[0:00:00] Dr. Diane: Can we harness the body's own immune system to fight cancer? Is it like Dorothy’s shoes? Did we have the power to cure ourselves all along? How can we coax our own immune system to fight back to recognize this ever shifting enemy and cure ourselves? Intrigued? Here we go. Hello, I'm Dr. Diane Reidy-Lagunes from Memorial Sloan Kettering Cancer Center and welcome to Cancer Straight Talk. We're bringing together national experts and patients fighting these diseases to have straightforward, evidence-based conversations. Our mission is to educate and empower you and your family members to make the right decisions and live happier, healthier lives. For more information about the topics discussed here or to send your questions, please visit us at mskcc.org/podcast. Today I am thrilled and honored to have on the show Dr. Jedd Wolchok and Grace Dunn to talk about the role of immunotherapy in the cancer patient. It makes me so excited because the pioneering game changing work that Dr. Wolchok performed is actually shown through the life and our living example of our beautiful Grace Dunn who's with us today. They're both extraordinary souls and I am thrilled to welcome them both to the show. By way of more formal introduction Dr. Wolchok is a clinician scientist and medical oncologist who specializes in the care of patients with melanoma. As a researcher he works to develop innovative ways to use the immune system to treat cancer. He was at the forefront of cancer immunotherapy trials, which we will learn about today. Our second guest is Grace Dunn, who is a 23 year old college graduate from Colby an avid runner and is my dear patient. Grace was diagnosed with a very rare cancer called adrenocortical carcinoma at the age of 18. And two years later, it unfortunately recurred to her lungs. Always fit healthy and positive. Grace has done everything right in life, and today Grace is here to share her story. So, Grace and Jedd, welcome to the show, and thank you so much for coming today.
[0:02:05] Dr. Jedd: Thanks for having us.
[0:02:06] Grace: Yeah. Thank you.
[0:02:07] Dr. Diane: So Grace. I'd like to start with you. Could you tell us a little bit about yourself and your journey with this disease?
[0:02:12] Grace: Mm-hm. So, I grew up in a small town, Farmington, Connecticut right outside Hartford. And I always played sports, was really focused on academics and I never ever had any health problems, never broke any bones, nothing. And so I eventually went to high school and I played soccer. I ran track all four years, and I was great. And I got all state and all these awards, so I never saw any signs of it in high school necessarily. And then when I got to Colby College, my freshman year, I was there for track as well. And when I started track, the season started in around early November, and I could tell that I was just slowing down and I didn't feel like myself. And I was unusually out of shape, which is just so abnormal for me and my lifestyle. So, I didn't really take it that heavily because I thought oh, I’m in college, I'm supposed to feel like this, like everything's going on at once. And then Christmas went by and then the new semester started when I went back to school in January. And it just started getting worse and worse, and I was getting very strange symptoms. I went to the health center, they told me it was a thyroid, but they set me up with an appointment a few months later, but at that point, when I went home for spring break, it was way too late. And my mom saw me and my symptoms were so strong, my face was huge. And she immediately brought me to the emergency room where I began my testings, CAT scans, X-rays, you name it, and they eventually found a large tumor on my right adrenal gland. So, I went in for all of the proper appointments and surgery quickly after about a week later, and they found they removed the tumor, and then they did a biopsy and it came back positive for adrenal cancer. So after that, I did mitotane and radiation for the duration of that summer, and I went to Memorial Sloan Kettering for a consultation along with the University of Michigan. And then I returned to school my sophomore year and I returned to track because I thought that maybe exercising and doing all this in normalizing my life would make it better and it would help a reoccurrence from not happening. So, I went two years all the way to senior year feeling fine, and not noticing any symptoms and hoping that it was never going to come back. But I got a routine blood test and a number was off. So they brought me in for a CAT scan and then they found five tumors on my lungs. So, there was a recurrence and we went straight to Sloan Kettering and luckily, there was this immunotherapy that I could try because surgery was not an option. And since it's so rare and aggressive and it came back, there was nothing else for me. So that landed me in the immunotherapy.
[0:04:44] Dr. Diane: Right. So you were diagnosed with a cancer where there's about 600 patients in the entire country that gets that cancer and that comparison to breast cancer where there's 200,000. So we have a lot of trials in breast cancer, prostate cancer, there's 200,000 patients a year that drive what we need to do. But this cancer as you said, one it is very rare. But two, it's very tricky because of these hormones that it could sometimes make, which can cause debilitating side effects like you had with the weight gain, etcetera. So as your oncologist, you're right, we're very, very limited in our treatment options for this very rare cancer. It's not for lack of effort. It's a tricky type of cancer that doesn't typically respond to the traditional chemotherapies that we use in other types of cancers. We have a couple of regimens, but those regimens can be quite toxic and aren't very sustainable. They work for a period of time and when cancer spreads to the lungs, it's harder to take it out because we know that cancer is like one centimeter of tumor is like a billion cells, so to just remove it when it's in a couple of places would be very hard to just make it go away. So thankfully, you enrolled on this trial, this clinical trial for adrenal cancer at the time it was the only trial with immunotherapies or it's actually still trying this concept and what was it like to go on a clinical trial, not knowing if it may work may not work.
