In this episode of On the Edge of Breakthrough: Voices of Cancer Research, Christine Brown, Ph.D., Deputy Director of the T Cell Research Laboratory at City of Hope, joins Monty Pal, M.D., F.A.S.C.O., to discuss how years of research in glioblastoma, one of the most aggressive and difficult brain cancers, are helping scientists rethink how CAR T cell therapy could effectively treat solid tumors.
In this episode of On the Edge of Breakthrough: Voices of Cancer Research, Christine Brown, Ph.D., Deputy Director of the T‑Cell Research Laboratory at City of Hope, joins Monty Pal, M.D., F.A.S.C.O., to discuss how years of research in glioblastoma, one of the most aggressive and difficult brain cancers, are helping scientists rethink how CAR T‑cell therapy could effectively treat solid tumors.
Dr. Brown shares lessons learned from treating patients with few options, including how tumors change over time and how the brain’s environment can limit immune‑based treatments.
The conversation explores Brown’s early leadership in delivering CAR T cells directly into the brain, rather than through the bloodstream. The episode delves into her key clinical experiences that revealed both the potential of CAR T‑cell therapy and the challenges of making clinical responses last.
Dr. Brown explains new up and coming approaches designed to improve durability and effectiveness, how these advances could extend beyond cancer to autoimmune diseases. She returns to a simple point: studying how real patients respond—what works, what doesn’t, and why—will shape every next step in her research.
Dr. Monty Pal (00:00):
I'm Dr. Monty Pal from City of Hope, and this is On the Edge of Breakthrough: Voices of Cancer Research. Each episode, we bring you the minds behind the science, the stories behind the data, and the breakthroughs that could change everything. Let's dive in. Welcome back, everyone. I'm so thrilled today to have Dr. Christine Brown, who's the deputy director of our T-cell research laboratory here at City of Hope. She's also a professor from the Department of Hematology at our institution. And gosh, just a real legend, if I may say, in the field of CAR T-cell therapies. And we're gonna get into the weeds of why, but thank you so much for joining us today, Christine.
Dr. Christine Brown (00:42):
Well, thanks for the invitation. It's fun to be here with you.
Dr. Monty Pal (00:45):
Totally, totally. You know, you've had such an interesting career. I saw that you went to Santa Clara University for college. Is that right?
Dr. Christine Brown (00:53):
That's correct.
Dr. Monty Pal (00:54):
A- and are you a California girl from the start? Where'd you grow up?
Dr. Christine Brown (00:57):
Um, believe it or not, I have been in California most of my life. So I grew up in the Bay Area, went to undergrad at Santa Clara, and then graduate school at Berkeley, and now here at City of Hope.
Dr. Monty Pal (01:09):
And with one detour in between, am I right? You were at Penn State for your postdoc, is that right?
Dr. Christine Brown (01:14):
Correct. So I did my, um, postdoctoral fellowship with Jerry Workman, who's a Howard, who was a Howard Hughes professor, and, um, that ... A great mentor and a great experience. But yes, I took a little break from California just to do my postdoc.
Dr. Monty Pal (01:30):
It- it's really a vortex. So I, on the other hand, have never left. You know, I did re- med school, residency, fellowship, and so forth, and the longer I stay, the long- the further sucked in I feel.
Dr. Christine Brown (02:00):
Yeah, I mean, it's a really good question because it actually was quite late for me. Um, my training at Berkeley, my postdoctoral fellowship was in basic cell biology, understanding, you know, gene regulation, both at the RNA and pro- um, chromatin level. And I came out of my postdoc with several high profile publications, a first author science paper, and I was gonna start my own lab. Um, that's what I wanted to do. But I had a two-body problem. My husband took a job in the Southern California area, and I, um, was starting a family. I was pregnant at the time, and so I was really at a crossroads of exactly what I wanted to do, what I could do in the Southern California area. And during that time, when I was thinking of interviewing for my own laboratory, um, I met Mike Jensen and learned about CAR T-cells in the early 2000s before everyone knew what CAR T-cell therapy was, and I was in awe.
