In this episode of "On the Edge of Breakthrough: Voices of Cancer Research," Leo Wang, M.D., Ph.D., pediatric oncologist, Clinical Director of the Gene Therapy Program and Director of the City of Hope Alpha Clinic, discusses the realities of caring for children with cancers that still have few effective treatments. He reflects on what it takes to begin changing those realities for patients and families.
While many childhood leukemias are now highly curable, Dr. Wang explains children with certain aggressive brain tumors still face the same outcomes they did a decade ago. This lag in progress is what drives his work today investigating CAR T cell therapy gene therapy in early phase clinical trials.
Throughout the conversation, Dr. Wang returns to the idea that progress in pediatric cancer care depends on collaboration across institutions, bringing together patient care, careful study and shared commitment across the research community. For him, the work centers on honoring the trust families place in the field and steadily moving discoveries from the lab to children who need more options and more time.
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Full Transcript
Dr. Monty Pal:
<silence> Welcome back everyone. I couldn't be more excited to have our guest today, Dr. Leo Wong, who's actually the head of our alpha clinic here at City of Hope. He's the head of our gene therapy program here at City of Hope. And on top of that, just a world class, world renowned pediatric oncologist. Leo, welcome to the program.
Dr. Leo Wang:
Thanks so much for having me. It's a real pleasure to be here, Monte.
Dr. Monty Pal:
You got it. So, you know, I'll tell you, we usually kick off things by really talking about everyone's origin story. What, what sort of got you into the field of oncology on the whole? Can you give us a little primer on your background?
Dr. Leo Wang:
Uh, yeah. So, um, I grew up in upstate New York, uh, and, uh, went to public school and then very early on discovered that I had a huge love of science and, uh, started doing research in a research lab at the University of Rochester, um, when I was like in middle school, um, and
Dr. Monty Pal:
In middle school. Wow. That's early.
Dr. Leo Wang:
It, yeah. It might not have been legal at the time, but, uh, <laugh>. But it was, it was a lot of fun. And, uh, I realized that I was both really good at it and really loved it. And so, um, decided that I was going to, you know, devote my life to that. Ended up going to MD PhD school after undergraduate, uh, and got my MD and PhD at that time in developmental immunology. So I was studying B cell development. Um, those are the cells that make antibodies, those are particular type of immune cell. Um, and then from there, uh, you know, when I was finishing up medical school, decided I really wanted to do pediatrics. Um, and that really was just born of a love for kids. Uh, and, um, coincidentally had my first kid at the same time. And so sort of paralleling what was going on at home with what I was seeing on the wards, and really fell in love with that patient population.
Dr. Monty Pal:
Interesting. We're, we're gonna get back to pediatric oncology specifically. Yeah. Because I think it takes a certain kind of person to be able to see, you know, children affected by cancer. Right. But before we go there, right. You have this really wild story to tell us regarding your siblings, right? All three of you are in different fields, right. Can you give us a little preview or primer on what they're doing these days?
Dr. Leo Wang:
Yeah. So, I mean, I don't know if that's that wild. It's like, um, you know, like, uh, it's pretty wild. It's pretty wild. Tell everyone, it's like the Emanuel family, like Ari Rom and, and, um, uh, the Z Emanuel, right? Do you
Dr. Monty Pal:
Know who those people? Absolutely. Yeah.
Dr. Leo Wang:
Uh, we're not like that. Um, so, so, uh, I'm the oldest of three. Um, my, and we all grew up in upstate New York. My middle brother is two and a half years younger than I am, and my youngest brother is 12 years younger than I'm. Um, and so, uh, in, in Chinese culture, uh, you know, the family names are often, um, you start with your family, your last name, right? 'cause that's the most important thing is the, is the family that you're from. And then, and then it's a three character name. And this, the first character of your first name, uh, is actually shared generationally.
Dr. Monty Pal:
Okay. So
Dr. Leo Wang:
I'm Wong Li the Okay. And my brothers are Wong, li Hong, and Wong Li Kai. So we all have the Wong, which is our family, and then the Lee, which is sort of our, our stratum within that, um, larger Wong family. And then the last part, that's where you get to be individual. Um, so my middle brother is Wong Lih home, and he is probably the, the biggest Chinese pop star, uh, ever
Dr. Monty Pal:
<laugh>. So this is, this is kind of a big deal, right? Yeah. This is kind of a big
Dr. Leo Wang:
Deal.
Dr. Monty Pal:
Yeah. You gotta tell me how that happened. I know, I digress a little
Dr. Leo Wang:
Bit. No, yeah. He, he did not work in the lab when he was in middle school. <laugh>, let's put it
Dr. Monty Pal:
That way. That's
Dr. Leo Wang:
What I guess, yeah. He, he's been very talented, uh, musically for, you know, we all grew up playing instruments and, and music was a huge part of our lives. Um, but he had a particular talent for it that was apparent very early on. And I remember we were, we were both in the, um, the Rochester Philharmonic Youth Orchestra. So like,
Dr. Monty Pal:
Okay. We
Dr. Leo Wang:
Were super like Asian nerd type, you know, phenotype kids.
Dr. Monty Pal:
Yeah.
Dr. Leo Wang:
Um, and I remember when, uh, I was in, I don't know, it must have been eighth grade, and he was in sixth grade. We were both in this very competitive youth orchestra. We both played violin. And I remember the, the director pulled me aside and he was like, Hey, is it really gonna hurt your feelings if I seat your brother ahead of you? <laugh> Okay, <laugh>. And I was like, no, it'll be fine. And, you know, um, and even at that point, it was very apparent that he was just way more talented than, than I was. And, and that as it turned out to be true, you know, continuing on. So he was extraordinarily, uh, gifted and was in all of the high school, whatever productions, and he was in a band and stuff like that. But, but I think that, um, you know, he wouldn't have gone on to do what he did except, uh, serendipitously in between, um, his high school and college years.
That summer, my maternal grandfather got sick, and he lived in Taiwan at the time. So my mother went back to Taiwan to, to care for him because my brother had graduated from high school and didn't have anything to do for the summer. He went with them, and every day they would go between where the, the apartment was that they were living, and the hospital was where my grandfather was staying. And they'd walk by this, um, you know, strip of basically shops. And then there was this one particular building that had this very interesting facade, and they didn't really know what it was. So one day they went inside, it turned out it was a nightclub. And Lee Home was like, well, I'm here all summer. I got nothing else to do, and, you know, maybe I can audition for the house band, or something like that.
And he didn't speak any Chinese at the time. So my mom went to the manager of the club and said, Hey, you know, my son is a musician, you mind if he auditions for your house band? And they're like, well, you know, normally we'd have auditions for the house band on Thursdays or whatever, but this Thursday we're not doing that because there's this like, national talent competition. It's like, you know, star search back in the days, like the winner gets a record contract, so whatever. And Liam was like, oh, I'll just, I'll, I'll do that then. And so he entered this competition, and after his first round, uh, people start calling him. They're like, Hey, we saw you at this thing. We'd like to give you a record contract.
Dr. Monty Pal:
So he, he was in this American Idol type of deal? Yeah, exactly. More or less, right? Yeah. The Taiwanese Taiwan Idol, I guess. Yeah. And your younger brother. Tell us about his story. Is he also in medicine or?
Dr. Leo Wang:
So Le Kai, uh, is, is the smartest of the three of us by far.
Dr. Monty Pal:
Okay. Okay.
Dr. Leo Wang:
And he was this kid who, when he was like seven, was just like, making these observations that just blew us all away. Um, and, uh, he's always sort of, because of that, been able to see the world in, in ways that I think that are not open to, to the rest of us. Um, and very quickly figured out how to sort of, you know, create his own path. So, um, he actually stopped going to high school, uh, in the middle of high school. He is like, I don't, and he came down one day and my, my dad happened to be home, um, which was rare, but, um, he came down and he is like, aren't you supposed to be going to school? And he's like, I don't, I don't really think there's any reason for me to go to school. Like, I already know everything they're gonna teach me. And my dad's like, okay, that's fair. Yeah, I agree. You can, you don't have to go to school anymore.
Dr. Monty Pal:
<laugh>. Wow. What an open mind. Okay.
Dr. Leo Wang:
Yeah. Okay. Which is really pretty weird. Anyway, he, um, you know, he super smart, got a perfect score on his SATs, and, um, ended up going to MIT, uh, where he learned a ton from there, there on, he went to work on Wall Street and was a very early, uh, quant trader. You know what that is? A quantitative trader that's, um, they wrote computer algorithms that would take advantage of, of very slight mismatches in markets.
Dr. Monty Pal:
Okay.