[0:06:01] Grace: Well first, when I found out I was going into the appointment thinking this is it, like, they're just going to tell me what I can do to prolong my life at this point. And when I heard about this trial, I actually was very excited. I wasn't really nervous at first because I was so shocked even hear there was something along with my family. So when I heard about it initially, I was very, very happy and relieved. But then once I thought about it for about a week or so, I was like, Okay, well, I can't get too excited because this isn't necessarily going to work. There's no research, there's nothing to really tell me that. Okay, you have this chance this chance. So, I went into it a little more scared the first time just because I didn't know how long I would be on it until I found out, “Oh, well, it's not working.” Or if they found out immediately that it wasn't working. I just had no idea going into it. So I was very scared at the beginning. But as the months went on, I didn't come to terms with the idea of potentially dying but I felt more settled knowing that I was going to the doctor and getting help. And growing up I knew every time I went to the doctor I was like, I'll be fixed and I’ll leave. So I kind of went with that mindset thinking, “Okay, this is going to help me and I'm going to be fine.” So I just kind of kept with that. And just six months later, I found out, they were kind of bigger. And then that's when I really started freaking out. And then I got the great news. We continued with the trial that they were shrinking. So I was like, Oh.
[0:07:19] Dr. Diane: So you go on this trial, I tell you that there's really not great therapies, but we have this experimental trial. And the first scan, it grows, and we all get really, really nervous, but you're doing great, you're feeling great. And then the second and the third scans, it starts to shrink. And then as we continued, what happened?
[0:07:38] Grace: Well, they just kept getting smaller and smaller. And I was on it for two years. And by the end of that they were so small.
[0:07:47] Dr. Diane: Yeah, so technically, they're gone from what we can see. We worry that there may be microscopic cells but according to the scans, there's nothing visible that we can see. Because of you and patients like you, we have now this positive trial where the patients on the study had enough benefit that we consider this now something that we're going to consider, possibly for what we call the National Cancer Care Network guidelines to approve as a possible treatment option. What would you tell other patients that are going on trials like that?
[0:08:20] Grace: Well, first, it depends which type of cancer you have, in some circumstances, it may be better or more research on that, and other circumstances like me, I would say that if this is your only option to be optimistic about it, and definitely do it, because you don't have much to lose, and it was just overall a great experience. It was eye opening. It was just knowing that me doing this trial, whether it works or not, is going to help people in the long run with this and you're going into research trial. So you're there to help others even if it's not for yourself, and just know that if you're optimistic, I feel like you have a better chance of it working just because it's your body, your mind your body I think they work very closely together. I think that's another big reason even scientifically if it's not that I'm here today, and I think just take it with a grain of salt at first but as you go on and you are getting better just go with it and be excited.
[0:09:14] Dr. Diane: No, and for that we're very, very grateful because it is a courageous act to go on a trial when you're not sure what to expect and what is going to happen. So Jedd this therapy has literally changed the natural history of a disease or the overall survival in general when it came back was less than a year. Immune therapy is a concept that historically is kind of an old one, right? Can you share with us how we eventually got to where we are today to help patients like Grace?
