Episode 11: Dr. James Olson on Medulloblastoma Cancer Research

Welcome to the SOC Box Predemption Podcast. The big questions serve with swagger. I'm Andrew and all of your hosts as we embark on this journey together. This episode is another deeply personal one. As many of you know, my son, William, was diagnosed with mesuloblastoma in January of last year. He's since embarked on an incredible journey of brain surgery, radiation and chemotherapy, and recently rang the bell, completing his treatment around Thanksgiving. His response to this adversity has been nothing short of amazing and awe-inspiring. His smile and laughter has never ceased, his poison strength, or well beyond his ears. And I've chronicled his journey on LinkedIn and other sources where you can see his incredible strength and optimism on display. William's resilience has earned him his well-deserved nickname, Iron Heart, and has made my favorite poem, "Our Deepest Fear" by Marianne Williamson, more cogent and real than I could ever imagine. I'll quickly share some of my favorite parts. Our deepest fear is not that we are inadequate. Our deepest fear is that we are powerful beyond measure. It is our light, not our darkness that most frightens us. Your playing small does not serve the world. There is nothing enlightening about shrinking so that other people won't feel insecure around you. We're all meant to shine as children do. It's not just in some of us. It's in everyone. And as we let our own light shine, we unconsciously give other people permission to do the same. As we are liberated by our own fear, our presence automatically liberates others. Throughout this journey, my seven turn eight-year-old son has liberated me. Along the way, I've met some incredible people in world changers. One of those world changers is Dr. Jim Olson from Seattle Children's. James Olson, MD Ph.D. His program director for the event at Seattle Children's Postdoctoral Scholars Program. A principal investigator in the Bentown Center for Childhood Cancer and Blood Disorders Research and Professor at the University of Washington School of Medicine. He co-founded three biotechnology companies and has mentored more than 30 graduate students and postdoctoral research fellows. He's chaired a national phase three clinical trial for high-risk, medulla bustoma patients that led to a 20% improvement in five-year survival in group three patients. Dr. Olson is the principal investigator on multiple projects that focus on developing effective new therapies for pediatric brain tumors. Methods that allow surgeons to better visualize the border of the brain cancer in normal brain and the discovery of immunotherapeutics for several cancers. Dr. Olson's game-changing research in immunotherapy could potentially revolutionize the standard of care as we know it and as the potential to replace radiation and chemotherapy. In lab trials, this treatment completely eliminated cancer and 90% of brain tumors that are otherwise universally fatal in children. Mice that received the treatment were alive and diseased for you while untreated mice died within 18 days. In this podcast, we discuss his research, next steps for funding and clinical trials, and what this could mean for families moving forward. So please, enjoy this conversation between myself and Dr. James Olson. Jim, welcome to the podcast. Thank you, Andrew. Happy to be here. Yeah, I was thinking about how to kick this off and people have certainly heard about my story and I'll definitely be sharing it on my platforms, but I guess I would say about a year ago today, the word "medula-blastoma" meant Greek to me. And I'd say, going through this experience personally with my child, I'm still in Naomi and I talk about this all the time. I'm still in denial that this has happened, which is probably normal for a lot of your families and patients, but I'd say I had to come up to speed real quick to oncology. As you know, I'm no stranger to cardiology and no stranger to clinical trials, but I will never forget the day, which was a little, which was actually almost a year ago, it was late January, early February, this journey started, where William was vomiting in the mornings, hindsight is 2020. Now that I talk to the medial community, and I think as a parent, the psychology of is it allergies, and we, of course, thought that. William's a maniac, as you've seen on the ice, so it was, of course, post-concussive syndrome, I took the sports medicine approach, and then the one day he grabbed the back of his head, after he vomited, grabbed the back of his head, and after subsequent complaints of headaches in that shrill scream that that fateful day to the ER, I remember that ER physician's words, like it was, you know, seconds ago when he said, "I don't have good news," and then this whole journey started, I'd say starting with brain surgery, resection, radiation at St. Jude, and then to return to Indianapolis for chemotherapy, and have met some incredible people along the way. William has rung the radiation bell in Memphis at St. Jude. He recently rang before the holidays, rang the bell here for his chemotherapy bell, and just the, I think this journey itself, having to get to meet you personally and Christy throughout the process, it's been an exceptional journey, and you're doing exceptional things, and now I thought I'd use most of our time today to learn who you are, to learn how far we've come, but also where we need to be. And so I can't wait to get into it with you, but maybe we start before we get into all your immunotherapy and targeted therapies and all these things, just, you know, maybe you could take us through who Dr. Jim Olson is and how you got into really pediatric oncology. Oh, sure. Thank you for having me, so I really appreciate the opportunity. So it's most unlikely that I would be here talking to you today in this capacity. I grew up in rural Upper Michigan in a little town between Eskadaba and Gladstone. The 40 families there all had the same address to give you an idea of how small it was, and I was raised