(03:05):
You know, how can you reprogram the immune system to recognize cancer and genetically reprogram, you know, uh, how, you know, how the immune system thinks and sees cancer. Um, and so I thought, well, this is an amazing experience. I've never been so translational, but there's still such a basic science side to CAR T-cell therapy, understanding the tumor, understanding the immune system and how to apply it to patients. So in 2002, I came to City of Hope and I haven't left.
Dr. Monty Pal (03:40):
It's interesting, because there's a couple of folks who have been on this program that have been here at City of Hope for, for decades. You and I came roughly at the same time I was, I got your- I think at the same
Dr. Christine Brown (03:48):
Time,
Dr. Monty Pal (03:48):
Yeah. Yeah, in 2006. So a couple of years later, um, you know, but of course I, you know, sort of went in a very clinical direction. You know, you've really sort of, I think, straddled the line between a lot of our, you know, sort of clinical trials and bench-based research. Uh, when you started in Dr. Jensen's group, um, you know, what was the main focus at that time? I realize it sort of evolved to a number of different solid tumors, but where did the clinical interest sit of the group at that time?
Dr. Christine Brown (04:15):
So, um, one of the reasons I was attracted to join his group is he wanted early on to apply CAR T-cells to brain tumors. And I thought that was, uh, you know, an incredible opportunity. Here's a cancer that has really, is very difficult to treat, very few therapeutic options. Um, standard of care really hasn't changed in decades, and I thought this would be an amazing approach to tar- try to, um, apply to this very difficult to treat cancer. So I came in in 2002 focused on brain tumors and CAR T-cells and brain tumors, and City of Hope was one of the first institutions to actually run trials in glioblastoma using CAR T-cell therapy. Mike's group was looking at, um, other cancers as well, um, blood cancers. We ran a trial with CD20 CAR T-cells, um, CD19 CAR T-cells, and then other cancers, pediatric cancers, neuroblastoma, but my focus had always been brain tumors.
Dr. Monty Pal (05:20):
Y- you know, it's interesting. I, I wanna remind the audience that, you know, we're at a point right now where, you know, there's dozens actually of CD19 CAR T programs that are out there in development, varying stages. Of course, there's several that are FDA approved, but you really got into this field at a time when, you know, this was all a bit of a pipe dream, uh, if I may, right? I mean, it just seemed as though this might not, you know, manifest clinically, which is, you know, probably exciting and scary at the same time.
Dr. Christine Brown (05:46):
I would agree with you. It was an absolute pipe dream. In fact, I couldn't get a grant to save my life in the early days, and now there's true believers, um, and there's a lot of energy around, um, cellular therapy and glioblastoma and other incurable brain tumors. You,
Dr. Monty Pal (06:03):
You know, one of the things that I always look at with so much awe, you know, uh, regarding what you've done is the team that you've built around you, right? You know, uh, we've mentioned Steforman a couple of times. There's also a number of clinicians, from what I understand, that you've really sort of paired closely with over the years. Maybe you could tell us a little bit how that sort of all came about.
Dr. Christine Brown (06:22):
I would say, um, I'm incredibly proud of the team we've built. I mean, I'm a PhD scientist. I can't build a translational pro- uh, program without incredible clinical partners and co-leads, right? So, you know, this program at City of Hope would not be possible without Ben and Bide, uh, Chief of Neurosurgery at City of Hope. He's been the clinical PI of the majority of our trials in adult glioblastoma s- and, um, yeah, so incredible person, incredible clinician and cl- incredible leader of the program. And then we've brought so many people in. It's just amazing. It's amazing to see, um, the talent that's, you know, wants to participate. So Lisa Feldman, um, as a neurosurgeon running- Oh, lovely. ... running some of our, running some of our trials, Jana Port now, um, running our trials in tumors that metastasize to the brain, Leo Wong running our pediatric brain tumor program, uh, you know, really amazing, uh, to have such a partnership and also the translational group that's partnering and building, because it takes what we do in the lab, bringing it to the clinic and all the infrastructure on the regulatory side, on the GMP manufacturing side, on the science side to understand what happens in the patients after we deliver these therapies.