[0:09:40] Dr. Jedd: Sure, but first I want to thank Grace, first of all for coming and spending some time with us. And second of all, for courageously as Diane just said, deciding to become part of a clinical research trial. It is the way that we make progress. And I think some of the things that you said, remind me of all the goodness of human beings, that we all know that you go into a trial and you yourself might not get better. But the fact that people even think about the fact that other people might derive some benefit, even if you don't. That's an extraordinary statement to make. And I thank you. It's a very, very important life lesson. And speaking of life lessons, the idea of immunotherapy is not new. It goes back to the late 1800s. To a surgeon at the hospital that is now known as HSS Hospital for Special Surgery who also practice here at Memorial Sloan Kettering. His name is William Coley. He actually was motivated by a young patient of his who had a sarcoma, a bone cancer of her arm, who the only therapy that she could get was sequential amputations of her arm until she died a very painful death and he became disenchanted with the ability of surgery to control all cancers, even though we know that surgery is highly impactful intervention. For many people with many cancers for folks, especially with very advanced cancer that has spread to other places, it's not the only treatment that we think about. And so Coley began to do research, and the only tools that he had in the late 1800s were his powers of observation. And he observed that patients who developed infections after he did surgery for them seem to live longer than patients who didn't get infections. Of course, this was the era before antibiotics, etcetera. So infections were not uncommon. And what he was really scratching at was the immune system because what he thought without very much background, since there was no field of immunology then was that there was some internal resistive force that was being enabled by these bacterial infections that was responsible for controlling the cancer. It took us as scientists almost 100 years to understand what Coley was hinting at. And in fact, it was many very devoted decades of basic science research that finally allowed us to understand some things about the way the immune system gets turned on and turned off. That led to the development of some medicines that allow the immune system to operate at a more effective level than it normally can, such as the medicine that Grace received. And it therefore was hypothesized really to be a potential way to treat cancer. And in the same way that you just described to me that adrenal cancer was a disease that didn't have many good therapeutic options and that most people would die of it in less than a year, that was the case in the disease that I see most often, which is metastatic melanoma. When I started practicing here in 2000 the median life expectancy of someone with metastatic melanoma was about seven months. And it stayed at that really disappointing number until 2011 when the first of these what have been called immune checkpoint blocking drugs, with nearly unpronounceable names, the first one being Ipilimumab or Ipi for short, was the first medicine ever to push that median survival from about seven months to about 10 months. Now based upon combinations of immunotherapy medicines, and also advances in some of the targeted therapies, the average life expectancy of someone with metastatic melanoma from a large clinical trial that we led here, of combination immunotherapy is over four years. And the reason I can't be more specific is because that more than that number of years have not transpired yet since the trial. So, we see a lot of reason for hope. We see a lot of reason, however, to also work harder, because even though these medicines in a disease like melanoma, which is one of the more sensitive diseases, that about 60% of people will have a decrease in size of their tumors. We're not going to be satisfied until that's 100%. So, we still have work to do.
[0:14:35] Dr. Diane: Absolutely. So why is it 60% and not 100%. People talk about these, like you said, these immunotherapies are essentially helping our T cells, the soldiers of our immune system attack the cancer in a way that traditional chemotherapy wouldn't necessarily be attacking, right and it's a different way. But then some of these cells are sort of still hiding in some patients and yet these T cells that are all revved up ready to go don't figure out how to attack. Why is that?
[0:15:06] Dr. Jedd: Well, it's a pretty long list of reasons. And I think we could have an entire podcast series on this because it keeps changing. But the bottom line is that some cancers are just at baseline more interesting to the immune system than others. That doesn't mean the person is more interesting, but the cancer, in fact, is more genetically damaged. And so some lessons that we learned from work done by colleagues here at Memorial by Tim Chan's group actually showed that the more genetic mutations the more genetic errors a person's cancer has, the more different it looks to the immune system. And therefore, the more likely it is that the immune system has seen it already. Because if something looks different than the normal body part that it came from, it's going to be interesting to the immune system. If something looks too similar to a normal body part, the immune system is trained to ignore that as a way to avoid autoimmune disease. And so we know that the mutation burden how much genetic damage there is, can affect how foreign something looks to the immune system, and therefore how likely it is that the immune system is going to respond when you take off its brakes. But we also know that T cells are not the only important players in this immune orchestra that there are other cells that in fact play an inhibitory role. These are called myeloid suppressor cells and our group and others are working on ways to limit the number of those cells as a way to help more people benefit from immunotherapy. But the truth is that there's quite a long list of reasons why some people do have regression of their cancer from immunotherapy and others don't.
[0:16:55] Dr. Diane: So the jury is out, so certainly genetic errors may be one.
[0:16:58] Dr. Jedd: Until I think we understand these rules better, it's best to live as kind of normal, healthy life as we can you did all the right things right?
[0:17:08] Grace: I can provide my everyday-
[0:17:09] Dr. Jedd: Your everyday right, your exercise, right? I think try to take care of your mental health, try to eat three square meals a day. Just enjoy the things that are wonderful in your life while your body is trying to heal itself. And we are working with a lot of folks here to try to understand other things that people can do. I mean, you had Dr. Jones on recently and both he and a colleague of mine, Dr. Betof [Phonetic] [0:17:35] are working on ways in which we can use exercise as the immune modulating activity and to understand what the value is there. We are also again studying this idea of the microbiome and what role that has in both the benefits as well as the toxicities of immunotherapy.
[0:17:56] Dr. Diane: Could you tell us a little bit about the Parker Institute for Cancer and what that's doing for understanding the immunotherapy treatments and the science behind all this?