by a single mom who had a minimum wage job, and she had confidence in faith in her kids, and I went to medical and graduate school. My sister went to Stanford Law School, and both of us have had really wonderful enriching careers ever since. Who's really through the generosity of the community who established scholarships for high achieving high school students that I was able to get into college, and later the National Institutes of Health supported my training through the MD and PhD programs, and so I'm always grateful for the taxpayer support that allowed me to enter into this community of physician scientists, and to take what I learned from the kids that I see in clinic to the laboratory, and then build therapeutics in the laboratory that we take back to the kids in clinic. And I really had no intention of being a pediatric oncologist. I was planning to be a family doctor and go back to upper Michigan, but really when I was taking my clinical rotations in medical school, every time I had some spare time, I found myself in the room of a cancer patient talking to them about their journey, calming them down the night before surgery, just felt community with them. My research and graduate school was on a way to make cancer light up through positive chronic mission tomography scanning, and it's a technique that is still used in Europe today to diagnose glioblastoma patients. And in that process, I met young people who were in their 40s, who volunteered for our clinical trials, knowing that it wasn't going to help them, but hoping to help somebody in the future. And these people were in the prime of their life to have young kids, and they were taking a day out of a life that often was only months long, to help people in the future. And I really grew an affinity for those patients then. Still, Pediatrics had never entered my mind as a career. And it was really toward the end of my third year of medical training that I took care of a young girl, seven-year-old girl at the University of Michigan, who passed away from a progressive neurologic disease that we really never understood. And after she passed away, her parents spent a few hours looking around the hospital until they found me. And they just gave me a really warm hug and said that her death was this beautiful as her birth or her baptism. And it was because of the words that I shared with them. And so that made me really think that maybe I had a gift for when medicine didn't go the way we wanted it to go, that I could still walk the journey with families and help them move to a place that was not where anybody wants to be, but where they can find some solace in the decisions they made, the beautiful life that was lived, and all of that. So I actually changed my career plans that already applied for different residency and started all over again at that. Wow. Wow. Well, you shared an incredible slide at the Wellness House in Hensdale, which showed the progress of pediatric cancer survival kind of through time. And I had two questions for you, what have been some of the biggest advancements, maybe for the layman. And then also can you comment on and I think you started to what practice was like when there weren't those advancements. And maybe the prognosises were bleak. Yeah. So yeah. So really when I was a kid, if I had certainly a brain tumor, but almost any kind of malignant cancer, the likelihood of surviving would have been probably around 10 to 15 percent. And right now for most cancers, we're up in the 80 percent survival range. So you know, that's in one generation that we've made that kind of progress. There's certainly some pediatric cancers where the survival is still close to 0 percent. And we have a long way to go, particularly for diffuse midline gliomas that affect the brain stem, also known as the IPGs. For recurrent, almost any kind of malignant cancer in the brain that is recurrent, the options and outcomes are poor right now and we really have a lot of work to do. And for kids who have high grade gliomas like glioblastoma, their survival is still around 5 percent. So we've made great strides but have a long way to go. The cause of those strides really comes down to a simple word which is cooperation. There were a lot of individual doctors who thought they knew what they might want to try next for kids with brain tumors, but had no institution that they have enough patients to actually conduct a trial and learn anything. So they banded together and formed national cooperative groups where all of these institutions would agree on the same clinical trial and then conducted across all of the institutions. So a kid diagnosed in Florida would get this being the same trial as a kid in Seattle or Los Angeles or in Indianapolis. And really, it's just been stepwise progression through that by finding the right radiation, whether it's local radiation or craniospinal radiation, by adding and subtracting chemotherapy agents one at a time so we can learn whether we're making the right step or not. Those have really been the mainstay of the improvements. There have been improvements in imaging and surgery as well. But the real gains have come from that combination of surgery, radiation and chemotherapy. And the reason that I bring that up is because it's wonderful that we're now curing about 80% of the kids who are diagnosed with cancer. The downside is that many of those kids are damaged by the treatments. So radiation can cause lifelong neurocognitive challenges, hearing loss from cisplatin, carboplatin, radiation, renal damage from cisplatin and similar agents. There's a real challenge for kids who survive in some cases in their adult lives. And we don't want to lose track of that because even though the number of survivor sounds good, we really want the number of survivors to be people who have full and healthy lives and don't have to be worrying about side effects deep into their future. And so that's why we've really focused on immunotherapy as a way to use the patient's own immune system to kill the cancer without using chemo