(07:48):
So it really is a team sport. So,
Dr. Monty Pal (07:50):
So I have to ask you, all of these elements that allowed for us to develop these in- house CAR T-cells, which we're, we're gonna get to in just a moment, did this sort of develop in parallel with, you know, your progression here at City of Hope? How did this come about? 'Cause I, I think it's a relatively rare aspect of our program, right, to have the ability to really do the science here and create the therapeutics and then, you know, deliver to patients.
Dr. Christine Brown (08:15):
So this has been, uh, you know, building that infrastructure to allow the institution to run these in- house trials that are built on in- house science and treating patients, both in brain tumors, blood cancers, and other solid tumors has been a major focus area, um, for myself and the team. So we really started from the ground up. We had to build teams to expand our GMP manufacturing, expand our clinical infrastructure. And, you know, now it's beyond any one person, so we've set the process in motion. We have the infrastructure now, but in the early days, we had to build every SOP, every assay. How do we release these cells? Um, how do we, um, write these INDs to the FDA? And so, um, it's amazing to see. I've been here for quite a while now, so it's amazing to see it take a life of its own.
(09:10):
We have run and open over 30 clinical trials based on City of Hope technologies treated over probably 500 patients, almost 500 patients- Wow. ... on City of Hope, home grown science. So that's amazing. That's a lot of trials to bring to the FDA, a lot of, uh, you know, group effort to, uh, make these therapies happen for patients.
Dr. Monty Pal (09:35):
Indeed, indeed. And, and it's great to see that whole sort of bench to bedside spectrum really sort of manifesting. Uh, you know, you'd mentioned the IL-13 directed CAR-T studies. In fact, we had Leah Wong on this program not too long ago, you know, talking about the application of that specific modality in pediatric tumors- mm-hmm. ... which is super exciting. And, you know, we got into a bit of the science behind it and so forth. I remember a really sort of big moment here on campus was your New England Journal paper. Mm-hmm. Um, and I think we're coming on the 10-year anniversary of it next year, right? If I recall correctly, I think it was published in 2016. Um, tell us a little bit about that and how that whole project evolved for the audience members that might not have heard about it.
Dr. Christine Brown (10:17):
Right. Um, that was really a remarkable case, right? So when you're doing translational medicine, you really have to study those remarkable responders and those patients that don't respond to understand how the therapy's working. So we had put a lot of effort, we had gotten a large SERM grant to put a lot of effort into optimizing the IL-13 receptor off a two CAR platform. And so we initiated a clinical trial, um, based on the science that went into optimizing. And the first evaluable patient that we treated had this remarkable response. So, um, this was not an easy case, you know? So this was a gentleman who had really poor prognostic features. So his tumor was MGMT and methylated, IDH, um, IDH non-mutated wild type, which really, um, pretends the worst prognosis. Uh, he basically recurred after standard of care in under six months. He went on to another clinical trial, progressed right through that clinical trial.
(11:22):
By the time he came to us, he had multiple tumors in his brain, in his spinal column, and, um, and so we engineered his T-cells. We treated him initially in his largest, um, tumor area that was resected, and he did, he fared quite well, but this was an example of how science and translational medicine go hand in hand. Our research in the lab said if we put these cells not in the resected tumor cavity, but into the cerebral spinal fluid, it's better at targeting this multifocal disease. So he ended up being the first patient that we ever delivered T-cells into the cerebral spinal fluid. And once we did, all his tumors melted away. And so I remember Benham, um, Dr. Badi calling me and just chills, right? Like, how is this possible? This is amazing. This is the potential that CAR T-cells could mediate. Now, the problem is he eventually recurred.
(12:25):
And so beyond being a remarkable response and then recurrence, which, um, is devastating, it says that we need to do more, which we've been doing. His response taught us a lot about how CAR T-cells engage host immunity and change the immune microenvironment in the brain. And we're build- we've been building on that ever since.
Dr. Monty Pal (12:49):
And this paradigm of injecting cells directly into the CSF, I mean, do you envision that 10 years from now as the way that we'll be delivering CAR-T to perhaps brain tumors or, you know, is, uh, systemic administration still a pathway you think is worthwhile exploring? What, if you had to pick a winner, what would it be?