Dr. Leo Wang:
Um, so in the time that it takes to register a trade between two, whatever it is, commodities or stocks, you know, um, there's, there's a very small window where there's a mismatch in the price between the seller and the buyer.
Dr. Monty Pal:
Okay.
Dr. Leo Wang:
Um, and so if you could take advantage of that, you know, even, uh, even though there's maybe a couple cents mismatch in the price, you can make a ton of money if you slip in and, and intermediate between that, that discrepancy. But it requires you to be very, very fast. Right. Human beings don't have the speed to do that. So you write and he's like writing algorithms software. Yeah. It got to the point where what actually was really important was not just the speed of the algorithm, but how close the computer was to the exchange.
Dr. Monty Pal:
Okay.
Dr. Leo Wang:
So if you put a mainframe like right on Wall Street, then you know, your, your lag was like much shorter than everybody else, and you could make millions and millions of dollars.
Dr. Monty Pal:
I, I feel like we've gotta have a podcast. I'm looking at my producers right now on, on the Wong Family, <laugh>. I mean, I think this is, this is really, we're, we're getting a little bit beyond scope here, but I'm, I'm really enjoying this. That's wild. Wow. Yeah. So, so he
Dr. Leo Wang:
Did that for a while and made a bunch of money, realized that that was not, um, making the world a better place and so quit. Um, and then actually worked in the entertainment industry for a while, then realized that that was not really making the world a better place in the way you wanted to. I think. So quit that and actually, um, went to go work at UCLA in a genomics lab
Dr. Monty Pal:
Mm-hmm <affirmative>.
Dr. Leo Wang:
Uh, and doing, you know, genomic sequencing, uh, to try to, uh, help people identify patients who have, you know, undiagnosed disorders. Like what, what the genetic mutations are that underlie that.
Dr. Monty Pal:
Just amazing.
Dr. Leo Wang:
Yeah. So, so that's, that's my family. Incredible. Are, are we outta time? Yeah.
Dr. Monty Pal:
<laugh>. Thank you for tuning in. There you go. No, and, and, and you know, it, it is just wild to see three siblings with such divergent interests, but also incredibly successful in their own right. Um, but we're gonna shift focus back to you for a second. We know if that's okay. And, and, you know, one of our first podcast guests was So Armenian, who is the chair of pediatric oncology here, one of my best friends here at City of Hope. We actually started the same year here about 20 years ago now. Um, and, you know, it was just, it was just so touching. Is it
Dr. Leo Wang:
True that he, um, that he called Conan O'Brien? No. He called you Uhhuh while he was with Conan O'Brien. Is that
Dr. Monty Pal:
True? He sure did. He, he's quite the celebrity himself. Yeah. In fact. And then I got one of the most lovely calls from one of my childhood heroes, Conan O'Brien, when, when Sorrow was out to dinner with him. Funny enough. That's amazing.
Dr. Leo Wang:
That's amazing. <laugh>, did you tell him about your
Dr. Monty Pal:
Podcast? I, I did. I did. Uh, Conan's working on the promos for it. <laugh> as we speak, bring up sorrow, because he had this just amazing touching story of, you know, what got him into pediatric oncology. And, you know, we didn't get enough time on that podcast to devote to how you sort of make it work. Right? I mean, seeing kids with cancer, especially having your own children, it's gotta be, you know, on, on some level so, you know, gut wrenching and emotional. How, how do you sort of deal with that element of the job? Yeah. That, that's a
Dr. Leo Wang:
Really important, uh, and, and a great question, Monty. Um, and I'll have to, I, I gotta tell you that, that I have a whole bunch of different answers to that question. 'cause it's an answer I get asked all the time, right? Yeah. I mean, I just got ask, asked it about 10 minutes ago, and you have have to kind of figure out what the answer is that people are looking for when they ask that question. Right. If somebody asks you that at a party,
Dr. Monty Pal:
Uhhuh, <affirmative>,
Dr. Leo Wang:
They don't want to hear, you know, that it's one of the hardest things that, you know, I've ever done in my life. Right? They, they, I think they're, they're looking for something that's a little bit sort of like, oh, yeah. You know,
Dr. Monty Pal:
I put in a box and put it aside.
Dr. Leo Wang:
Right, right. And, and then move on to whatever is next.
Dr. Monty Pal:
Mm-hmm <affirmative>.
Dr. Leo Wang:
Um, so, so I have a bunch of different answers, but, um, you know, for, for this audience, I think, um, I think we can sort of get a little bit deeper into it.
Dr. Monty Pal:
Yeah, lots. Absolutely.
Dr. Leo Wang:
The, the reality, I think you're right that, that pediatric oncology has to be a calling. And, you know, I'm not, um, I'm not a religious person, but I'm a very spiritual one. And I, I think that if you don't feel truly called to, to perform this service, um, then it will, uh, ultimately I think it'll be too much. It'll, you know, it'll overwhelm you. And I have a lot of friends and colleagues who have sort of gotten lost in that, which is, which is hard. Um, it is, it is without a doubt, the, the greatest honor and the most humbling honor of my life to take care of children, uh, with cancer and their families. Um, it is sometimes devastating for sure. There's no, there's no question about that. Uh, but it is also tremendously uplifting and fulfilling, and it's full of joy and full of hope. Um, you know, one of the amazing things about kids is, as, as I'm sure you know and your listeners know, is that like kids are, are full of emotion. They can't contain themselves. Right. Like, you know, if you ever watch like a 4-year-old, everything that that 4-year-old feels is out there. Right.
Dr. Monty Pal:
There's no restraint.
Dr. Leo Wang:
There's no restraint. Yeah. And it's, it's so wonderful. Even kids who are getting chemotherapy, who are going through radiation, like, they have moments of just pure joy and laughter where they're like running around or, you know, like playing with their new toys or whatever it is. And, and that resilience or that a bulence is just, is, is so sustaining, it doesn't in any way detract from how hard it is. Um, you know, being told that your child has cancer is hands down the most difficult thing that any family ever has to go through. I think that, I don't think there's any question of that. Um, and it is that counterpoint, that tension between, you know, the absolute worst thing that's ever happened to your family, and these moments of, of pure unrestrained joy, hope, and happiness, um, that make this such, um, such a tremendous honor to be a part of, just to walk with these families along this journey that is so intense, so deeply personal and, and so sacred. Um, that's ultimately why I do what I do. And I think that the, those of those of us who, who are called to do this, who are chosen to do this career, that we all feel that,
Dr. Monty Pal:
And, and, and what's your outlet? You know, I mean, for me, you know, uh, being here for 20 years now, I've had patients that I've become incredibly close to who, you know, pass away. Yeah. Um, you know, I, I think the outlet for me is going into the garage and maybe banging on the keys or playing music with, with my kids, you know, as, as I think you're well aware of, you know, I also do find the research to be sort of a nice
Dr. Monty Pal:
Outlet. Mm-hmm <affirmative>.
Dr. Monty Pal:
You know, what are your outlets for all the, you know, angst that you must have over, you know, some of these really, you know, horrific tragedies that we see in the clinic occasionally.
Dr. Leo Wang:
Yeah. That's a phenomenal question. I don't have a good answer for you to be perfectly honest. I mean, um, therapy is a really important part. Mm-hmm <affirmative>. Of, of dealing with, uh, with the psychological, um, well, dealing with the, the grief. Yeah. And, you know, there's a lot of grief, um, and a lot of sadness. Um, I think we all have our own ways of dealing with that, but it is, as you know, very difficult to figure out how to carry the stories of our patients with us, um, to respect and honor that without letting it pull us down. Um, and so one of the things that, um, that I do is, you know, I, each patient I've taken care of, uh, many of them give me mementos, you know, pictures, cards and stuff like that. I have those all in my office, and they sit right by my computer monitor so I can see the patients, um, and remember their stories and think about how to do things better in the future. Um, and so I, I feel in some ways their, um, their presence and their strength and their courage and, and the hope, um, that they put in our team here at City of Hope and in me, you know, in my team, um, every day when I go in to see the next patient, and that's sustaining.
Dr. Monty Pal:
Um, I, I love that. And, you know, I love the fact that you brought up therapy. I think it's something that's actually very underutilized and
Dr. Monty Pal:
Yeah.
Dr. Monty Pal:
In our profession and in many professions in medicine, you know, it takes a lot of courage to bring it up, frankly. But, but I do think, I think
Dr. Leo Wang:
Everybody should be in therapy.
Dr. Monty Pal:
Yeah. I mean, I think that's just like a baseline. Indeed. Indeed. And just, you know, having that person to talk to that, you know, sort of ombudsman or, you know, independent party to mm-hmm <affirmative>. Really just, you know, sort of pour your heart and soul out too. It's just, it's so key and something we don't often, you know, take advantage of in our day to day.