and radiation. It's the vision that we have for the future. And so Jim, for those that barely understand, you know, they've kind of followed along the journey here with William recurrence. And here's some biology and genetic questions for you. Genetically, what's occurring with recurrence and what is it about recurrence that makes things so dangerous? Is it those, they were the underlying substrate was unaffected by the chemotherapy or is it something like antibiotics and there's an evolution occurring with that, you know, what exactly is happening with recurrence and what makes a recurring medial or any cancer more dangerous? Yeah, usually, as you say, the recurrence cells are cells that were probably there at the time of diagnosis. And the surgery was in a place that didn't remove them from the brain or spinal cord. And the cells were a resistant to radiation and they were resistant to chemotherapy. And in many cases, they're hiding out in that little layer that is like seren wrap that coats the brain in the spinal cord. And it's called the leptomanin G's. And the cells that are hiding out in that spot, if their resistance to radiation and chemotherapy and they're in that really nice little environment that cuddles them and makes them happy, then when they start spreading, they're going to spread up and down the spinal cord and the brain. And they are already resistant to chemotherapy and radiation. So what new things do we have to offer that could be beneficial? Well, that's part of the reason we're still focused on the immune system because, you know, unfortunately, you can't take something like immunotherapy and move it to front-line therapy right away. You have to start by showing that it has an activity in patients who have recurred despite chemon radiation. And then you can start moving it forward as they've done with childhood leukemia, where one of the T-cell engages, the kind of drugs that our lab works on, is now front-line therapy. And it approved survival for kids with acute lymphocytic leukemia from 86% to 96% in the last clinical trial. And so that's huge. And that's given right at the early parts of treatment, not waiting for relapse or anything like that. That actually is keeping kids from relapsing. And it's, you know, our vision of where we want to get to for the kids who have brain tumors. Right. Now, here's more cell and tissue biology just for the layman here, myself included. So, as we've done methylation tests on, you know, let's say Williams-Tumor, and he's, you know, and now there's a subtype of a subtype and all the genetic substrates. It makes me question, I mean, high level, what is pediatric cancer, not a lifestyle cancer, what is pediatric cancer? And what is mejulo? When you see all how different mejulo is, the question has to be asked, well, what is mejulo or what is pediatric cancer in a perfectly healthy child? Like, what exactly is that? And maybe just maybe mejulo, the multiple phenotypes of mejulo, we could stay there for the listeners. But, you know, when the more you learn about mejulo, the more wacky your mind goes, well, what is this? Right, right. Yeah. The cerebellum is the back part of our brains, and it's the part of our brain that is really important for things like balance and doing math and putting things in order. And because of that, there's an enormous amount of redundancy in the cerebellum, meaning the neural circuits are really repetitive, so that, you know, we don't fall and kill ourselves every time we're in a situation where we're trying to keep our balance. And because of that, the granule cells, which are the little tiny round blue cells that make up a lot of the cerebellum, are the most numerous and proliferative part of the brain as a child is born and into their first year. So a lot of the brain is formed before birth, but the cerebellum just back part of the brain develops somewhat before birth and somewhat after birth, and it's literally billions of cells that are dividing. And when you think about it, all of us come from a single egg and a sperm that make embryo, and we become trillions and trillions of cells, and every time one cell turns into two cells, the entire DNA code from that cell has to be copied for the baby cell, for the sister cell. And of course, when you are transcribing billions of instructions in DNA, there's going to be errors. And there are enzymes that go through and look for those errors and fix them when they can, but there's a few that they miss. And usually when they miss them, they're in unimportant areas of the DNA. We have mutations, all of us have tens of thousands of mutations in our body, maybe way more. And we don't notice them because they're in parts of the genome. It's so vast, you know, it's it's universe-sized kind of scale. And one mutation here and there is not a big deal. But every once in a while, one of those mutations is in a gene that is supposed to tell the brain yourselves to stop dividing. And if there's no stop signal, the cells will keep dividing. And as they divide, more errors can collect. And sometimes just a second signal will tell that cell, oh, not only keep dividing, but divide faster. And so these are normal cells that are intended to be brain cells that have just got an imbalance of their go and stop signals. And it's really, it's really that simple. It's not about exposure. In most cases, it's not about family history or passing genes down from parent to child. It's numerical bad luck when you have trillions of events that are occurring across trillions of cells. And the repair mechanisms are fantastic, but not 100 percent. Yeah. Now here's an interesting one too, because there's been, you know, an assault on an already pathetically low investment in childhood cancer, as you know. Hence, hence this conversation. And I think a lot of grassroots and private support, which is incredible, because that's where we need to be. Two part question again, if another billion dollars was thrown in five, 10 years ago, would we be much further? Or is also the difficulty how rare? You