Dr. Christine Brown (13:08):
Yeah, pick a winner. So, you know, our studies say that on a per cell dose basis, you wanna put cells where you want them to work, right? And so we got around a lot of barriers with the blood brain, um, barrier restricting immune access by going local regionally. Now, our peers have, um, moved from systemic delivery to following our local regional delivery approach, but I can't say that we might not in the future find ways of improving, um, how these cells traffic to the brain through systemic delivery. So for now, we're focused on local regional delivery, but there's still a lot of questions about whether you should include lymphodepletion with local regional delivery should you, um, infuse multiple times or one time. So there's a, still a lot we don't know, and this is an evolving science. So for now, we've seen responses in with local regional delivery, as has other institutions now, and we see changes in the CNS microenvironment that show that these cells are bioactive, but, you know, what the future holds, I'm not sure.
(14:22):
And, you know, there may be reasons to move to systemic delivery, albeit, um, local regional delivery is well tolerated by patients. And one of the benefits of local regional delivery is that now you have access to the CS- um, CNS. The CSF, you can pull out the CSF and look how those cells are working. So a big aspect of my research program is both moving new science to patients, but also understanding from those patients how the science is working. And by having access to the CSF, we're able to query the microenvironment and understand maybe why a patient responds better than another patient or another patient progresses through therapy.
Dr. Monty Pal (15:06):
Uh, I'm really seeing sort of the team dynamic here. I remember when I first came to City of Hope going to some of Jana Portnow's talks. Mm-hmm. So Janna's a brilliant neuro oncologist on the medical oncology side. Mm-hmm. You mentioned Benabadi, who's one of our surgeons, and she was talking about using, uh, CSF catheters, for instance, to- mm-hmm. ... sort of consistently measure analytes and so forth. And it's good to see a lot of that sort of research crossing over to understand how, you know, some of these novel therapies might work. It's funny because I actually, you know, have consider myself a dabbler when it comes to CAR T. I've done a couple of trials in that space- More than a dabbler.
Dr. Christine Brown (15:39):
Dr. Monty Pal (15:39):
Dabbler.
Dr. Christine Brown (15:41):
Uh,
Dr. Monty Pal (15:41):
But, you know, what I will say is all the same things that you're thinking about in brain tumors, right? You know, how do you sort of penetrate, uh, the brain, blood brain barrier? How do you, for instance, you know, assess the need, if at all, for lymphodepleting chemotherapy? These are all things that I'm thinking about in the context of RCC clinical trials too. You know, and, and in that regard, I, I just wanted to kind of take us, take, have you take us through a little journey on what other tumor types you think might be reasonable candidates for CAR-T therapy. What other diseases are we looking at here internally?
Dr. Christine Brown (16:12):
So I think you bring up an important point that a lot of these barriers to solid tumors span many different solid tumors. So getting the cells to infiltrate and penetrate the tumors at large numbers, getting these cells to persist and expand in the hostile tumor microenvironment and knowing what antigens, um, to target, um, in order to eliminate the tumor. And many of these solid tumors are highly heterogeneous. And so my thought was that, um, or my belief is that, you know, we learn from all solid tumors, um, sort of how to make the therapy more effective. And so if we can create an effective therapy in glioblastoma, we've now learned, um, to help the treatment of all other tumors, including renal cell carcinoma, or if we, you know, have a win in renal cell, I think that's gonna help me in glioblastoma.
Dr. Monty Pal (17:12):
Yeah, indeed, indeed. And, and in terms of the city of Hope sort of portfolio, you know, I'll tell you, I have a little bit of insider knowledge because I'm fortunate enough to sit, um, on the thesis committee for one of your brilliant, brilliant postdocs, uh, Beta, who's developing some CD70 based CAR-T technologies. Um, I see direct application of that, for instance, in real cell. Mm-hmm. I'm very excited about it. You know, I'd love to, you know, sort of collaborate with you clinically. I mean-
Dr. Christine Brown (17:36):
As, as would we, we're planning on it, so more to come.
Dr. Monty Pal (17:39):
Excellent. A- any, any other sort of, you know, diseases that you're particularly interested in targeting here in house with our technologies?
Dr. Christine Brown (17:48):
Absolutely. Well, so most of my research program has focused on brain tumors, right? Mm-hmm. But I have dabbled outside the brain, but they're not- Oh, you've done more than dabble. Okay. I'll ...