Dr. Monty Pal:
Yeah.
Dr. Leo Wang:
No, I completely agree. And then, and then the other thing that you said is the research. I mean, I think that, um, one of the, one of the advantages of, of being a, a clinician scientist, a physician scientist, is that, you know, the, those things are synergistic, right? The, the things that you see in the clinic help you figure out how to ask the right questions in the lab, and then vice versa, the things that you learn in the lab, you can take back to your patients. Right? That's how we got to this clinical trial, which I think has changed so many lives. Um, but that, that helps a lot for me, right? The, the, um, the pain, the sadness, the frustration that we couldn't do more for each individual child, um, you know, spurs me to go back in the lab and motivate my people, um, my scientists to, to do better, to ask, you know, smarter questions to get to answers faster so that we can, you know, in three years get
Dr. Monty Pal:
To, uh, a better therapy. I, I love this. You, you know, pediatric oncology is one of these spaces where, I mean, there's gosh, just been amazing, amazing discoveries early on, I would say near the inception of oncology with multi-drug chemotherapy and so forth. I mean, really transformative outcomes initially, that there's still certainly a lot to be done. Um, and, and I will say, I mean, I, I kind of feel like you're at the forefront of it. Um, you, as I mentioned at the outset, run our gene therapy program here at City of Hope. You also run our Alpha Clinic, uh, alpha Clinic, I think is a term that's used in a different way at several institutions. Yeah. Tell us about the City of Hope Alpha Clinic and what that involves.
Dr. Leo Wang:
Yeah, it's, um, so, so the, the California Institute for Regener for Regenerative Medicine, the California Institute for Regenerative Medicine, serm, um, has, you know, as you know, supported science, uh, in California for a long time. And it's really become one of the pillars of, of how California has been so successful in making, um, biomedical advances. Um, one of the things that they have sponsored is the Alpha Clinic Network. The Alpha Clinic Network is a network of nine sites in California. It's all the ones that you would think of the major center. So, you know, it's US and Cedar-Sinai and, uh, U-C-S-D-U-C-S-F, uh, UCLA, um, USC and Children's of La Stanford, um, uh, uc, Davis and, and uc, Irvine. Um, and, and we are all tasked, um, through the Alpha Clinic Network, um, with building clinical trial infrastructure that gets new stem cell and regenerative medicine therapy, clinical trials to patients in California, as you know, uh, there are huge gaps in access and affordability for novel therapies, right?
If you live in la, if you live in San Francisco, if you live in San Diego, relatively easy to get to a center that's performing these, you know, miraculous new therapies if you live in Barstow or Fresno, you know, um, it's much harder to do that. Uh, and, and we have both had this experience where we have patients that we'd really like to help, but they, they can't get to us because it's a two hour commute each way. And, you know, they can't leave work to come here to get therapy. Um, and, and so, um, the state of California recognizes that, that that's a problem, and that we need to address that problem. So what the Alpha Clinic is supposed to do is help stand up clinical trial infrastructure that will bring these therapies out to those patients. Um, so, so that's what, that's what the network is for.
And within City of Hope, the City of Hope Alpha Clinic actually is uniquely positioned among all the Alpha Clinics because of city of hope's unique ability to have a network, uh, that reaches not just across California at this point, but all across the country. Nobody else is like that, as you well know. And, and so our ability to leverage internal infrastructure that we've already built, or that's already being built by people like at Kim and Elizabeth, buddy and, you know, all of our, uh, colleagues at in Chicago, Atlanta, and Phoenix, they're already answering these questions, right? How do we get what we have built in our, you know, storied history to patients all across the country? Well, those are fundamentally questions of implementation, access and equity, um, that the Alpha Clinic can learn from. And we're partnering with those folks to, to do that.
Dr. Monty Pal:
Brilliant, brilliant. You know, and, and let's dive a little bit deeper to some of those specific novel therapies. You know, I think that your work in the space of CAR T-cell therapies is well known. May maybe give our audience a a little preview of what you're most excited about within your clinical domain first, but I do want to talk about your laboratory in just a second related to CAR T cellular therapy.
Dr. Leo Wang:
So, I think what you said earlier about pediatric oncology really having some remarkable success stories, uh, is, is absolutely spot on, right? Like, so in the 1950s, if you were a 3-year-old with leukemia, um, there was very little that we could do for you. And often the, the recommendation was, you know, spend some time with your family, make some treasured memories. I'm sorry, we can't, we can't carry your child. Right? And now, 2025, the cure rate for a acute lymphoblastic leukemia, a LL is like 95%, meaning we make the cancer go away, it never comes back. You know, I have patients that I took care of when I was a fellow and, uh, younger attending who they're now graduating from, you know, high school and, and you cannot tell that they ever had cancer.
Dr. Monty Pal:
Right?
Dr. Leo Wang:
Right. I mean, this is a remarkable testament to the ability of biomedical research, clinical translation, and, and the work that people like saw Armenian are doing to make sure that cancer survivors become cancer thrivers and having full, fulfilling lives. Unbelievable. Unfortunately, that's not the story that we tell about kids with many types of brain tumors. Um, and in there are particular types of brain tumors called brainstem gliomas. So DIPG and DMG. These are diffuse midline gliomas, diffuse intrinsic pontine glioma, where unfortunately, the conversation that I have with patients and parents in, you know, 20 25, 20 26 is exactly the same as, as we had in 19 50, 19 55. It's sort of, unfortunately, there's nothing that we know of right now that will cure your child's cancer, that will make it go away and never come back.
Dr. Monty Pal:
And can I ask you, before we get into the treatments for this, how, how often are these diagnoses encountered? Is this a frequent diagnosis?
Dr. Leo Wang:
So, um, the diffuse midline, diffuse intrinsic ponting gliomas, there are about 400, 500 of those probably a year in the United States. Um, so it's not a common diagnosis, but it is a devastating diagnosis
Dr. Monty Pal:
Indeed. Yeah.
Dr. Leo Wang:
Um, the more we learn about the underlying genetics of these disorders, the more they sort of get subclassified as you, as you know, from your own work. Um, so now, you know, there's a new WHO classification of brain tumors, and there are many, many different types of brain tumors. And this one, you know, has now been subdivided into a couple different ones. But yeah, it's, it's a relatively, um, uncommon diagnosis, fortunately. Um, but unfortunately it's still a, a, a fatal one because of this revolution in, in genomics and genetic understanding of how cancers are driven. We now have, um, new and exciting therapies for these, for these tumors. Uh, actually there was a, an FDA approval for the first time ever for, for kids who have this tumor.
Dr. Monty Pal:
Hmm.
Dr. Leo Wang:
Um, it's called dova prone. Um, and, uh, that was largely led by academics who understood, you know, very early on that there were these set of compounds that uniquely were, um, effective in H three K 27, um, mutant gliomas. And so now, you know, it's, it's been FDA approved as FDA approved last year, and, and, uh, and we're really excited about that. Yes. Um, we are hopeful that that port tens, I think, a sea change in, in the understanding of and management for these disorders. Um, as, as you know, the first sort of targeted therapies for many other cancers were, you know, in the nineties, two thousands. Right, right. Um, you know, Gleevec and stuff like that. And so in, in some ways, we're sort of far behind the, the curve. Um, but I think this is just the beginning of, of opening the floodgates for those therapies
Dr. Monty Pal:
And those diseases. That's, that's exciting. And, and tell us about cell therapies in particular and their role in this particular space. You know, o one of the things that I've been so intrigued by in our overarching program here at City of Hope is, is this creep that we see of cell therapies of, you know, for instance, um, you know, some of the adoptive cell therapies in particular mm-hmm. Into solid tumors.
Dr. Monty Pal:
Mm-hmm <affirmative>. Yeah.
Dr. Monty Pal:
Uh, probably made the most headway in melanoma. But, you know, we've got some very active programs and prostate cancer that Tanya Dorf is running with Steve Foreman. You know, I've been involved in some kidney cancer trials. Yeah. Juan Viki doing some great stuff in colorectal. Yeah. Are we kind of at this place where we're ready to sort of penetrate brain tumors? Uh, like the, the use of the word penetrate that's, yeah. <laugh>
Dr. Leo Wang:
Advised, right. Um, yeah. So it, you know, I, I don't think of it as a creep so much as it a diffusion, right? So anytime there's a new technology, um, whether it's genomic technology or, you know, cell therapy or gene therapy, or even like, you know, in, in other fields like AI or, you know, compute or whatever, um, you, you prove the case in, in one area mm-hmm <affirmative>. And then everybody recognizes the potential of that thing. And then they're like, well, we wanna apply that to all these other things. So, um, I think, and I think you would agree that people like Steve Foreman, Christine Brown, Ben, but d have seen the potential of cell therapies for solid tumors, including brain tumors for decades, right? I mean, they've been working on this for a long time, but it's not until recently that we've been able to sort of start to unblock some of the critical obstacles to successful implementation. And, um, and I think that a lot of that really started here. Uh, you know, um, Mike Jensen, Steve, Steve Foreman, Christine Brown, um, Ben and Badi really led the way in, you know, first in human, uh, trials of, of CAR T cells for, for brain tumors. Um, and they had that landmark publication in the England Journal in 2016, which really did open the floodgates. You know, there are now, um, at last count, I think six or seven ongoing clinical trials in this country of CAR T cells for brain tumors mm-hmm
Dr. Monty Pal:
<affirmative>.