know, these, you know, this is not like the heart failure adult population that we've talked about, where there's so many patients, there's so much knowledge to be had by a scientist. These are also incredibly rare patient populations. So is it that? Is it the lack of funding? Is it bold? I know we talked a little bit about machine learning and AI, but is some of the difficulty gym with the advancements that it's also very rare? Yeah. You know, it is rare. These are rare cancers. Yeah. But they have common drivers and common vulnerabilities with much more common cancers. So the tea cell engage that I talked about when we met is a medicine that would benefit people who have breast cancer that has metastasized to their brain or colon cancer or lung cancer that has metastasized to the brain, adults with glioblastoma, and kids with primary recurring brain tumors. So in those cases, it's absolutely a lack of funding and a billion dollars thrown in five years ago would make all the difference in the world because that molecule, we're doing everything humanly possible to advance it to human clinical trials. We could be opening those trials 12 months from now, but we're gated by finances. Okay. And so I think that the and I also would like to say that because of those cooperative groups that we set up, we were actually ahead of the adult cancer research communities. In terms of we had a thousand megaloblastoma cases profiled like you talked about with the epigenetic profiling. We had a thousand cases before any of the adult cancers had a thousand cases and we had the first thousand genomes done for megaloblastoma patients before breast cancer or prostate cancer. So because we these are rare and because we cooperate, we have placed ourselves ahead of the field instead of behind the field in terms of knowledge. And we had all these subclasses of cancers figured out before many of the subclasses of adult cancers were figured out. So we are absolutely financially constrained from realizing the new therapies that could benefit these kids so they wouldn't have to go through chemon radiation. Yeah, that's profound. And to your point earlier, Jim, and then we could get into your research here. I think of safety and efficacy. The efficacy of the standard of care right now is impressive on how far we've come, but the safety is safety profiles, as you've mentioned, unacceptable. And so as we talk about the idea of immunotherapy and targeted therapies, the way I've explained it to my friends and colleagues and laymen has been, you know, we're trying a sort of a landmark approach with radiation and chemotherapy. We're trying to kill fast growing cells or to target with external intervention. The promise of immunotherapy, how I understand it is, you know, the body itself seeing these anomalies that you mentioned earlier and taking care of business and crossing the blood brain barrier and doing what it means to do. So to me, the promise there is maximal efficacy, massive improvement in safety, hopefully, right? If that's where things go, but is that what immunotherapy before we get into your research, Jim, is that what it's offering other cancers, adult cancers, and you mentioned leukemia and other things, is that the promise of immunotherapy in general and maybe kind of bridge that into your research to for us? Yeah, so you have to be a little careful because immunotherapy actually refers to a whole bunch of different kinds of therapy. Yes, right. That's sheer and common, the fact that we're engaging the immune system to kill the cancer cells. Some immunotherapies are highly effective and highly toxic. And they're closer to the therapies for pediatric cancer that we've been talking about in that there are people who are alive today because of these therapies that wouldn't be alive without them, but they had to go through a lot of side effects to get to that point. And even if that's where we start with immunotherapies for kids with brain tumors, there's room to build on that to make them safer and safer and safer. So I'm not, I don't want anybody to be fooled into believing that the first drugs that come out of the gate are going to be like super safe and you're going to walk out and take a pill a day and be doing great. There are some therapies like that and there's some immunotherapies that are already very safe and are very well tolerated. So I think that what we're trying to get to is, first of all, taking those kids with brain cancer that have a less than 5% likelihood of surviving, many of them with 0% chance of surviving and convert that into maybe 30 or 40% likelihood of surviving. And it may take a lot of intensive care to get them there. And part of that is not because of the toxicity of immunotherapy, but because of the challenges of treating a tumor that's in the brain and the small space that is enclosed in the, you know, the base of our brain stem is enclosed in this little tiny space. And with immunotherapy or other therapies, if you get swelling there, it can actually choke off the blood to parts of the brain and things like that. So I don't think it's going to be easy, but I think that each of these is a stepping stone. And what we want is something that shows a big enough improvement among the first therapies that the community sees a reason to keep moving forward. You know, if we change survival from 0% or 1% to 30 or 40%, but it comes with toxicity, there's still going to be a lot of people saying, yeah, let's refine this. Let's work past the toxicities. As you know, from cardiology and stuff, the things that we do today that are so elegant make some of the things that we're doing in the 50s and 60s look barbaric. But those advances that were made in previous decades generated momentum to get to the place where we could have smaller and finer. And you know, in some cases, things that used to be done with massive surgeries are now done on an outpatient basis. And so it's going to be the same with this. You know, we need a couple big wins in the next five years. And that will generate momentum