Interview with Prof. Dr. Jeffrey Drebin, President of the 2024 President Elect of the American Surgical Association

Dr. Jeffrey A. Drebin is Chair of the Department of Surgery at the Memorial Sloan Kettering Cancer Center and holds the Murray F. Brennan Endowed Chair. He is also Professor of Surgery at Weill Cornell Medical College. He was previously the John Rhea Barton Professor and Chair of the Department of Surgery at the Perelman School of Medicine of the University of Pennsylvania. He received his M.D. and Ph.D. degrees from Harvard, where his Ph.D. work involved the development of the first monoclonal antibodies targeting the HER2/neu oncogene. He subsequently performed his surgical training in General Surgery and a Fellowship in Surgical Oncology at the Johns Hopkins Hospital. Upon completing his clinical training, Dr. Drebin was recruited to Washington University School of Medicine in 1995, rising to Professor of Surgery and of Molecular Biology & Pharmacology in 2002. In 2004 he was recruited to the University of Pennsylvania as Chief of the GI Surgery Division and in 2009 he became department Chair. At Washington University and at the University of Pennsylvania he established himself as a busy clinical surgeon, focusing on pancreaticobiliary, upper gastrointestinal, and liver surgery. He also established a successful translational research lab, receiving research support from the NIH, the Department of Defense, and the Burroughs Welcome fund for this work. Multiple surgery residents who worked in Dr. Drebin's laboratory have themselves gone on to successful academic surgical careers. He has published over 150 peer-reviewed articles, chapters, editorials, and reviews, and has served on the editorial boards of multiple journals. Today, we are honored to have Professor Jeff Drebin, M.D., Ph.D., from Memorial Sloan Kettering Cancer Center, and the 2024 President Elect of the American Surgical Association, as our guest. We extend our sincere gratitude to Professor Drebin for taking time out of his busy schedule to join us at the 79th Annual Meeting of The Japanese Society of Gastroenterological Surgery. In addition, we deeply appreciate your participation and your contribution to the journal, Annals of Gastroenterological Surgery, an official journal of JSGS. Thank you very much, Professor Jeff. Recently, you published a paper in Nature about the mRNA vaccine for pancreatic cancer, and I wanted to ask you a few questions regarding this topic. It's a very hot topic (A brand new technology, mRNA vaccination for pancreatic cancer) and exciting paper, but I have several questions. The first one is about the personalized and rapid biosynthetic one, which boasts high efficiency with high immunogenicity neoantigens for the prevention of recurrence, particularly in the case of minimal residual disease (MRD) in pancreatic cancer. How do you determine the neoantigens? The mRNA vaccine work, I should give credit to my junior partner, Vinod Balachandran, who's a surgeon scientist at Memorial Sloan Kettering, who really has done a lot of the important laboratory work. Vinod not only has a very big and successful laboratory, he's also a pretty good surgeon. But Vinod's work had suggested that some patients who are long-term survivors have evidence of a T-cell response, and therefore raise the question of could we stimulate a T-cell response with a vaccine, and in this case an mRNA vaccine.1 There may be other approaches that would work well. The first patient to get a vaccine in our trial was in December of 2019. Although we all know of mRNA vaccines from COVID and COVID vaccines, the first patient in New York to get it was in 2019. It happened to be my patient. But all of us within the group had patients in the trial. In December of 2019, he got his first dose of a vaccine made by BioNTech specific to his tumor. The choice of mRNA had to do with the desire to be able to do this quickly, to have a broad antigenic representation from the tumor and some thoughts about safety. Although those were all things we evaluated in the phase one trial. Certainly, there are ongoing studies using a similar approach with peptide vaccines as well as DNA vaccines. And so, I wouldn't claim this is the only approach that will work. But it was an approach BioNtech was interested in working on. Genentech participated in providing atezolizumab, the PD-L1 inhibitor. And so, we sort of had both corporate support. We had our group, which was a relatively busy Pancreas Cancer Surgery Group. And so, we did the trial. You identified individual personalized neoantigens from the mutations. However, there are four major genes that dominate pancreatic cancer. We have come to understand that these big four genes may overshadow the potential for other neoantigens to emerge. How do you decide on favorite neoantigens? In terms of antigenicity, pancreas cancer has a relatively low number of antigens.2 For most of our patients, they could fit up to 20 antigenic domains in the mRNA vaccine. Most of our patients didn't have 20 expressed neoantigens. In fact, I think the one who signed up for the trial couldn't participate because he had none. But most patients had anywhere from one to five or six. The responsiveness to the vaccine didn't correlate really with how many antigens they had interestingly. The strategy that Genentech used was to look at both sequencing to identify mutations that