Dr. Monty Pal (18:17):
Okay. We
Dr. Christine Brown (18:17):
Can extend their target recognition. We can add cytokines to promote their expansion or persistence. And in there, we're l- looking at a wide array of different solid tumors focused a lot on ovarian or, um, and sarcomas. So we're very interested. We're bringing to clinic, um, a B7H3 as the first prototype of this technology. Oh, cool. And so I'm very excited to see where that goes. And we'll probably test that in brain because B7H3 is expressed in glioblastoma, but it's expressed on so many other cancers. We look forward to looking and evaluating that in other cancers. And I will say that we've initiated a collaboration with Stanford and UCLA to test our IL-13 CARs in solid tumors. Um, and their IL-13 receptor alpha-2, our lead program in brain tumors, it's expressed on neuroendocrine tumors. And, and so in collaborating with these other institutions, we've been testing this in other solid tumors and have seen some indications of response.
(19:25):
And so we're excited about that as well. And then on top of that, I've been in collaborating with Enrique Montyro to use CAR-T cells in autoimmunity, which is a really, really exciting area. And so working with Enrique, um, we've been engineering CAR-T regs, um, to target activated T-cells. And, and on our first trial, um, has been in graft, chronic graft versus host, um, disease, and that's being presented at ASH right now.
Dr. Monty Pal (19:55):
Oh my gosh. No kidding. I didn't realize that. Okay, very good. You know, it's interesting. I mean, the Nobel Prize, of course, this year was issued for, you know, T-regs- Yes. ... and their genesis, right? The scientific backing behind it. Um, and, and it's just wild to see almost the reverse application of CAR T-cell therapies on oncology pan out in perhaps control of autoimmune diseases like graft versus host disease, also like rheumatoid arthritis- Yes. ... right? Crohn's disease. Type
Dr. Christine Brown (20:21):
One diabetes, you know.
Dr. Monty Pal (20:22):
Type one. There you go. Yeah.
Dr. Christine Brown (20:23):
So very different area for me, right? And it's great to partner with the, the diabetes program as part of this. So we're excited about this program.
Dr. Monty Pal (20:32):
I assume the backbone is the same, right? The technology that we're building this upon, there's a lot of similarities between the two. Is that fair?
Dr. Christine Brown (20:39):
Yes. A lot of the similarities, in fact, they used kind of some of our knowledge of building CARS for cancer in the building of the CAR T-cell for the T regulatory cells, but it targets, um, CD6- Okay.
Dr. Monty Pal (20:52):
... which
Dr. Christine Brown (20:52):
Is upregulated at high levels on activated T cells. So it's really there to modulate overactive or activated T cells that are targeting normal tissue.
Dr. Monty Pal (21:03):
Brilliant, brilliant. Y- you know, we've talked a little bit now about different applications of CAR T cells in and of themselves, right? Um, but, you know, I think there's this burgeoning literature around other modalities that may complement CAR T-cell therapies. So I'm referring to strategies like radiation and so forth. Do you, do you think there's the potential that combining CAR-T technologies with, you know, other sort of separate strategies might yield benefit?
Dr. Christine Brown (21:31):
Right. So absolutely. And it's important for us to test those, right? So, you know, as, uh, as a scientist involved in CAR T-cell therapy, we can engineer that cell. We can engineer that cell to locally deliver cytokines and other biomolecules into the tumor microenvironment, but we can also combine that therapy with other therapeutics in order to enhance its activity. And so we recently ran a trial where we combined with checkpoint inhibitors in the brain. And so, um, we're reading out the outcomes of that study and it looks very intriguing. Um, we're working with a company to combine with a small molecule inhibitor that targets the TGF-beta pathway.
Dr. Monty Pal (22:17):
Okay.
Dr. Christine Brown (22:17):
We've done some preclinical studies, um, run by a, a fellow, David Akavan when he was here, looking at the combination of radiation and CAR T-cells. So I think, you know, there's so much to learn, and it's gonna be important to both look at these combination approaches and next generation engineering approaches for CAR T-cells. And I think that's where we're at clinically is really understanding what the best combination or the engineering approaches for solid tumors because probably single engineered or single targeted CAR therapy is not gonna be the huge winner for solid tumors. We need more.