to keep plugging away. Right. And, you know, you shared, you know, and in Hensdale that in the last 30 years, this research that we're talking about today, it's some of the most exciting you've seen in oncology. Can you maybe talk a little bit about the preclinical results and, you know, kind of how that, you know, transpired and then why you're so excited about all the folks listening to fund human trials. Sure. Yeah. So, you know, the one of the reasons that pediatric brain cancer, many other cancers escape the immune surveillance is because they coat themselves with proteins that signal to the immune system. This is self. I'm one of you. Don't kill me. They me alone now. And the more immune activity there is, a protein called interferon gets released by the T cells or other immune cells. And when the cancer C cells see that interferon, they put more of this coating on their surface. And the coating on the surface is a protein called PDL1, PDL1. And we reasoned that if we made a connector molecule that bound to PDL1 on the cancer cell surface on one side and bound to immune cells like T cells on the other side, they would tell her the immune cell to the cancer cell and instructed to kill the cancer cell. And if the neighboring cancer cells tried to get away by putting more PDL1 on their surface, it would actually make them more vulnerable. Now they're a great target. Yeah. Instead of having a thousand copies of PDL1 on their surface, now they have 10,000 copies on their surface and they're an even better target for our molecule. And so we made a molecule that is exactly that. It's a connector molecule. It's called a bi-specific T cell engaging. A lot of people in the field refer to them as bi-specific or T cell engages. But bi-specific just means it has two ends, one binds to the cancer cell, the other one binds to the immune cell. It connects or engages the T cell and it causes the T cell to kill the cancer cell. And in many cases, that same T cell can release and then go kill another cancer cell and release kill another cancer cell. So many of your listeners will be familiar or more familiar with the idea of CART cells. And CART cells are already in clinical trials because of brain tumors. And the big difference is that for CART cells, you take a patient's own immune cells out of their body and you genetically engineer them to recognize cancer cells, expand them, put them back into the patient where they go after the cancer cells and start killing the cancer cells. This has been a monumental progress in pediatric and adult cancer. And there are a lot of people who are alive because of CART cells that wouldn't have been alive without them. And what CART cells do and T cell engages, the drugs that we make do are very similar. They both use T cells to kill cancer cells. The difference is that the CART cells need to be engineered outside the patient's body. And that process takes several weeks, sometimes up to six or eight weeks, getting down lower now. And it costs a lot of money. It's like a half million dollars per patient. And then you put them back in and those cells that have been engineered can go after the cancer cells. But none of the other T cells in the patient's body will be enabled to go after the cancer cells. And the difference is with the T cell engages, these are off the shelf, therapies, they're in a bottle, they can be shipped anywhere in the world. And you just inject them through the vein, and they connect the T cells that are already in the patient's body to cancer cells in the patient's body. And so there's a near endless supply of T cells that can be used. There's no manufacturing, you don't have the wait time. You can use it in areas that are resource limited. And so we think that I personally believe that CART cells are an incredibly important part of immunotherapy. And I'm hoping that they're stepping stones to things like T cell engages that are off the shelf and less far less expensive to use. Have the clinical results, Jim, been with CART, have with recurrence, have there been published results that it's made a massive dent or improvement in survival or in any cancers that I'm aware of? I've heard a lot of press, but I don't know specific to this population. Yeah, we can't be specific to this population quite yet on recurrence. The first big sign that CART cells were going to be important is in the leukemia area, which is off in one of the first places. And so a CART cell vector that was discovered at Seattle Children's by my friend Mike Jensen and his team went to clinical trials in patients who had relapsed multiple times with leukemia. Okay. And when those patients received CART cells, even though many of them were already hospice care when they went into the clinical trial, over 90% of those patients went into complete remission. I think the number was 92 or 94%. And after three or four years, most of those patients were still in complete remission with no detectable disease. So this was the huge, wow, engine that drove immunotherapy, like money came flowing through venture capital into CART cells, into T cell engages into immunotherapy in general, that coupled with the checkpoint inhibitors, like the PDL1 and PD1 inhibitors that Merck and BMS and others advanced, all of that just generated this enormous enthusiasm around immunotherapy. It turned out that when we moved CART cells and T cell engages from leukemia into solid tumors, that they were more challenging to cure. And part of that is because of this ways that the cells have of protecting themselves from immunotherapy. And as I said, that's the reason that we built our molecule so that the more they tried to evade our immunotherapy, the better the target that became. So it's a very, I always have felt like cancer is playing chess while the oncologists are playing checkers. And they get to make a whole bunch of moves while we make one move and think about it very carefully. And this feels to me like we're actually playing chess as well. Like, all right, if that's your move, we're anticipating it. And