Dr. Leo Wang:
Um, and that was all started because of this one really this one patient experience, you know, right. Where, where they treated this patient, he had this unbelievable response. I mean, this is the kind of response that you show the images, and you don't even have to say anything, and everybody stands up and applauds. Right. Um, and when once people saw that potential, then the diffusion happened, they're like, oh, we should, we should all be doing this. Now that doesn't mean that there aren't still significant obstacles to making everybody like that patient, of course, right. But, um, but we're now seeing at, at least in, in my field, pediatric brain tumors. You know, we're seeing Stanford, St. Jude, Texas Children's, um, soon it'll be Children's National in DC and us all have ongoing clinical trials. Now, our clinical trial, um, is, is, uh, a multi center trial. We we're open at University of Michigan in Ann Arbor and also at CHLA down the street. Um, so, so patients can come to, to any one of those sites to get that therapy. Um, but, uh, but I think that we all recognize, again, that, that there is tremendous potential for these therapies to really improve the lives of patients with, with brain tumors. And, and I think, um, hopefully we'll get there soon
Dr. Monty Pal:
And, and maybe dive into some of the minutia around this therapy. Like, tell us about the targets and so forth. Uh, I'm really excited and keen on hearing about that.
Dr. Leo Wang:
Yeah. So I mean, um, you know, we could spend hours just on, on the minutia. Um, but the fundamental idea as many of your listeners will know about is that, is that chimeric anti receptor T cells, or CAR T cells are fundamentally this way of taking, um, immune cells, uh, t cells in this case, uh, which are the cells that normally kill viruses, uh, that are virus infected cells, um, and reprogramming them to recognize and kill cancer cells. And Car T cell technology really revolutionized how we think about and treat hematological disease, right? Sure. Leukemia, lymphoma has really changed the landscape. It's become not just a multi-billion dollar industry, but has, you know, legitimately changed the lives and trajectories of countless patients at this point. And so this I relatively simple idea that you, you know, your immune system's really good at killing things. Can we repurpose the immune system and retarget it towards cancer cells so that, um, so that we can, you know, we can, uh, really spark a, an, an anti-tumor immune response, um, has, has launched this entire field.
Now, this is not a new idea. Your immune system does this normally, most, most people by, certainly by, by my age, but probably by your age as well, <laugh> will have had, we're not that far apart, uh, will have had, um, cancerous cells, right cells, that, that something went wrong. They started proliferating, dividing outta control, but your immune system recognized that, uh, that wasn't supposed to happen and killed them. And, and you never developed cancer because your immune system worked. So in many ways, people who do develop clinical cancer, um, their immune system was unable to stop that, the, that we call that immune surveillance. And so there was a, a failure of immune surveillance. And so, you know, this is this idea that got the Nobel Prize, you know, uh, for Jim Allison, um, that, that if you can reawaken the immune response to cancer, that, that you can, uh, that's a, a potent weapon in your arsenal.
And so, um, so what people who developed chimeric anti receptor T cells did was to, to take patient, originally patients T cells, and then reprogram them to recognize specifically things on the cancer cells, and then put them back into the body, and then they just go in and search and destroy cancer. Um, and again, that's been transformative for leukemia lymphoma, not so much yet for solid tumors. I, I think there's a lot of enthusiasm about that Oh, yeah. Moving forward. Oh, yeah. As, as you know, uh, as a solid tumor person yourself, you know, solid tumors are different from leukemia lymphoma, right? They, they hide in a specific area of the body. They can weave these sort of cocoons around them. Um, they have their own vascular supply, their own blood supply, and then they can, um, develop these immunosuppressive elements, uh, within them that, that kind of put the immune system to sleep.
And so a lot of the work that we're doing now is focused on addressing those components. So a, we need to get the CAR T cells to the tumor, right? And you can do that in a number of different ways. You can inject it directly into the tumor. You can direct, you can inject it into the blood supply that feeds the tumor for me, for blood, for brain tumors. Um, you know, we inject the CAR T cells into the cerebral spinal fluid, the, the, the fluid that bathes the brain and spinal cord. Um, and that's based on work that came outta Christine Brown's lab and, and Crystal Michael's lab at Stanford showing that, uh, in preclinical models, if you deliver CAR T cells into the CSF, you need about, um, a 10th of the dose that you would need if you were delivering this, the same car T cells intravenously.
Dr. Monty Pal:
And, and nuanced question here, but do you still need all the same conditioning, chemotherapy, all the pre-treatments ahead of time?
Dr. Leo Wang:
Oh, I love this
Dr. Monty Pal:
Question. Yeah. So,
Dr. Leo Wang:
Yeah. Do we have like an hour? So this isn't, this is a very active ongoing debate. Okay. So we know that for, um, for CAR T cells that target, uh, leukemia lymphoma, you absolutely need what's called lymphodepletion, which is, um, chemotherapeutic preconditioning that sort of resets the immune system, clears out some space, allows the CAR T cells to divide, to grow, to ate Right. And not to Right. And
Dr. Monty Pal:
Gives it some room.
Dr. Leo Wang:
Yeah. It, some room. Exactly. I don't wanna say it's a, it's a burning question for me. And for the people who do what I do, like this is the, the kind of thing that keeps us up at night.
Dr. Monty Pal:
Yeah.
Dr. Leo Wang:
Um, is, is, do we need lympho depletion? Do we need preconditioning for solid tumor targeted CAR T cells one and two, does the route of delivery matter? So do we need lympho depletion for solid tumor targeted CAR T-cells if we're delivering them intravenously versus local regionally. Okay. So those are two very open questions. And, um, there is very good preclinical data from Christine Brown's lab, from Reisman's Lab, and from other labs that, that are very convincing that say that if you provide lymphodepletion for solid tumor targeted CAR T cells, it helps.
Dr. Monty Pal:
Okay. Okay. Okay.
Dr. Leo Wang:
Um, but a, we don't know if that's true in humans. And B, a lot of those studies were done with systemic delivery. So intravenous delivery of CAR T cells. So lymphodepletion acts to, like you said, clear out, you know, mixed space, but that's mostly in your, in your blood systems, your blood and your bone marrow. So if I'm injecting CAR T cells directly into the tumor itself or into, you know, the CSF, does that really make that much of a difference? One of the amazing things about, um, our ability to do these clinical trials and also to collaborate with others who are doing similar clinical trials. And here I have to say, pediatric oncology, um, you know, we talked about this a little bit. It is, it is a bit of a, a sacred space, um, in that, fortunately not that many kids get cancer.
Um, but because of that, we recognize that in order to learn as much as we can, we have to work together. Right? So, you know, I have colleagues on speed dial in Seattle, at Stanford, Texas Children's at St. Jude. We're talking all the time because we all have sort of parallel trials. And not only we're sending patients back and forth, like if our trial's full, we'll send in Seattle, Seattle's full, they'll send me that kind of thing. But also it's kind of like, you know, oh, we saw this thing on our trial. Have you seen anything like that?
Dr. Monty Pal:
Mm-hmm
Dr. Leo Wang:
<affirmative>. And, you know, I got a text the other day that was like, Hey, I, I've been going through our data and I think I see this thing. And I was like, wow, that's super interesting. 'cause I think we might be seeing something similar. And now we're talking about co-publishing the, you know, the, those data so that, that everybody can learn from it. To answer your question about whether lympho lymphodepletion is, is helpful and or required for a solid tumor targeted CAR T-cell delivered either systemically or local regionally, we're all talking all the time to try to answer that question. So, like, Stanford has a trial where they're treating kids with diffuse intrinsic ponting glioma and diff mid likely. So the D-I-P-G-D-M dmg, the
Dr. Monty Pal:
Same two diagnoses you
Dr. Leo Wang:
Referred to. Exactly. Yeah. They had one arm of their trial that included, um, lymphodepletion and systemic delivery, and then another arm of their trial that was, uh, intraventricular. So CSF delivery, um, and initially without lymph depletion, and then one with lymph depletion, Seattle has always done intraventricular delivery, so CSF delivery without lymph depletion. And we've always done, um, intraventricular delivery, so CSF delivery with systemic lymph depletion. Right. So, so between the three of us, we actually have sort of all of the bases covered,
Dr. Monty Pal:
Right? Right.
