor that lasts for 7 days but without systemic uh levels of the chemotherapy. This is very effective. Then you have the tear as I mentioned so. The standard of care comes from these meta-analysis we published in 2002 of six randomized controlled trials. At that time point, the median survival for intermediate was 20 months and now is the standard recommendation.AE is still key bilization. But uh also Y90 that is what is widely used in Sinai mostly throughout the US, it's also strongly recommended but with a low level of evidence because you don't have randomized controlled trials or meta-analysis of uh pool data. So, well, we have the standard of care, let's say TA, uh, can we merge that combine that with TKIs and immunotherapies? Well, for 10 years between 2009 and 2019, there were 10 randomized controlled trials combining TASE with TKI or Afenib, riboni and others. All the trials were negative. Uh, what we learned from these trials is the new standards, the newest standards for, uh, uh, uh, outcomes, the modern randomized control trials reported the outcomes of median survival 26 to 30 months, progression free 7 and 8 months and objective response 50%. OK, but still, we're using a treatment that has been there for 20 years with without a major advancement. Now I'm showing you the emerald one in which they combined your volum map, uh, that is a checkpoint inhibitor antiPL1, VA, anti-VHGFAA versusta and here probably you cannot see that properly, but the hazard reaches 077 P value 0.32 uh positive trial for progression free survival. Conversely, the volum map alone. Doesn't make any difference so it has a rate of 0.94%. So Bevacizumab is providing on top of immunotherapy the the delta either because of he has Beva has anti-tumoral effect per se, an immunomodulatory effect per se with normalization of the vascularization and increase of T cells within the tumor. More interestingly, in my view, because I was last author of the paper, sorry, was lembatini plus pembroli map, but objectively with lemba plus pembro plusta versus dual placebo plusta, this was a double blind buti cultural trial with a double duy that is very difficult to do and and were run by uh Maxson here in Sinai has a rate of 0.66. So the other was 0.70 plus. Here is 0.66 P value 0.002, and there is a substantial difference in progression free survival and is the first trial with a hint of an impact in overall survival in the first. in the ASA ratio was 0.8 and per value 0.087. We reported that last month in Lancet, but it's the first time that we are showing differences in survival in a modern, uh, randomized control trial. Well, now, so we talk about early new adju and Aju and intermediate plus minus, uh, immunotherapy, but the revolution has happened in advance. So, Here we are advanced just to drop you two figures. 15 years ago, the natural history of HCC at advanced stage lead to median survival of 8 months, 8 months. Now with all the therapies that we have, the median survival is up to 20 months. So this is, and I'm sorry because I was the first author, this is the, this is the breakthrough. Well, this is the most quoted paper in liver cancer ever. It's 12,000 citations at this point. So this is the New England paper. What's the beauty of that? Uh, uh, we had no clue that this was gonna work. I have to disclose that. But it's a multikinase inhibitory. It's a dirty molecule blocking 40 kinases. But the beauty was that it is the first time that you were showing that the drug, systemic drug was better than a control that best supportive care. Uh, and here you have the data doesn't look, I mean for me it looks very exciting, but if you are an oncologist or it's very exciting, but if you're saying, OK, 7.9 month median survival, we're moving to 10.7, OK, looks good, but this was really a breakthrough and as you can see in 2016, this is a naturee disease primer we published in 2016 and as you can see for systemic we only have sorafein. And Sorafenib was there in 2008 until 2019, 10 years, nothing happening because all the drugs that tried to beat Sarafenib failed. This is the most potent drug head to head to serrain. This is like matini but very potent multikinase inhibitor also blocking 30 kinases, uh, including FGF receptor 1234, BHCF 13. And you can see here the head to head comparison. They have two watches, one for superiority, boom, negative, and then one for non-inferiority. So this is a smart design because they were able to rescue Lembatini and Lembatib got approval by FDA, EMA and all the international regulatory agencies for the management of the disease. So Lembatinib, second drug in the field, and this was published, you can see Lancet 2018. So then in second line patients progressing to the TKIs. We have regular anib, Kaposaninip, and Rausilumab. I'm not gonna extend on that. These are TKI Ramosanumab is a monoclonal antibody only working in patients with FE more than 400. But let's move to the true meat here, right? So what happens therefore, because this is. The era, the period of TKIs, Sorane 2008 up to now 2019, where immunotherapy is kicking. So these are the trials in front line, most of the trials in front line and in second line in red negative trials in orange non