could give rise to neoantigens, and then RNA sequencing to determine that they were expressed. The idea being that if the RNA was present, protein would be present, and therefore, there would be antigenic protein present in the cancer cell. Because the numbers were relatively small that fulfilled both criteria, it wasn't a question of having to narrow it down. We could put every mutation that was present in the patient onto their vaccine. I want to confirm that your work on the mRNA vaccine predates the COVID-19 pandemic. While mRNA vaccines are now widely recognized due to their use in combating COVID-19, was your system developed before the pandemic? Our mRNA vaccine was developed before the COVID-19 pandemic. Everyone knows that mRNA vaccine is very famous for COVID-19, but the system ignited before COVID-19. Actually, the COVID vaccine became a perfect control. Because after we started our trial and we saw some evidence that those who responded to the vaccine had a longer survival than those who didn't, one interpretation may be those who responded have a good immune system. Those who don't respond have a bad immune system. It's not the vaccine. The vaccine is just a selection for those who have a good immune system. But all of them got COVID vaccine. The COVID vaccine response in the pancreas tumor non-responders was as good as it was in the pancreas tumor responders. Their immune systems were equivalent. There was no difference in their ability to react to the COVID vaccine. It was simply that they didn't react to their own tumor vaccine in some patients. Pancreatic cancer is a very challenging target because it is often surrounded by non-inflamed tissue, CAFs, or fibroblasts. Your system seems highly effective since it targets the cancer after a pancreatectomy, which should enhance its effectiveness. Is my understanding correct? This is an adjuvant vaccine. We are talking about trying to put together a trial of a neoadjuvant vaccine. As you point out, one of the concerns in pancreas cancer is that the microenvironment of the tumor may suppress the immune infiltration of T cells or the function of T cells. And so, by doing this in an adjuvant setting, we have removed the tumor and it is really a minimal residual disease that we're hoping to treat. That may not have as many problems in terms of the microenvironment. Can your system be implemented on a global scale? Could you elaborate on how we can move forward with this? The next step—this was a phase one trial. It was really to say, could we do this? Our goal was to get the vaccine into patients within 10 weeks and we succeeded. The goal was to make sure that it didn't make people sick. We succeeded in this before the COVID vaccine, so we didn't know that an mRNA vaccine would be relatively safe. Then, the sign of efficacy was very encouraging. But again, responder versus non-responder is a poor indication of whether a treatment ultimately will work. And so, to validate this, we're now conducting a prospective randomized trial in patients who have pancreaticoduodenectomy and will either get standard adjuvant chemotherapy or chemotherapy plus the vaccine. Now, it's only in pancreaticoduodenectomy patients, because one thing that came out in the phase one study was pancreaticoduodenectomy patients were more likely to respond to the vaccine and patients who had a distal pancreatectomy with splenectomy were less likely to respond to it. We now know from animal studies that splenectomy may decrease responsiveness to the vaccine.1 We hope that pancreatic cancer patients worldwide will be able to access your system. Are there any plans to expand this treatment globally? The trial is a worldwide trial. I don't know that any sites are open in Japan yet, but if there are places that are interested, I suspect BioNTech would be happy to support them. I was in Korea 3 or 4 months ago and actually they have one site now that's open and it's open at a bunch of places in the United States. We hope to accrue several hundred patients for the phase two study if the results are good. One of the things that makes pancreas cancer research quicker is that if patients don't respond, they tend to not do well, and you get an answer quickly. If there is good evidence of efficacy at that point, I think it'll become a standard. I'm very interested in the current status because, in the Nature paper, the patient who had a good response showed 100% survival. What is the situation now? The number we are now the 4 to 5-year mark, with two relapses among the eight cases, both showing a good response. I believe they're both still alive, but I think two have had a relapse. Six out of eight are still relapse-free at 3, 4, or 5 years. Whereas 100% of the non-responders relapsed. Recently, some papers have shown that microbiota can influence immunotherapy. Do you have any data on whether the mRNA vaccination is affected by dysbiosis or microbiome? I don't have data, but I think it's an I suspect as we the are affected by the I suspect there will be but I don't have an to ask a more Do you believe that neoadjuvant chemotherapy is for all pancreatic not just I don't our group of a of At I think there are still some patients who to some who get is if if that would a major with and a that it'll respond in a that that or a of the than a do But a patient with a disease well from and and no other them to surgery. I believe that