[0:18:03] Dr. Jedd: Sure so the Parker Institute is a group of organizations that was put together by Sean and Alexandra Parker. And they are very generous philanthropists who had decided that cancer immunotherapy was really the disruptive technology of cancer medicine. And as many of you know, Sean has been an important entrepreneur in the tech industry. And so disruptive technology is very important to him and he is a self-taught student of immunotherapy. And he through his attempts trying to help a friend of his through a difficult cancer diagnosis, really educated himself about different approaches to cancer treatment and became quite intrigued by immunotherapy. And so he and Alexandra decided to try and accelerate research at several institutions Memorial Sloan Kettering, University of California San Francisco, University of California Los Angeles. Stanford, University of Pennsylvania, MD Anderson Cancer Center and Dana Farber Cancer Institute are all now working together to try and explore different ways that the immune system can be used to treat cancer. Both the checkpoint blocking drugs such as what Grace received, but also medicines actually that are made of a person's own cells. So CAR T cell therapies or engineered T cells that have been produced from a person's own immune cells are major focus of the Parker Institute. And the two very basic rules are the Parker Institute, which were taught to us on the first day by the CEO Jeff Bluestone, where we need to collaborate like hell, and we need to do kickass science. Those are the only two rules. So we've learned to come out of our silos, to really play nicely together and to really take risks to try and make the most progress and innovate as fast as possible-
[0:20:02] Dr. Diane: Teamwork.
[0:20:03] Dr. Jedd: That's right.
[0:20:04] Dr. Diane: It's a beautiful thing. It really is very, very powerful. Vaccines, can we treat cancer with a vaccine, we can prevent certain cancers like cervical cancer with their HPV vaccine. But, for example, a lot of people focus on nutrition to treat and we're going to have a whole podcast on that. And I think probably we have good data that suggest nutrition can prevent certain cancers, but what about the role of vaccines as it relates to treatment?
[0:20:29] Dr. Jedd: So two important facts about prevention. One is that the Hepatitis B vaccine actually is a very important way to prevent cancer. In fact, one of the most prevalent cancers in the world hepatocellular cancer, and then of course, HPV vaccination, and that's a really important way to try to prevent cervical cancer. And also we now know other HPV related malignancies are becoming more prevalent including cancers of the mouth, which are related in some people to HPV as are some cancers of the anal area. So, I think that HPV vaccination is something that needs to be seriously considered, not just in young women, but also in young men as well. So, this is a very important public health message. There are some very recently published quite elegant studies from our colleagues at Harvard and some other colleagues in Germany, showing the potency of something called Neoantigen vaccines. And these are vaccines that are actually custom designed, based upon the pattern of mutations, the genetic damage in an individual patient's tumor. So, it's quite impressive to me, that we now can have a surgeon remove a tumor, and we can send off that tumor for sequencing to have all the gene sequence in that tumor. We can make some educated predictions about what the immune system can or cannot see in that tumor and return that information in the form of a vaccine to a patient custom made in about three or four months. Now, the problem is that for some of the diseases in which this is being studied three or four months is unfortunately too long. So, we need to be quite judicious about who we offer approaches like this to. But I think we are making progress. I think that vaccines will be combined with other immune therapies and hopefully we'll find a more prevalent role in the future.
[0:22:26] Dr. Diane: So not yet ready for primetime, but certainly in the context of clinical trial some really exciting work that's being done?
[0:22:31] Dr. Jedd: Accurate.
[0:22:31] Dr. Diane: Amazing. Grace, any closing remarks to share?
[0:22:36] Grace: Just essentially, I woke up one morning and had stage four cancer and I thought I had zero percent chance of living. And then before you know it, I had 100% chance of living, so don't give up if you're given horrible prognosis.
[0:22:49] Dr. Diane: Jedd, anything to add?
[0:22:50] Dr. Jedd: I don't think I can add anything to that really eloquent.
[0:22:53] Grace: No. I think we should leave on that note.
[0:22:55] Dr. Diane: Thank you both so much for sharing your stories.
[0:22:57] Grace: Thank you.
[0:22:56] Dr. Jedd: Thank you.
[0:22:59] Dr. Diane: I want to thank my guests. Dr. Jedd Wolchok and the beautiful Grace Dunn. Thank you for listening to Cancer Straight Talk from Memorial Sloan Kettering Cancer Center. For more information or to send us any questions you may have, please visit mskcc.org/podcast. Help other people find this helpful resource by rating and reviewing this podcast at Apple podcasts or wherever you listen to your podcasts. These episodes are for you, but are not intended to be a medical substitute. Please remember to consult your doctor with any questions you have regarding medical conditions. I'm Diane Reidy-Lagunes onward and upward.
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