here we are ready for a checkmate. Wonderful. And in the preclin, you know, was this, was it, was it Petri dish and cell and tissue engineering gym where the, I mean, to probe the hypothesis for the preclinical results, was it just building upon, was there a spark of insight or was it building upon and just bringing it to this patient population with any twists in the molecule or how did we go, how did we get here? Oh, I wish I could say that we carefully planned it out and our strategy was right. No, embarrassingly, we included it in a experiment that we were doing with a drug company. The FDA requires when a drug company gets a new approval for a cancer drug for an adult indication that if it could be used in kids, that it gets tested in preclinical models and then in clinical trials and we were doing a study like that. And we needed a negative control of a molecule that we didn't think would have any activity. And I put this molecule, or we put this molecule into the experiment as a negative control because it's shaped like an antibody. And so it's a pretty big molecule. And I and others believe that it wouldn't cross the blood brain barrier. And we knew that these brands and glioma patients often have an intact blood brain barrier and the most model we were using at an intact blood brain barrier. For those of people who don't know what a blood brain barrier is, it is the lining of the blood vessels of the brain that keep that coming close out of the brain. But it also keeps most drugs out of the brain and it certainly keeps proteins the size of antibodies out of the brain, which is the size of the drug that we were using. And so we put it in there with the intention that it would show no activity and that it would help us just see how fast these tumors grew in the absence of effective treatment. And what we saw instead was that 70% of the mice were alive at 100 days, whereas all the mice that didn't get treated were dead by 18 days. And all the mice that were alive were neurologically normal. And when we evaluated their brains, there was no cancer left at all. And so we were wrong. We were we were correct that the drug doesn't magically cross the blood brain barrier. But what we didn't think about was the fact that this drug could bind to the T cells out in the rest of the body. And then those T cells can crawl into the brain across the blood brain barrier. And so they're already decorated with our T cell engages all over their surface. And now they go in and there's just like cancer cells to eat left and right that are coated with the PDL1 molecule. And they're just ready like Pac-Man to start eating them away. Wow. It's so they're happy there. And they send out signals to call more T cells to come in and be back up. And they proliferate. And so we're seeing we've now tested 14 different patient-drived models and we're seeing survival benefits in 12 of those 14 models. And in many of the models, we're seeing complete eradication of cancer where you can't detect it even at the very sensitive molecular level. So the most exciting ground breaking research in 30 years was off the mistake of a negative control. That's right. Wonderful. I mean that science, I mean the science surprises us. And yeah, serendipity has been part of almost every major discovery in science. Yeah. Yeah. Anything else, Jim, that comes to mind something like that either in your research or cancer research that is just we were something something like this just took us in an entirely different direction or helped us discover a new paradigm. Yeah, I think one example was antibody drug conjugates. There is a whole field where they decorate antibodies that go to cancer to deliver drugs inside the cancer cells to kill them. And that was originally intended to be a way to deliver radiation to cancer cells. And when they did the first experiment, Fred Albobaum and Irv Bernstein at the Fred Hutchinson Cancer Center, they injected oblivious human patients with antibodies and they learned to everybody's surprise that the antibodies instead of coding the surface of the cancer cells got internalized into the inside of the cancer cells. And so they reason why don't we attach a toxic molecule to it instead of radiation or instead of just using the antibody? Why don't we send a poison in on it? And so they targeted a molecule, it was called a myelotargue that where they attached a cleatomycin to an antibody that went after cancer cells. And that was the first antibody drug conjugate that ever got approved by the FDA and was marketed by Pfizer. And that was all based on an assumption they made that they saw a result that was different than what they expected and they you know it was fertile soil. They were prepared to make a change and to take that in the direction that they weren't planning on but which ultimately led to the whole field of antibody drug conjugates. That was a lot of serious of cancer therapeutics right now. Incredible. I mean, incredible. And maybe the the listeners that don't know, I think everyone assumes that when a child rings the bell everything's over. And I try to explain to folks that you know actually it's a it's a it's this horrific cycle that parents go through specifically with Medjulo and of you know we're going to do a scan in three months. And there's this apprehension of recurrence. And this is why this is so important that you can have an incredible warrior in Iron Heart and my son William who's had who's had an incredible response and is doing great today. But every parent maybe that had that bell ringing experience that has to deal with the horror of recurrence has I mean real note there's really not an evidence base. I mean if you ask 10 oncologists what to do with recurrence you might get multiple different answers. And I think that's what's so excited about your research. And Jim so from the preclinical models to now walk us through where you want to go next and and what that would look like potentially if if it's as favorable it has been preclinically. Yeah so you know we've been working on this