neoadjuvant chemotherapy be for one pancreatic cancer because, to or cancer, one pancreatic cancer still has a less adjuvant chemotherapy may not be for one pancreatic cancer. How would you for one pancreatic cancer I don't with you at I think pancreas is no cancer, other than which a tumor is so cancer, cancer, cancer, cancer, these are of the Pancreas cancer, less than it's an disease in many For the is that if you look at the neoadjuvant data, there are patients who don't have tumor and have surgery. You have to look It's not people because it's to But about or of people are made by the neoadjuvant that they come to surgery. And so, you have to those patients with the that you surgery in patients who are to have after which all and is very of I your point that it's a disease this is he I think it's that people get I'm not so sure that whether you get it or get it at the will make a As you there are studies on to to that in a randomized but I don't think we have the Although there have from the was one that that neoadjuvant is There was also a the which suggested neoadjuvant actually had a to get to surgery and did not survival on an to treat. I suspect if you ask five get five in the United have the approach of should get some very and I don't that would be one to the I understand in many in that's standard. I don't have a to it We tend to a more of an and that if people are with no evidence of we to surgery. for one of my who would do And in our patients get for eight I do I at the of so four If they're having a response by and by the tumor has responded we may do surgery at In my it's not that to tumor at may It I for the to if the cancer cells are the is still It's more if I'm doing it for a to get it from an to make a a we would more do 4 At 4 people are often a out by and so we give them a by doing a In your or your is the indication of neoadjuvant for pancreatic I don't do neoadjuvant for If a patient to could I have I should have it. I them that it's But in in my we did a neoadjuvant trial I was at the University of had patients who to participate in the trial because they I just want my tumor I don't want any or any not I don't think it's but I think a to it have cancer. it out of as as In most patients don't if you you can it It's the you say, I would to do neoadjuvant and the patient you it out You pancreatic cancer, but some have to or cancer. Certainly, if the is if there to and is my If it's at that or if the tumor I would them for a good point, I didn't point that I think if the are very as was pancreas cancer is a at and that high are to relapse. And so, we would do neoadjuvant in that the Memorial is of the cancer in the United do you use or for the indication of of the pancreatic We do have a We were one of the first places to do sequencing of all of our We have over of all at Memorial But the we tend not to use for It has used for minimal residual disease status after surgery. In fact, there was a trial that was by who is our Chief of Medical focusing on the did a study at a vaccine approach for minimal residual disease either by of or with This was a vaccine trial that was also very encouraging. We have good data that adjuvant than months has a than patients who get a from the from and the We tend to think of months as an important We don't have a lot of data for but if months we tend to do 4 months If 4 months they will get months If is doing well and to all months before having we do some Most patients sort of get out before but we think important in but I There have really good studies in the neoadjuvant into The other thing is to look at the you the patient. I think patients who have after my is that's a bad who have very evidence of tumor response the tumor is again, should have a adjuvant if the neoadjuvant didn't I think you have to this to the patients. I should at the that who the global trial that was my of the to Cancer group, and that was one of the that we a and from and in fact, at the University of where I was ago I came to I would more patients got and than For one if to do of chemotherapy plus some other because and may be a it's to with of That being our tend to with as their first whether in the neoadjuvant or the adjuvant an as as As you the number of patients surgery has or patients over are receiving We believe that the and are similar to those of patients. However, there be patient papers have also the efficacy of adjuvant chemotherapy in I think this difference to the in survival and patient I think this is an We know that pancreas cancer is a disease of At in the United it every of the and the We it in people in their but not in the and You the question about whether neoadjuvant or I think it's often the case that are with either or and to patients. And so, it a I my patients as having but our is pretty And so, the number is to And so, I them it's to so a but in they're to get this is really where may a in people and a of But I think surgery is really the only And so, if you can do it you have to be You want to the patient who will a big I think we would be more to do a major as to a relatively I think I ask patients is they're don't do or they have a I ask them about how they I had a who was I can you a of in a but our is in the so I five I the up and in I was to do well after I think you have to had I a of out of and I have or I'm on four then I think you to be more and the patients Japanese the