Dr. Leo Wang:
And so we've been able to talk to each other end, um, and, and figure out some, I think really not just scientifically interesting, but clinically important things. Right. So, so what I'll share, and, and this may be where we're getting out, you know, ahead of our, over our skis a little bit because it's not published data. Um, and so maybe our lawyers will have some, some issues with that <laugh>. Go ahead. But, uh, but what we're seeing is that, um, lymphodepletion does a couple of really important things, even if you're delivering the CAR T cells directly into the cerebral amount of fluid. So we know that the brain tumor microenvironment, like I said before, really immunosuppressive. And there's a thought that lymphodepletion would reprogram some of that immunosuppressive microenvironment. It's really hard to get serial brain biopsies from patients. And so we, we can't really go back to the tumor very effectively and say, okay, we gave lymph fi depletion, what happened to the tumor? Is it still immunosuppressive? Um, I think the field is moving in that direction, but it's, as you might imagine, it's a bit of a, um, it's a bit of a big ask.
Dr. Monty Pal:
It it's tricky, isn't it? Yeah. And, and you know what, please, you finish your thought first. I'll jump in. Um,
Dr. Leo Wang:
Uh, but, uh, you know, we're hopeful that that new technologies, like things like, you know, um, liquid biopsy will help to answer those questions. But putting that aside for now, none of, none of the trials that currently exist, um, mandate repeated biopsies. So, so we, we have proxy measures, we have, we can look at the CSF, we can look at the peripheral blood. Obviously we see the clinical, you know, progression, and we see the, the MRI imaging to see how these, these kids are doing. But what we have seen is that, uh, in three, at least three trials, patients who do not receive lympho depletion are develop, are developing anti-car immune responses.
Dr. Monty Pal:
Hmm.
Dr. Leo Wang:
So we're putting these things, right. So we take the tcell outta the patient, we reprogram the, to, to recognize and kill cancer. We do that by putting a chimeric and the gene receptor, uh, on the cell surface of the T-cell. So that's a receptor that's synthetic, it's engineered, and it's made up of some components that exist in, in biology, but other things that we invented. And so those things are foreign. And so it turns out that if you don't give lympho depletion, patients are developing, they're recognizing those parts of the construct as foreign, and they're raising the immune response against that. And we think that that probably has real consequences. So you're infusing these CAR T cells into patients, but their immune systems are fighting that infusion rather than fighting the cancer. And so that attenuates the efficacy of these CAR T cells, probably, we don't know that for sure yet,
Dr. Monty Pal:
But I, I think that se equates to pretty major, you know, finding, I would say it's something that, you know, I personally have struggled with in the renal cell niche, right. In my CAR T trials that I've run. You know, and, and I would love to say to patients, you, you don't need to get that chemotherapy, because I do think it really changes the therapeutic index
Dr. Leo Wang:
Mm-hmm. Of these compounds. Mm-hmm. Yeah.
Dr. Monty Pal:
Entirely.
Dr. Leo Wang:
Mm-hmm. So are you, are you giving lymph depletion in
Dr. Monty Pal:
For the most part, yes. For the most part, yes. But we have toyed around with some cohorts where without and di I think the dynamics change a little bit.
Dr. Leo Wang:
Yeah. So, so there's a flip side too, which is that one of the things that we've seen on our trial is that, um, in patients who are not receiving lymph depletion, when you infuse CAR T cells, you actually train endogenous T cells into the CSF. So, so normally, as you know, you shouldn't have T-cells in your CSF, right? Right. If you have T-cell in your CSF, you have meningitis. That's a bad thing. They're fighting some sort of effect.
Dr. Monty Pal:
Sure.
Dr. Leo Wang:
But what we're seeing is that over time, as we infuse CAR T cells into the CSF over patients, they're getting, they're pulling along normal T cells. Right. And so those things go away if you lymph deplete. So an open question is what those T cells do. Um, and we have seen that some of those T cells, uh, are reactive against the car. So that's bad. We've seen that others of those T cells are not, they're, they're activated endogenous killer T cells that are not CAR T cells. They're getting pulled into the mix by the CAR T infusion. And if we could repurpose those cells to kill cancer cells, then we'd be doing ourselves a favor.
Dr. Monty Pal:
That's really interesting. That's, so, you know, I have to say that there are few labs perhaps as well set up as yours to study these types of phenomenon. My understanding through, you know, reviewing your work over the years is that, you know, you really have a beautiful sort of translational setup here where, you know, you're running these trials, you know, you've got the, you know, sort of dynamic biomarkers in patients, and you're able to kind of take those directly to the laboratory and, you know, through both in vitro and vivo modeling, really sort of dissect some of these phenomena. Is that fair?
Dr. Leo Wang:
Yeah. I think that that's, that is the, in my opinion, that's the perfect use case for a physician scientist mm-hmm <affirmative>. Right? You know, you're, you're seeing the patients, you're putting them on trial. They're generously sharing all of their data with you that you get to take back to your lab and study to figure out what's going on so that you can figure out how to make better therapies for the next generation of patients. Right. And, um, that's super complicated. Uh, and it takes a lot of goodwill and a lot of very dedicated, very passionate people across that whole thing. But yeah, I think there are not that many places that are uniquely positioned to do that. City of Hope is one of them. Um, and I feel just incredibly fortunate to be a part of that. I mean, this is, this is something that this predated me, will postdate me. You know, this is something that City of Hope has made its name doing for forever, right. Patient-centered
Dr. Monty Pal:
Care and research. It, it's definitely a neat model. I, I wonder if you could share with the audience maybe, you know, one of the key findings from your lab within the past two, three years or so that really, you know, draws from these clinical experiences that we've had with patients.
Dr. Leo Wang:
Yeah. I think, um, there are a number of things that I think that I'm really proud of, uh, my lab for, for doing. Um, before I get there, I think there are a number of things that I'm also really proud of City of Hope for enabling our, our work to do. Um, and, you know, here City of Hope writ large, but also Christine Brown, Steve Foreman, you know, the, the T-Cell folks. Yeah, yeah. I mentioned that our trial open at University of Michigan at CHLA, and it's, it's really the only trial of its kind that has that, that reach. Right. So, so there was another pediatric brain tumor CAR T trial that was open at a number of different centers, um, that was funded through, uh, the Pediatric Brain Tumor Consortium. The PD PBTC, which was supported by the NIH, its funding was cut earlier this year. And so this trials all stop.
Dr. Monty Pal:
Okay.
Dr. Leo Wang:
Um, and so now our trial is the only multi-site CAR T trial for children with brain tumors. Oh, gosh. Wow. Which is, which is a huge problem. Um, you know, because we all recognize that we need to be able to do these things at multiple different places that we can learn. Um, but even before that, uh, that trial, um, which was run by Chauvin AYA at Texas Children's, um, that trial was an intravenous trial. So you gave one dose of CAR T cells through the vein. Um, and it's for technical reasons, much easier logistically to do that kind of a trial to ship those cells. Our trial, uh, is as, as we've talked about, delivering the CAR T cells directly into the CSF, and that's a much more challenging logistical trial. So it was a huge and very heavy lift to, to make that happen for Michigan CHLA.
But we were able to do it. And, um, we did that largely by leaning on the expertise of Seattle Children's, where colleagues had piloted or pioneered some of the technologies that would allow us to do that. Now, they didn't open it, you know, at multiple different sites, but they were able to go to the FDA with some process improvements that we then borrowed Okay. In, in our process. And that allowed us to take the next step and now deliver these cells at a variety of different sites, you know, across the country. Um, so, so that is something that actually I'm incredibly proud of. 'cause it was a lot of work. It was very difficult to do. Um, and, and honestly, it's not something that, um, you know, that doesn't lead to a publication or a grant or a, a news story, but it is critically important in making these therapies a more accessible.
And nobody in the Midwest would've been able to get these therapies until, you know, university of Michigan came online. But also really important for how we bring these therapies to the next level. And so our team at City of Hope did it 'cause it was the right thing to do, you know, and, and, um, and you, you won't see that in, you know, whatever the New York Times or the Wall Street Journal or the, you know, the lay press, you won't really even see that in New England Journal or science or whatever. And it's not gonna get a podium presentation at asco. Um, but, but super important. I'm really proud of that. Um, that's largely the work of people like Jamie Wagner, um, who's the regulatory, um, person within the, what we call the T-Cell Therapeutics research, um, laboratory. So that's, you know, Steve and Christine's, um, uh, infrastructure. Um, but she worked tirelessly. She and her team continued to work tirelessly behind the scenes to get the kinda stuff done. And you may never hear about it, you know, um, and
Dr. Monty Pal:
Which is why I wanted to bring it up. That's awesome. And, and I assume on top of this, like major Herculean, you know, task of delivering cells, you know, on, on, on the other side of it, right? By these collaborations, you probably have an opportunity to pull a lot of translational specimens back into your laboratory. Is that right?