inferior lembatini and in green positive trials. I explained you sorafeni and I explained you Ramorego Cabo, but here we have three combinations with immune-based regimes that have been positive. So these are the sec this is the. Second era of the systemic therapies in ACC. OK, which, which immunotherapist? Well, you're familiar with the antiPD1 pembro nibo anti PDL1 Azo derba anti CDL4 EP rein, right? This works in the lymph node, the others work in the tissue micro environment. But now there are other drugs of course you have LAC 3 inhibitors, TGT inhibitors, T3 inhibitors, and so on and so forth, and the objective response rate ranges from Hopkin's disease, 85% up to down to hepatocellular carcinoma 20% objective response with single agents. So the first two trials were a disappointment. And we were very disappointed because we are always behind the, the big four, right? Behind um non-small cell lung cancer, behind colorectal and in immunotherapy behind melanoma, melanoma is opening the field. Everybody is following melanoma, and here these are the two first trials, one in front line, nivoluma, boom, negative. Pembroli map second line negative. Objective response in both cases 15% was a lot of disappointment, so it's not gonna work in HCC. Well, the, the. The conclusion was probably we need combinations singleation it's efficacious but only targeting objective response in 15% is not enough to drop the effect. And second, eventually we need biomarkers of response and I'm gonna address now in this second part of my lecture, these two scenarios. Well, why combinations and which combinations? I mentioned that 65% of HCCs are called. They are very unlikely to respond to checkpoint inhibitors, so you need to shake these tumors per se with single agents, they are not gonna respond. First of all, because they don't have actually CD84 or CD8 or CD8 uh in, in the tumor. They don't have T cells, so it's very difficult to activate the T cells if the T cells actually are not there. And all these drugs on top have immunomodulatory effects, not only anti-tumoral effects. Globally, some increase the detic cells, increased T cell infiltration, PD1 expression, or N1 neutrophils, and others decrease MDMCs, decrease T. rex or M2 uh TA. Um, uh, tumor associated macrophages, so, so the combination of first giving this drug and on top giving immunotherapy look appealing because then you can switch cold tumors to hot tumors and when the tumor is hot is when the checkpoint inhibitor can act. Well, the first study, this is the second breakthrough. The first study that demonstrates that was the Inbra 150 combining Atesolizumab plus bevacizumab versus Sorafenib 19.2 months versus 13.2 months, you see, so naturally 8 months now with Sorafenib we're moving to 13.2 with Aoe we're moving to 19.2. Well, but another study not combining with Bavacizumab, but an AO IO DA and and and anti B1 and and antiD1 and and tremeliumab and TDA4 in combination they were superior to sorafeni uh has a rate of 0.78. But recently last year in ASCO they presented the combination of NOIP also similar concept antiPD1, anti-CDI4 and here you can see 23.7 months. It's not because this combination is outstanding, but also because more and more patients progressing from line combination are receiving effective drugs that is, these drugs are. Also improving the outcome. So it's around 50% of the patients in these trials are exposed to second line drugs that are effective and as a result, the outcome is improving, but now we're talking about 24 month media survival. Well, so what we're doing with all these drugs, and here we publish uh a, a summary based on the recommendations of guidelines ASCO, ESO, ESL, SLD, AGA. NCCN. So most of the guidelines on the scientific society recommend a Teso be in frontline. Particularly if the patients are not at high risk because now an upper GI endoscopy is needed prior bevacizumab due to the risk of bleeding, right? So then if there is no high risk of bleeding, then aolizumab is the preference, uh, Azoe, uh, if there is risk of bleeding, there are two strategies. One is treat the viruses with carvedilol and banding, blah blah blah, or move to ao ao Durvatreme niboipi. And then for those patients with contraindications to checkpoint inhibitors mostly with autoimmune disorders or liver transplantation, then sorafenib and lembatini are doing very well in patients progressing to front line immunotherapies, there is a debate because now we don't have trials, we have educated guests. there are no trials up upon progression so far published, so the educated guess, some of the physicians in the guidelines are pushing to after a test of giving Nibo IP with the concept that the populations that respond will. Only some overlap, but others will be different populations of patients and therefore it is a justification to give IOI and second line. Others stick to the norm. OK, lemba is working very well. Let's give lemba and then upon progression to that you have Rabo, Cabo and and rama. And finally, let's talk about biomarkers because another strategy would be, OK, why don't we select. Those patients that actually respond to immunotherapies and how we can do that. Well, you can see these trials