of both and and However, in the United the is often very Are there any to the I think has not on very One of the if to do I think that's a good to also do If not to do not It's You weeks to really the not a few And so, I'm not sure for a and then doing If to months doing I think it's a good But in if to do surgery you just to do surgery. the of on is in our I wouldn't it that with I if I have an and a the will every It's not just some of that's because there are very few I on. There are who I would of it's It's we know that surgery by not do very well, that really is for to have the long-term survival. I think it's often the case that our don't want to with but if they come a big it them a more to then give again, our I that's a standard. But there are places that do in patients. Actually, we previously published a paper chemotherapy versus surgery in patients over the of In that we that the of adjuvant chemotherapy is for long-term survival. As you adjuvant chemotherapy may be for long-term survival in very patients. But in that would you for adjuvant One of the don't get any support from any so this is not any specific I'm not a so I don't have to give any But I think the studies of had results than and not that than or and in the adjuvant In patients, that's actually where I to the What often do is do a of and if the patient then the I had a it the He about from where the and he would over to get his chemotherapy and to his after his and got months of adjuvant I again, if you the patients, that it's not only or and there is has some I have a who I did a on in the few months who's now with it. The survival of a is only 4 if they of pancreas cancer. at get some of I and I should that by our it's not that I but I have a lot of patients I think one of the things we know is that can cancer, but the will the patient. And so, the is to a dose of that will the cancer but not the patient. are really an approach to a dose to the tumor doing to In a of on the of whether it's whether it's of focusing the these are not as important as actually the of the it's to get a dose of or 10 the dose that we for pancreas was That dose is really a and pretty good evidence that will but in good long-term control. The other thing is that we know that pancreas in the of patients have they have and so the tumor is not a very It's approaches have the of being But for a disease that's to be on the that may not be a good In fact, data that may be to more approaches because of the to the And so, the approaches that our use is to get up to about of the tumor and to the and to do it with a dose that patients to get very and that we are doing more and more for either or in patients who have surgery. In is only for pancreatic cancer. What are your thoughts on its indication for pancreatic We actually have a similar I wouldn't it's There are several very good by very in which particularly in the neoadjuvant setting, is of that for many and a number of their that are at other where that would be standard. not our For patients, if they have a neoadjuvant neoadjuvant we don't do we're in a situation of disease or disease that's not to But the not surgery. that a get months of If they responded well they may get and then still have surgery or Now, for patients with and I think all there are patients who know that response to chemotherapy is to in a tumor that's the or the In those patients, can in long-term control. it for But I just saw a patient with this this we're being to do or 3 after a patient with disease had a got got and now their has had it out and had a new put and now that's up and they with and we're to do a 3 after their that cancer is still but it's not or done a few of them and several of my have done on patients with disease is not I'm encouraging. But I think it's an indication of in some patients, really people We published a paper in which we at about patients who had for or disease versus who had surgery. The really because, of the surgical group to be the group to be in the in the group, in the in the surgical But we then at the of recurrence, and the with was than with surgery. Now, was more if you the tumor there and didn't it out, so 3, 4 you cancer, it's not we know that patients who have disease are more likely to have disease than patients. But it's that the is good. The other thing we do is have a patient a or two after a has it's at the The that's most is the and now got may be they can you The answer we But they can often do treatment for That again, at it in for years. That may be a not a but a Our standard is 4 months of In sort I think it to the question of One of the of neoadjuvant chemotherapy is a group of patients who are to have after if you do a I think the is of to give a of they use as a but they don't get chemotherapy the If you that they have they have should get chemotherapy and then if they are able to get after that a to get the of patients out which is not that than how they do with surgery. I think one of the questions that we really in very good data of a You the tumor. It The then can stimulate and the immune system. I don't think we have evidence of that in pancreas cancer. In But I don't think it's I think it's well and I know there are on. to up this Thank you very for your and about pancreatic cancer. We in pancreatic cancer, but with Professor Drebin a of In the we may be able to pancreatic cancer. Thank you very for your