Dr. Leo Wang:
Absolutely. Yeah. Yeah. So one of the great things about our collaboration with the University of Michigan is that has actually spurred a couple of really interesting, um, scientific, uh, projects. So, so the, the group we're working with in Michigan is, um, one of the investigators, Carl Oshman, who's a really well known, um, D-I-P-G-D-M-G sort of biology researcher.
Dr. Monty Pal:
Okay.
Dr. Leo Wang:
Someone in his lab recognized that. So, so, um, okay. So these, these tumors are driven by a mutation called H three K 27 m. What that does is it epigenetically deregulates these tumors. Um, and so the, the chromatin structure changes, which normally, you know, chromatin is the open or closed, and if it's open then it's accessible and you can read it and you can transcribe it and make our mRNA, which then turns, turns into protein. Um, but if it's closed, you can't.
Dr. Monty Pal:
Sure.
Dr. Leo Wang:
And, uh, what the H three K 27 M mutation does is it messes with all of that. And so things that are supposed to be open or closed and things that are supposed to be closed are open. And so you end up with this dysregulated transcriptional program that then in part leads to, to cancer. But one of the things that Carl's group recognized was that this mutation, this H three K 27 M mutation, it actually upregulated the expression of IL 13 receptor alpha two, which is the target of our car.
Dr. Monty Pal:
Oh, no kidding. Okay.
Dr. Leo Wang:
And we wouldn't have known that had we not started working with them. 'cause they have all this, this data that they've been working on for a really long time. So they just took a look and they're like, yeah, this is really interesting. And so now we have this, this tie-in where our labs jointly are working on, you know, what is the linkage between this mutation and upregulation of, of the target? And can we leverage that in, you know, because Carl's developing, um, therapies like small molecule drugs that, that target this mutation and the downstream transcriptional consequences of that mutation. And are there ways that we can use that knowledge to increase the expression of our car target so that we can be more successful at, at killing these tumors?
Dr. Monty Pal:
Brilliant. Brilliant. I I love that. And I mean, it's target validation, right? I mean, you've demonstrated that this HK presumably histone related mutation, right? Yeah, yeah. Is, you know, kind of, uh, driven this abnormality in IL 13 signaling and boom, you've got a CAR T targeting it, right? Yeah. So that's,
Dr. Leo Wang:
So that's really
Dr. Monty Pal:
Exciting. Yeah. I love it. No, that's great. See, we've, we probably could do a whole podcast on CAR T, we could do a whole podcast on the Wong family, right? <laugh>, we, I think we decided we're gonna do that at some point. We could probably do another full podcast on gene therapy too. Right. So you, you lead our efforts at City of Hope related to gene therapy. You know, this is something that if you, if you follow biotech, probably one of the most exciting new frontiers right. In the field of medicine, you know, writ large. Um, tell us about what City of Hope is doing in the gene therapy space that you're particularly excited about. Just, you know, a couple of highlights. Yeah. So, um,
Dr. Leo Wang:
You know, I wouldn't say that I, uh, so I'm the clinical director, uh, of our, our director of our clinical gene therapy program right now. I wouldn't say that I lead gene therapy at City of Hope. I mean, that, that title really belongs to John Zaya, um, who for a long time was a, uh, a mentor, um, and colleague, the Department of Pediatrics. And, and John, um, you know, is, is just a, a titan in the field of gene therapy. I was one of the first people to, um, to work on gene editing for things like HIV and, um, you know, for, for other infectious diseases like CMV collaborated with Steve Foreman, um, for a long time on, on developing cell therapies to target, um, infectious diseases. Uh, John unfortunately passed away, uh, not too long ago, by the way, was the director of the Alpha Clinic, um, before me.
Um, and so that, you know, he really is, I think the, the father of gene therapy at, at City of Hope, and I am, uh, just trying to, just trying to make him proud. I think there is a lot, you're right. I mean, gene therapy has been around for a long time, uh, you know, uh, around 50 years clinically. Um, and it's had fits and starts. And, you know, when I was a resident in Philadelphia in pediatrics, I worked with a woman named Kathy High who was pioneering gene therapy for hemophilia, um, using adeno-associated viral vector, so AAVs. Um, and then when I was a fellow in Boston, um, I worked with Don Cohen, who's at UCI and David Williams, who's at Boston Children's, uh, on a lentiviral based gene therapy for a disease, um, called X-linked chronic Granulin disease, uh, XCGD, which is a, um, immune deficiency in boys.
Um, and so it's been, you know, it, it's been around for a really long time, but you're right, that in the past few years, there's really been this explosion, um, of, of interest in clinically applied translational gene therapy. And that is, I think, due to a number of, of confluences, right? There is, on the one hand, you've, people have developed, people like David Lou at, at the Broad at Harvard have developed these phenomenal new technologies in Alex Morrison at UCSF, of, of really going in and with unbelievable precision altering, just even a single base, right? You can just edit one thing, um, which we never used to be able to do before. Uh, and so a lot of that's built on CRISPR Cas nine. Um, uh, you know, that came out obviously out of, uh, Jen Doudna and Emmanuel Sharpe's work, um, and Feng Jang at MIT.
But, but that has become sort of these precise surgical genome editing tools that are now you're seeing, um, people really excited about applying in patients. The, the clearest indication of that, um, or the clearest use case of that is in patients with single gene defects, single gene disorders, like sickle cell disease, where there's just one base that's wrong. Um, and that causes this terrible devastating disease called sickle cell disease. Um, and there are lots of different ways to fix that. Um, and, and fortunately now we have two FDA approved gene therapies for sickle cell disease. They actually take very different strategies, um, in how they fix the disorder. So the technology that came out of a company that used to be known as Bluebird Bio and now is known as genetics, is a lentiviral based technology where they're introducing a full copy of an antis, sickling beta globin, okay.
Into hemapoietic stem and progenitor cells. So those cells, once they turn into red blood cells, they're protected against sickling, but they've introduced a whole new protein, and they use a len, they use a lentivirus. Um, and that's FDA approved, and it's very, very effective. The other main technology, uh, which is backed by a company called Vertex before that, um, CRISPR TX is a CRISPR based technology where there's a genome edit. And so they take the hematopoietic stem regenerative cells, the blood forming stem cells, and they edit very precisely a region of the genome that actually regulates what's called hemoglobin F. And if you do that, you can cause red blood cells in grownups to create a lot of this fetal hemoglobin. So normally fetal hemoglobin is produced by babies, infants, and it goes away as you when you're born. Um, but that hemoglobin F is protective against sickle cell disease.
And so if you have high hemoglobin f generally, even if you have sickle, um, cell, the sickle cell genotype, you don't have clinical signs of disease. There's a whole population of, of people called, um, HPFH, hereditary persistence of phenyl hemoglobin. Those patients generally don't have sickle disease, even if they have the sickle genotype. And so what Vertex figured out was how to edit a particular, um, enhanced region of a gene called BCL 11 A. And in those patients, now they have much higher levels of hemoglobin FNA, they are also cured with sickle cell disease. So this is just two very, very different ways of getting at the same problem and curing the same disease. And they're both now FDA approved. And I'm very proud to say that our team at City of Hope was able to bring both of those therapies to patients here at City of Hope. We were the first, um, first center west of, uh, Texas to, to offer that therapy once it was FD approved. And, um, and, you know, we now have a very, um, strong, I would say, explosive program where we're, we're able to cure these patients. That's led by Michelle Wong and Pediatrics and Pam Becker on the adult side.
Dr. Monty Pal:
I see. You know, I have to tell you, this is something I'm, I'm, frankly, incredibly proud of too. It's interesting you mentioned CRISPR Therapeutics, you know, working ultimately, you know, the Vertex and develop this technology. I was actually working at CRISPR on their car T trials in renal cells. So I saw a lot of these developments happening, uh, in parallel. Um, and, and, you know, I did think, gosh, when it comes to implementation, how are we gonna make this happen? And then when I heard you share the news internally that we were getting this technology moved along here at City of Hope, it just made me, you know, really, really proud to be part of a place that, you know, has early access to these types of technology. And I have
Dr. Leo Wang:
To tell you, Monty, this again, was an example of us City of Hope deciding to do Right thing.
Dr. Monty Pal:
Yeah.