are showing. Uh, a 40 year survival of 30%. So there is a proportion of patients that actually respond that have a very good survival because these patients have a very poor survival, median survival of 8 months. Now 30% are alive at 4 years, and this is another trial showing that. And the reason is that they achieve complete or partial response when they are exposed and their responses are long lasting responses. Medium duration of response generally with IOIO is maybe 20 months, which is a lot. So can we identify the responders to single Asian and more important to combination of Asians in order to move the median above 3 years, 36 months. This was a dream 1015 years ago to get 36 month median survival in frontline. So how we can do that? Well, not a small cell lung cancer in with Pembrolizumab, they have a companion diagnostics that is the immunostaining for PDL1. If it is positive in front line more than 50%, boom, this is the indication, and in second line more than 1%. Well, it's not working in HCC. What about tumor mutational award then? tumor mutational works well with high mutational loads defined as more than 10 mutations per megabase, and this barely happens only happens in melanoma, lung cancer or bladder cancer, but not in hepatocellular carcinoma have between 3 and 4 mutations per megaba. So tumor mutational burden doesn't work to enrich for uh responders, but we have. The immune classification. So what if we are able to identify a signature that is able to capture the immune heart tumors? This will respond and this has happened. So we have one signature published in JF, our signature published in gastro, and another signature, uh, reported at ACR. So there are already 3 signatures that are capturing the hot tumors and are associated with better outcome. And then also we know that that the excluded class is associated and I will explain that later on with some type of mutations of betagatening also TCF beta signaling and so on. So can we use these tools to differentiate the tumors? Well, the problem is that while we are expanding our time in signatures for single agent, the field is moving to. combinations and already here you have the same, the same concept, uh, CD8 T cell density, uh, TF factor signatures as predictors of a test of. Well, I'm gonna show you our study with 320 patients treated with a test of. Well, first of all, from a prior study with single cell sequencing, we were able to recognize uh close to uh 35 immune populations and by using the transcriptome analysis, uh, we generate gene signatures to recognize 21 cells. And we failed to recognize the other 14, but this was a very useful tool because single cell sequencing is very tedious. You need fresh frozen tissue by the side of the patient. It's a very sophisticated analysis and then you cannot translate that to real life, but we translate the. Cells into signatures and as a result of that when you have the transcript on then you can use that in large court of patients by doing RNA set and we did that. And the first concept is what we knew. Look, if you have hot tumors, there is a percentage of hot tumors that are immune active and here you have uh CDA temera, CDA uh texts and macrophages CXLL 10. These three cell types epitomize what is an active tumor, they will respond. These are classical immune responders, OK, we recognize the cells but not so much novelty here. Then we were surprised because immune cold tumors were responding to a testoe. How come? And we figured out that it is because they were responding to bevacizumab. They they were mostly and, and the, the biomarker to that that predict response is this receptor NNP1 and and certainly those patients with high NRP1 did not respond to beA I suppose that nothing happens with solafenib and here you have the P of interaction. So we had this biomarker that uh predict respond to Bevacizumab. And then the other interesting concept is that, OK, what about primary resistance? So you are giving azoe, nothing happened to the patient. No response whatsoever. First CT scan MRI or second CT scan MRI boom, progression. Medium time to progression 2 months, 3 months, median survival 8 month terrible. These are very aggressive tumors. Something happens here. What happens? Well, we have two explanations first. A percentage of hot tumors, and this was also in the paper of Marrow. A percentage of hot tumors are not responding or whatsoever to immunotherapy or immunotherapy combinations. Why? Because they are dominated by immunosuppressive cells. So these cells are CD 14 monocyte and TreM2 macrophages. These are the two types of cells in our study that were associated with lack of response, despite hot tumors were there. And this, and now we're doing spatial transcriptomics to understand the distance between these cells and the active cells whether this. If there is a very close distance, uh, probably these cells are able to inactivate the other cells and don't allow the other cells to actually, uh, attach to the, uh, antigens and kill the neoplastic cells. So this is an interesting message that goes align with what I mentioned before in Nin Ajuan and then there are other tumors that are immune desert. You are not expecting uh to, to