Dr. Monty Pal (23:01):
Right. No, indeed. You know, I'll riff on something that you just brought up, which is, uh, TGF-beta. It makes a lot of sense to me to target that. Maybe that would help in T-cell persistence, for instance. Mm-hmm. I, I imagine that might be one of the goals of many. Um, but, you know, we had human FONG on the program a couple months ago, and he'd alluded to the possibility of oncolytic viruses and those other sort of novel strategies that oncology- Yeah. ... contributing to the activity of T-cells. Could you maybe explain that to our audience, how there might be some theoretical synergy between the two?
Dr. Christine Brown (23:31):
Absolutely. So, you know, we want to engage the immune system. So CAR T-cells engineers the immune system to recognize the cancer, but in the first case that we talked about, the remarkable response that we reported in the New England Journal of Medicine, we saw that the T cells also activated host immunity. And so we know that interplay is very powerful because the host immune system sees many different epitopes that are expressed by the cancer. So if you, if we can create the spark for CAR T-cell therapy that then the rest of the immune system takes over, um, that is the ideal situation, right? And so oncolytic virus does the same thing. It activates, it not only kills the tumor, the oncolytic properties of oncolytic virus, but it also can activate host immunity, and that's an important pa- you know, mechanism of action of oncolytic virus.
Dr. Monty Pal (24:30):
Yeah, I was, I was quite excited to see the prospect of, you know, one sort of in- house City of Hope technology complementing another, right? I mean, this might be really neat to have, you know, these two programs developing in, in parallel and maybe merging to at least some extent. I, I thought that was pretty cool.
Dr. Christine Brown (24:45):
Yeah. So Karen Abudi is also running a, a trial with neural stem cells that are loaded with oncolytic virus in the brain, and we've been talking about possibly combining that. We've been also talking with others about combining and human fong about combining oncolytic virus with CAR T-cells for brain tumors. And Yuman probably talked about their approach, uh, that Saul Priceman, Steve Forman, Anthony Park have developed where the oncolytic virus expresses a target that's then recognized by the CAR T-cell. So there's a lot of options, um, and a lot of promise in these, um, combination approaches.
Dr. Monty Pal (25:27):
Yeah. I, and I'm gonna bring something up here. You have to forgive me because my naivete in this, in this sort of area maybe prevents me from describing this appropriately, but in vivo generation of CAR-T, right? This, this seemed to me to be really exciting. I think I came across a review and, and nature reviews not too long ago describing how, you know, we might able to be able to one day to have a patient synthesize their own CAR T-cells. Can you describe that?
Dr. Christine Brown (25:53):
Right. So a really, really hot area of research is this in vivo gene modification. So can we, um, target T-cells and have, engineer them to express the chimeric antigen receptor in the patient? So there's no need to harvest, um, the T-cells, genetically mo- uh, modify them ex vivo and, and then expand them. It all can be done in the patient. So it would make, um, the therapy, you know, off the shelf, as you would say, so you'd be ready to engineer those patients' T-cells. And so it's been tested mostly in blood cancers at, at the moment. I think it's an exciting area. It's rapidly evolving. We need to, you know, have another podcast in a bit to see where, uh, where the field is. You know, it might not be appropriate for all settings, right? So will it be appropriate for brain tumors? I don't know, right?
(26:52):
Will it be, you know, how will we overcome some of the specificity or complex gene engineering? There's still hurdles and still science, but it's working in some cancers and there's, you know, clinical reports, um, so it's exciting.
Dr. Monty Pal (27:08):
Yeah, no, indeed. I, I read about this and I was just blown away. I mean, we've come so far when it comes to CAR T-cell therapies. And, and this whole process of generating them in vivo seems to circumvent- mm-hmm. ... a lot of the problems that we oftentimes face in terms of ensuring T-cell persistence and, you know, again, target effector ratio, all this other stuff that really comes up day to day and, and I would say, you know, clinical practice. Um, yeah, very cool. So, you know, I'm gonna shift gears for a second here, Christine. I actually know you from another dimension as well, right?
(27:53):
Uh, both of you are engaged in the sciences. When you get home at the end of the day, is it still shop talk?