Dr. Leo Wang:
Um, you know, the, the, the sad reality is that these therapies are super expensive. They're very
Dr. Monty Pal:
Millions, right?
Dr. Leo Wang:
Millions. Yeah. It's like three, three point, uh, 3.1 million, um, uh, for the Bluebird product or the genetics product. And, uh, 2.8 I think for the Vertex product. And, um, um, you know, it was gonna be really difficult to, to provide those therapies because we have to, we have to buy the product. So, you know, that's writing a check for millions of dollars, and then we don't get reimbursed for that, um, sometimes for months. Um, but you know, here I have to give credit to Susan Brown when she was here. Um, Kelly Tomlinson, uh, Vince Jensen, Steve Peterson, and Sorrow Armenian for really just making the case that this was a, a moral imperative, um, for our patients. And despite the fact that we didn't have a solid business case that was gonna make our accountants super happy, um, they're like, we think that this is a core part of our mission. This is what we need to do. And so they gave us permission, they gave us the green light, and we did it. Um, that's, that's been one of the most gratifying things for me in my career at City of Hope about being here, is that, uh, you know, we, we always put patients first and, and, um, we make decisions that allow us, I think, to, to really push the envelope and, and do things that are innovative and bold, um, and write, uh, for, for patients.
Dr. Monty Pal:
Indeed. You know, I've, I've, I've held you hostage here for a long time. We've covered so many topics. I mean, you know, the gene transfer therapies we talked about Car T again, I'll, I'll lean on the Wong family, who I'm still very intrigued by. We
Dr. Leo Wang:
Haven't talked about the Paul family <laugh>. I mean, I wanna hear more about, about your, your garage band, literally Garage band,
Dr. Monty Pal:
Right? Right. Yeah. We're, we're gonna, we're gonna trade places for this on a, on a subsequent podcast and do that. But, you know, we always wrap up this podcast by asking our guests what I think is actually a tough question. The title of this podcast is On the Edge of Breakthrough Voices of Cancer Research. And, and that term on the edge of breakthrough, I think it came with a lot of thought. What does that mean to you being on the edge of breakthrough?
Dr. Leo Wang:
I, I think there are very few true discontinuities in nature, right? Most of the time something that you think of as a sharp edge. When you get close enough to it, it's actually not, it's actually a continuous surface, right? Um, and so, you know, you can always like, take a derivative. It's not, it's not an un um, it's not a cusp that you can't take a derivative of because there's no slope that it actually is a smooth surface, continuous surface. And I think that we've, we've talked a lot about things that seem like breakthroughs seem like cusps, but if you actually are in it, you realize it's been going on for a long time. Gene therapy has been, been here, been in and out for 50 years. Cell therapy has been going on for decades. So, so we stand in many ways on the precipice of amazing new innovations, inventions, cures, therapies. But when you actually get into the weeds, you realize the groundwork for these things has been being slowly built over generations, scientific generations. Right? Like Steve Foreman, John Zaya, the people who came before them, they've, you know, Jim Allison, they've been, they've been doing the work slowly, continuously over decades. And, and you and I now get to stand on their shoulders and proclaim from the rooftops that we've cured sickle cell disease. Right. Which is a breakthrough. It's a revolution.
Dr. Monty Pal:
Yeah.
Dr. Leo Wang:
Right? But that's not an edge. This is something that has, people have been slowly and laboriously working on it. And Stewart and here would be very upset if he knew that I didn't call him out here. Um, you know, people have laboriously been working on this for, for entire careers, right? I, I feel immensely privileged to be able to stand on the edge of what looks like from the outside, what looks like a precipice. Right? Looks like we're about to leap into the, the great beyond the void of infinite possibility, and also to recognize that that's not what it is at all. This is generations of painstaking work by people who are far smarter, far more accomplished than I am that I get just to carry across the finish line. This is what we did with the Brain Tumor CAR T trial, right? I didn't build that technology. Christine and Steve and Mike Jensen, they worked on that for decades before I got here.
Dr. Monty Pal:
Sure.
Dr. Leo Wang:
I just was the person who had that, the privilege of bringing it into the clinic and the privilege of talking to patients about this revolution, right? Similarly with the sickle cell gene therapy, I didn't build that, but I was able to bring it to patients. And I mean, the Alpha Clinic's the same way. You know, we have all these great therapies and, um, it seems like all of these new things, whether it's in vivo gene therapy or, you know, um, AI or, uh, personal avatars like twinning, you know, all these things seem like cusps like revolutions, and, and they are, they are truly revolutions. Um, but it's incredibly humbling for me and grounding to recognize that, that that edge is actually a continuous surface.
Dr. Monty Pal:
Beautiful. I, I, I love that. I'm not supposed to do this, Leo, but if I were to rank all the responses to that question I've gotten on this podcast, that might be the best for, for so many reasons, did
Dr. Leo Wang:
You hear that Dr. Armenian
Dr. Monty Pal:
<laugh>, you brought in calculus, you're talking about, you know, derivatives, and I was waiting for integrals and law of LA and foyer transforms. But, you know, may, maybe that's for a subsequent episode, Leo, that's for this Russ Rock episode. Yeah, there you go. We'll bring Russ our, our mathematical oncologist on here. But Leo, honestly, tremendous, tremendous conversation. I thank you so much for being here, and I hope you'll come back again soon. It's been an absolute pleasure.
Dr. Leo Wang:
Uh, but can I, can I flip the script just for a second before we end? I, I want to you ask that question all the time of all of your guesses. Yeah. I've never heard you answer it.
Dr. Monty Pal:
Oh, gosh. On the answer. This, this is tough. You're not supposed to do this, Leo, to be honest, <laugh>. But, but what I will say is that, you know, I think that on the edge of breakthrough to me just means walking through this campus, you know, truthfully, as I look to every single laboratory that I pass by, as I look to every single clinic, I'm seeing things that are being done that are gonna represent the standard of care tomorrow. You know, whether it's the IL 13 directed CAR T that you're working on, whether or not it's the stuff that you know, your wife Stacy's doing in the area of precision oncology to really sort of bring this to every patient. You know, whether it's the stuff that I'm seeing in my own clinics with, you know, uh, uh, uh, standardized, uh, targeted therapies for renal cell. Um, I think it's just happening all over the place here. So on the edge of breakthrough to me means, you know, being on the City of Hope campus.
Dr. Leo Wang:
Love
Dr. Monty Pal:
It. Love. It's now number
Dr. Leo Wang:
Two.
Dr. Monty Pal:
<laugh>. There you go. <laugh>. Thanks a a lot. Thanks so much, Leo. So much has been happening lately in terms of, you know, reforms, in terms of how we think about drug therapy and approvals and so forth, that I, you know, I, I see both sides of a change that's been proposed to really sort of limit the number of studies that are necessary to move towards a drug approval, right. Going from, you know, the bare minimum requirements and, and perhaps, you know, sort of trimming it down, um, on the plus side, right? You know, you, you might potentially see this as a process that expedites time from, you know, the drug in developments hands to the patient on the other side. You know, you might see, you know, safety concerns around accelerating the process too much. What, what are your perspectives on this?
Dr. Leo Wang:
This is a great, and really time in question, I think is something that we're all struggling with. And, and, and as you know, you know, um, we get this patient, we get this question from patients all the time, right? Like, why can't I have this thing that, that I'm really excited about? Uh, and why is the FDA keeping me from that? And it's a really difficult question. I have patients all the time. So pediatric brain tumors, the particular brain tumor we're talking about the DIPG, the brainstem glioma. There, there are no curative therapies. There is now one FDA approved therapy that's not a cure. And they come to me all the time saying, like, I read about, uh, you know, this combination of six drugs that this person in Germany is advocating, I want do that. Right? And, and I'll say to them, well, you know that that's not proven, and this person will happily take your money to give you this thing that we all know is not proven. And I had a mom say to me, what choice do I have? How am I not gonna do that? It's just money.
Dr. Monty Pal:
Mm-hmm <affirmative>.
Dr. Leo Wang:
Right? And so this is a really, really important thing that we need to keep in mind, and we have to hold both parts of it simultaneously, which is really challenging. On the one hand, um, we do need to protect against dangerous things, right? You see stem cell clinics pop up, you know, in this country and certainly in other countries that will gladly take people's money and, and sometimes will cause them serious harm, right? Even death. And so there has to be some protection against or regulation of that. On the other hand, I think there is this recognition that the drug approval process, particularly for patients who don't have other options who are in rare populations like my patients, it is too slow. You cannot run a conventional, you know, phase two, phase 3000 patient trial for a new drug for patients with pediatric brain tumors.