for a number of years when we presented at scientific conferences we've talked to venture capitalists about whether they would get behind this if we started about to company around this T-cell Engager. And they've all had the same concern. And that is PDL1 is expressed not only on cancer cells but on some normal cells as well. Things like the cells in the lungs that help us breathe and the eyelid cells in the pancreas that make insulin and and other really critically important parts of staying alive as humans. And what if our drug caused T-cells to kill those normal cells and they're really you know at the same doses that were needed to kill cancer. And so we respect that concern and we have the same questions and so we've just finished a series of advanced toxicology studies where we've been able to show that you can safely administer these drugs at doses that are effective for killing the cancer cells. And we showed that there's no respiratory insufficiency, there's no pancreatic insufficiency, at doses that caused the cancer cells to die. While we were doing all that work we discovered and even safer portion of the molecule to part the binds to the T-cell. We've been in the whole field we've been using a variation of the same antibody that was discovered in the 1980s and it has a lot of liabilities meaning that it causes a ton of side effects that are unrelated to its benefit against cancer cells. And we've discovered an alternative that appears to be much much much safer from all of the experiments we've done and in some case it looks to be more effective that is killing the cancer cells even better than the parent molecule. And so even though we were already less than a year away from potentially opening clinical trials we're going to take a little step backwards and replace that molecule that people used to use with the new safer molecule and go forward with the manufacturing and the toxicology studies because we think that by time you run human clinical trials properly all the way through FDA approval you're talking about a hundred million dollars or more. You don't get to do that a second shot. So we're willing to take a few months and raise some extra money to advance the safest molecule for kids that we can possibly advance. And so that's why even though we already raised the money to do those toxicology studies we're raising money to do it with a safer version now so we can submit that to the FDA and we're looking to foundations and such to help raise the money for the manufacturing step because all of these things manufacturing toxicology used to all be in the realm of biotech and covered by investors. But right now in the current national environment the biotech investment sector is so diminished that the VCs are tending to invest in drugs that have already been in human clinical trials in China rather than investing in new ideas that are coming out of universities in the United States because they've already got human trial proof as opposed to something that looks promising. The challenges that most of those that are coming out of China are kind of me two drugs that have already been pioneered and advanced and what we're missing by doing that are these drugs like the PDL1, CD3, T-cell and Gage are the one that we're working on. And I will be the first to say that this drug is either going to be an amazing winner that causes tumors to melt in patients that don't really have any other options at doses that are safe to those patients or it's going to tell us really early that there's toxicity that we can't overcome because you can't you can't predict everything in the preclinical trials right and so I really believe that you know we're within 10 or 20 million dollars from having that answer and if that answer is that this is causing tumors to go into remission safely then we'll be able to get all the money we need to get the rest of clinical trials done because now you have human clinical data to support it and we've now caught up with where the Chinese biotechs are with the you know kind of less forefront candidates that are being advanced. Yeah it's a question that needs to be answered no doubt from your your clinical results and for the listeners that haven't seen it yet please please look at the Iron Heart link for Seattle Children's and Dr. Olson's research it's incredible yes to your point is preclinical and we we're always surprised when it goes into humans but let's talk about the home run gym if all goes well the listeners were funding everything's going well where would you see the start of this trial and then a home run in the trial beyond magula in general where this idea if this is a home run let's talk about next steps in timing for magula but also and beyond. Yeah well one of the biggest challenges in developing a therapeutic for kids with brain tumor is what VCs we call the small market yep and so in this case we're very fortunate because we see that lung cancer and breast cancer and colon cancer the metastasized brain is also melting in our preclinical studies so that's good for two reasons one is that we can start our safety trials and adults and after we've treated the first six or nine adults safely we can initiate the pediatric clinical trials to run concurrently with the adult trials and that's very different than we used to do where we had to complete the adult trials before starting the pediatric trials now we're appropriately doing them concurrently with just a little head start on the adult trials so in the best case scenario we're gonna see adults with metastatic cancer to their brain we're going into remission at doses that are well tolerated by those adult patients and then quickly followed by kids who are getting remissions and their durable remissions and they're doing that at doses that are safe that could lead to a FDA approval and you know kind of for the first time kind of having real hope to offer these families that currently have very little to look forward to because of the nature of their kids primary cancer or because it's a recurrent