respond to checkpoint inhibitors, but they are. Very with very poor outcome and very aggressive tumors and they are characterized in our hands by not signaling and TGF beta signaling that is a very potent immunosuppressive in the micro environment in the stroma. So this this is uh our conclusion regarding the mechanism of action. So here I'm summarizing, so I don't know if you can see here in yellow and in blue are the two types immune active or angiogenesis driven response. So some are responding to checkpoint inhibitors, the other to beva plus checkpoint, let's say. On the other hand, in purple, you have primary resistance either driven by immunosuppressive cells or by not signaling TCF beta signaling that are cytokines related to. Uh this of beta cytokines related to immunosuppression and in between all the others. So and I take advantage to this picture in order to explain in this slide what I envision what is the future of HCC in the next 55 years in my view. Well, first of all, so those patients that have molecular that we can call molecularly based responders. So this 33% of the HCC population will have a survival of more than 30 months. So what's the, what's next for them? Well, they respond. So how we can improve that? Well, one is with triplets. Now we are running a trial here and when leading this trial internationally, the IR 152 Ao Beba and Tit based on the date of the Morpheus trial. And with this triplet we think that this may even further increase the response and and the response will be more long lasting. OK, this is one strategy triplets. Another strategy because at one time point you keep adding triplets, but on the balance you have the toxicity and the toxicity is a bottleneck so. There is a trial, the CARS trial in which they have a combination, but the treatment related adverse events grade 34 is 80%. Look, this is a red flag. You cannot accept grade 34, 80%, right? So then when you keep adding. Drugs at one time point they will reach a ceiling of toxicity. Then it's the time for the biomarkers. It could be better to select the populations. So then probably then the industry will invest in we have recognized the biomarkers, but the biomarkers are not approved because they, they need a specific path approved by FDA and they're not investing in that. Probably this will be the way. What happens in the other side, those tumors that are primary resistant to immunotherapies. Well, what I envision here is a. We need new drugs, for instance, TCF beta inhibitors or not inhibitors or wind inhibitors, plus minus checkpoint inhibitors eventually. But certainly new types of drugs or eventually cell therapies we don't know if CARTIS or all CARIs are an embryo phase in HCC, I have to say, and mostly in solid tumors are effective in liquid tumors, but nonetheless, this could be another approach.vacines, there are some hints in HCC with a couple of papers, one by Jaroran in Nature Medicine suggesting that vaccines. Are able to personalize the, the vaccine to the antigens expressed in a given tumor. Uh, it's a very expensive approach but eventually this can be an approach as long as you are able to neutralize the immunosuppressive signals. So this is what I view for this subgroup of patients. So conclusion. So the first thing is that the incidence is growing 1 million this year risk factors FC is decreasing and muscle is the fastest growing incident, uh, and etiology. Molecular aberrations in HCC unfortunately are unactionable. Immune classification we're lucky enough that we are able to decipher precisely the immune active and the non-inflamed tumors and eventually associated with immunotherapy response for early resection, transplant, and local ablation are for there forever. Adjuvan treatments have failed. We thought that Teoe was positive but ultimately was negative. New adjuvan Ajuan are the approaches in my mind that are more sound. In intermediate, we have chemobilization as a standard, but now with these two trials just reported, probably the guidelines will change. Frontline advance we have immune-based therapies mostly Azoe Durbatremen IOEP and in patients with contraindication we have mostly lembatinib that is now more prominent than sorafenib and in second line either sorafenib lemba or even AOIO patients uh progressing to aoe and in terms of biomarkers. Predictors of response to immunotherapies have been identified but are not approved. Gen signatures for single agents and uh predictors of response, as I mentioned, or resistance to a test of. So finally, I would like to thank the liver cancer program that now we're at the 20th anniversary. So, I, I, uh, we created the Scott Friedman that is here in the audience, Myron W and myself and also Sam Waxman, we started the program in 2005. With 22 faculty members now, 7 labs, we, we reported more than 1200 papers. We are the number one NCI the one and only, I have to say, NCI recognized program in the US. The first US referral center for HCC with 400 patients per year with an annual funding of 5 to 6 million NIH grant, now we have 9 RO1s or UO1s, and certainly I know the world very well. I think we are the number one program in the globally. So thank you very much to the program. Thank you.