You, you're never gonna enroll that trial. So we need to find a different way. And, and I will say, um, I think that the sentiment is a really good and really important one. We need to find a better way of figuring out how to get the right drugs to patients quickly. We also need to be able to figure out how to protect patients from harm from people who don't have their best interests at heart. And I think it's great to say, you know, we're gonna move away from a lot of this sort of cumbersome red tape bureaucracy that's sort of grown up in our regulatory agencies that I think maybe is, you know, a product of just history or a product of an era when therapies looked different, right? So, so, you know, cell therapies are super different 'cause each one's individual versus like a drug, right?
Where you could just make kilograms of it and then just double it out. So we need to, we need to modernize our thinking about how we, how we get drugs developed, therapies developed, and get them patients. Um, the other thing that I think bears saying is that there is a lot of uncertainty, a lot of, um, whiplash around how that's being rolled out, which is, which is really difficult. And I think challenging. Uh, you know, the FDA had a round table, um, a few months ago with leaders in the cell therapy in gene therapy space, which I thought was great that they had done that. Um, but the person who was one of the heads of that from the FDA side, VA Psad, who was the head of, of, uh, Siber at the time, then lost his job, uh, and then very quickly got his job back again. So in that kind of climate, it is, it's very difficult to know what's gonna happen, you know, next week, next month.
Dr. Monty Pal:
Yeah.
Dr. Leo Wang:
Um, and, and we need to be able to have a, some sort of certainty so that we can at least make plans about, about how things are gonna look.
Dr. Monty Pal:
Indeed. Indeed. Absolutely. You know, it's funny, I was just at, um, headquarters of asco, American Society of Clinical Oncology a couple weeks ago, and I was with, uh, Rick Paster, right? Yeah. And, uh, you know, I've
Dr. Leo Wang:
Had, people are really excited about this.
Dr. Monty Pal:
Yeah. <laugh>, I, I have to tell you, I mean, I, I was thrilled to hear that he'd be, you know, potentially heading up Cedar, and of course, news came out yesterday, right? That he's retiring, he's stepping down, he's not taking on the position. So there's, there's, you know, a lot of, I didn't know that. Oh, okay. You just revealed that to me. <laugh>. Wow. Yeah.
Dr. Leo Wang:
Yeah. So there's a lot of that, right? I mean, I think it's tough. You know, Tony Lata from the Farber, who now is heading up and
Dr. Monty Pal:
You must know him well from your, I
Dr. Leo Wang:
I don't know him. Well, Farber okay. But I know
Dr. Monty Pal:
Him.
Dr. Leo Wang:
Um, and he's a great scientist and a, and a, I think it, you know, he's a very strong moral fiber, so,
Dr. Monty Pal:
Okay.
Dr. Leo Wang:
You, you, it is exactly what you're saying right there. There are, there are people, you know, that I think they all wanna do the right thing. I think not supposed to do the right thing. I think V Psad wants to do the right thing. And, um, I think one of the challenges is that there are lots of sort of mm-hmm <affirmative>. Calcified, you know, conservative processes that have grown up in government bureaucracy that probably shouldn't be there anymore. Um, but I think we need to figure out how to, how to modernize those structures without losing, you know, the ability to really do good quickly.
Dr. Monty Pal:
Yeah. Makes perfect sense. Maybe on what I'll call, you know, a more positive note. You know, one thing that I know that you and I both feel strongly about is training, right? And, you know, I think that training we often refer to as the time that you spent in med school or residency, but indeed, I mean, I think it starts when you've got, you know, kids who are the same age as my own 11, 12, 13, right? We've really gotta start introducing them to the sciences, you know? Absolutely. Very early on.
Dr. Leo Wang:
And it never ends. I'm still in training.
Dr. Monty Pal:
Yeah. There you go. That, that's a great way to think about it. Uh, what are your thoughts on, on STEM and the necessity of this as we think about, you know, revised curriculum and so forth in the modern age?
Dr. Leo Wang:
Yeah, that's a, that's a great question. Um, and, and here I, I'll, I'll disclaim, uh, which should be clear, I'm not an education expert, right? I don't, you know, I don't do education for, I mean, I teach as part of my career, but I don't have a PhD in education theory or anything like that. So, um, I think it's a very complicated question, and it's a complicated question at every single stage of the pipeline. We know without a doubt that we have a very leaky pipeline, both in the clinical sciences, clinical medicine, and in research science. Right? We are losing people at every step of the way. And, um, and I think we, we need to address that overwhelmingly, the people that we lose along the way are, uh, the people who don't have the resources or the privilege to stay in the pipeline. And so what you get out is different from what you get in, right?
We we're losing women, we're losing minorities, we're losing, um, you know, underrepresented folk in our field, particularly in the basic sciences. Uh, and so, um, we need to do a better job of making sure that we support, uh, diverse perspectives so that when we finally are, you know, hiring new professors and stuff like that, we have people who can bring a whole range of human and scientific experience to bear. 'cause otherwise, we're not gonna ask the questions, right. Um, that we need to ask. I don't have solutions necessarily for how to do that. Uh, I think we need to provide resources and we need to provide mentorship, and we need to provide, you know, support for those people. Uh, um, and it, it can't just be, um, it can't just be, you know, here's your mentor, here's your pi. Um, it has to be, uh, well, for, for, for example, actually when I joined Fellowship, I had two young kids.
And, um, my fellowship didn't include childcare, and we had grossly underestimated how much childcare was gonna cost in Boston. And so all of a sudden, uh, we were left with a situation where, you know, we didn't have very much money at the time, and our childcare situation followed through, and I had no idea how to solve the problem, um, because I was gonna need to be working as a fellow, you know, what, how an insane amount of time, right? And Stacy was in her first faculty position, and my fellowship director was like, okay, well, you know, why don't I make a few calls and see if I can get you into like a Bright Horizons or something there, you know, some equivalent of that.
Dr. Monty Pal:
Sure.
Dr. Leo Wang:
And, uh, I can give you, uh, I can't remember how much it was, it was like, not a lot of money, a couple thousand dollars, will that help? And, and that for me at that time was the difference between drowning and not drowning.
Dr. Monty Pal:
Mm mm.
Dr. Leo Wang:
Um, and that's not something that you see, right? I mean, that's not something that you can program into a training program where it's like, oh, we're gonna figure out what your specific vulnerabilities are and address that. Um, but it is something that we need to do, you know, whether it's, um, childcare, elder care, you know, whether like some of our graduate students are sending money back to their families, right? Right. And like a graduate student stipend is not a lot of money. And so we need to think about those sorts of things holistically. And I think our, our graduate school does a phenomenal job of that, um, really, really strong. David Ann and Mark La Barge and Sarah Banister and that team, they're really good at, at understanding what the pressures are, the stressors are for, um, for
Dr. Monty Pal:
These young people coming into these schools. So really individualizing it, right? I mean, making sure that, you know, you're, you're really looking into the heart and soul of your student, your grad student, your postdoc, et cetera. Yeah. And making sure they, they have the ts crossed NIS dotted in their, in their non-academic life.
Dr. Leo Wang:
Exactly. Exactly. And that's a different question I think from workforce training. You know, part of the Alpha Clinic's mission is to, to do workforce training, right? Mm-hmm <affirmative>. Because we need to train the people who are going to manufacture and deliver these complicated cell and gene therapies to patients, and we don't have enough of them.
Dr. Monty Pal:
Right.
Dr. Leo Wang:
And, and there, I think, um, you know, it's, it's a, a sort of a totally different set of challenges and questions. Um, when you think about our current education system from, you know, elementary all the way through, I think we are again at a, what seems like a cusp, what seems like a precipice between the old way, a conventional way of, of education and the new way of education. You know, we're increasingly seeing as, you know, that uh, college educations are being sort of less of a, um, a marker of, of a predictor of success than they used to be. And I, I think we're seeing an increasing gap in, in available jobs and, and what it means to be a skilled versus an unskilled worker. And obviously everybody's scared about automation and stuff like that. Yeah. So, so in thinking about how we refashion education to incorporate things like AI and automation so that we position our young people to take advantage of not the marketplace that existed when we were in school, but the marketplace that will exist when they are ready to enter the workforce, that's super important.
And again, here, way outta my depth, I'm not an education person. Um, but what I'll tell you is in the workforce training portion of the Alpha Clinic, you know, a lot of what we're doing is, um, I won't call it vocational training, but it's highly skilled training. And we're taking advantage of things like virtual labs so that we can teach people the highly complex set of skills and techniques that they need to learn to make themselves marketable for a position in a manufacturing facility like Avi Ons here at, at City of Hope, where they can make these really intricate, delicate living therapies for patients. So I think we need to do more of that.
Dr. Monty Pal:
Brilliant, brilliant.