cancer. Now I'm thinking back to cardiology and adults here if you prove it in high-risk patient populations next list we talked about the word frontline therapy home run results in in high-risk recurrent patient populations yeah if that is indeed a home run would would is this an would it be an adjunct or would there be if they're most likely be another trial as a frontline therapy post surgery or what would be multiple steps for sure yeah the ideal time to use it would be right after therapy right after surgery at the beginning of treatment because that's when you're going to have the smallest amount of cancer in your body and that's when immunotherapy is most likely to work with the least amount of side effects it's going to take several steps to get to that point but that's exactly where you would like to be and that's exactly the point where you could say all right let's do that and not immediately treat with chemo or radiation and or or do it concurrently first and then later try try reducing but in the one example of lung cancer where we thought about this we said you know what's going to happen when somebody comes in with recurrent lung cancer and we want to give this T cell engaging but standard care is already osamurtenib which is a tyrosine kinase inhibitor and so we tested our molecule alone osamurtenib alone and the two together and we learned is that when you put the two together the animals all went into complete remission and they stayed there and our molecule was better than osamurtenib in the preclinical trials but the combination was the best of all so we may find that sometimes combining it with standard therapies actually is really effective in that ideal for that progress that we need to make because nobody's going to let you stop the standard of care therapies while you try your alternative therapy you can have to start by giving them you know both to the patient and then backing off on standard therapies if you get good results let's go to my earlier question on what is menjulo because to your point each of these strategies would be specific to the biology right potentially right there's menjulo as a whole and then different types of menjulo there might be entirely new standard of care with adjunct with frontline therapy for for WNT type menjula and so all these different things it just it's so exciting Jim to think about as a parent that one there's hope for for for for for kids with recurrence but as a parent who's gone through this now with the horror of chemotherapy and radiation wanting to save your child but having to accept the risk of side effects down the road your your mind wonders to an entirely new paradigm where that the day in the ER one day from now where that they they get that diagnosis where we don't have good news the paradigm is entirely different one day potentially with the work that you're doing and so and I wanted to make sure the listeners knew that that you know recurrence is a very very scary thing where there's very limited evidence there's active clinical trials as dr. Olsen mentioned and Carty and and other things but there's there's not been a great advancement honestly until the the O332 protocol was probably the biggest you know the the cargo that I joke that the I got to share William scan results to one of the lead investigators for the for that trial and and we've come so far but 80 percent survival with the toxicity profile is not enough and especially for kids and so you know I I can't thank you enough Jim for the life changing work you've done for all families and for all the listeners thinking about oh well it's easy you should get funding isn't easy and you've heard dr. Olsen's plea that you venture capitalists it's not quite that easy you would think the government it's definitely not that quite easy in the current landscape and so it really takes a grassroots effort from each of us to say it's not good enough and that every family deserves hope and a future for their trial for their child without toxic side effects and that's where we need to be targeted therapies without the the side effect profile that we have today and well Jim I'll I'll share the link to your research I'll ask every listener to to to to donate and we'll be following along very closely and thank you for being an iron heart for for my family and for all families out there I can't thank you enough yeah it's my pleasure and I just want to back up one second to what you said about grassroots which is that this molecule that we're using was built on a hundred dollar donations wow because that's how we started this whole protein science thing and lots of people chipped in a hundred bucks to help us make the first candidate and so that grassroots effort is really important and then what is also important is those people that can do more you know my wife and I made our biggest gift ever to Seattle Children's to support this program and programs like it because I really believe that I want to be part of something that lasts for generations and that benefits kids and so for listeners who can make a bigger gift there's ways to do that that you know we have teams that can help you you know efficiently do that for tax purposes or that and they can reach out to me through you and we can put them in contact with those people that can help them make those transformative gifts as well that's a such a great point that every dollar for all the listeners a hundred dollars a thousand dollars whatever your means are every dollar is going to potentially game changing research to save kids lives and adults lives to your point and we got to start somewhere and there's not just this flow of cash from venture capitalists or the NIH just on offer it is your donation entirely and that's why I said it it will take iron hearts all of us together every hundred dollar donation every every amplification of this podcast of of Jim's research please donate and again Jim thank you so much for who you are and what you're doing to move the dial forward for for all families my pleasure and thank you