Dr. Christine Brown (28:02):
You're gonna, uh, well, you're gonna get me in trouble because it's
Dr. Monty Pal (28:06):
Deja
Dr. Christine Brown (28:06):
Lai household to him,
Dr. Monty Pal (28:08):
Right? Oh, right, right. Okay.
Dr. Christine Brown (28:11):
Dr. Monty Pal (28:51):
In the
Dr. Christine Brown (28:51):
Scientific field.
Dr. Monty Pal (28:52):
That, that's interesting. Let me ask because my wife is in business, very different field and so forth. So I don't know, we're still sort of flipping the coin to see what our kids might be interested in down the line. Have you and John sort of got your kids headed down the path of the sciences or what are they interested in?
Dr. Christine Brown (29:07):
So we really didn't push the sciences, but both seem to be somewhat interested. Okay. So both are in college. They'll both graduate this year, even though, um, one, because my son took an extra year, so they're one year, they're not twins. Okay. They were one year, um, in school, but, um, our son is doing applied physics, um- Okay. ... and our daughter, uh, who's two years younger is doing chemistry.
Dr. Monty Pal (29:34):
Oh, wow. Oh, brilliant.
Dr. Christine Brown (29:35):
So we'll see. Okay. They both want to go to graduate school, but we'll see. So-
Dr. Monty Pal (29:39):
Yeah, you never-
Dr. Christine Brown (29:39):
Interesting.
Dr. Monty Pal (29:40):
You never know. I wouldn't be surprised if I see them in the lab here one day every time I, you know, open up a newspaper, right? It's a, you know, different, uh, person, uh, leading the, leading the edge there. Um, in terms of the CAR T-cell space, this has, you know, come up time and time again just because of the pathway towards drug approvals and so forth. How do you see things working out for novel therapies like the ones that you're developing in a five or 10 year horizon? I mean, do you think the approval landscape is really changing for these drugs? Is the bar lowering? Is it increasing? What, what's your projection here?
Dr. Christine Brown (30:13):
You know, I don't exactly know, right? I mean, it seems like things are changing, but the FDA has been a partner in our phase one trials here. And, and one of the important aspects of moving these novel therapies to the next stage is biotech investment, VC investment. And so, you know, there's been a lot of changes recently, but, you know, what we can do at City of Hope, and I think we're very unique, is we can bring these novel ideas to patients. And if these patients are getting outcomes, um, there is gonna be investment. That's my belief. And so, um, you know, there's a real momentum in brain tumors, and I believe that the horizon is bright for novel therapies for this devastating disease that needs new options in hopefully the near future, hopefully in the future that I'm part of. And, and if we're able to show meaningful clinical benefit, I believe the, the FDA wants that as well as, um, the biotech community wants that as well, even though it is an orphan disease and not a lot of companies want to jump into such a, a challenging, um, cancer.
(31:29):
But I'm optimistic.
Dr. Monty Pal (31:31):
I, I like that perspective. It is an optimistic perspective, but I don't think an overly optimistic perspective. You know, my, my interpretation of everything that I'm hearing in the news nowadays is that, you know, the, the bar may be changing a bit, but if there's clearly a drug that serves a particular unmet need, there's gonna be a pathway for it. I,
Dr. Christine Brown (31:50):
I certainly hope so. And I believe so actually, so.
Dr. Monty Pal (31:53):
Yeah. Christine, I have to tell you, anybody that's, you know, done college here in the US, right, probably remembers Napster, you know, and, uh, downloading music for free, which I, you know, certainly am guilty of. Um, but the, the head of Napster at the time was Sean Parker, who- Uh-huh. ... you know, has really just made a monumental sea change, I think, in immunotherapy research, really through garnering a lot of public interest in it, right? And starting this amazing Parker Institute for cancer immunotherapy research that's, that's done wonders, I would say, to get good projects going. And, I mean, you're one of few who are a member of that institute. Can you tell us about, you know, what that membership means?
Dr. Christine Brown (32:31):
Yeah. So, uh, I'm really amazed that, that Sean Parker took an interest in cancer immunotherapy and, and put together, um, his philanthropic, uh, Pisces organization that, you know, so the goal is to bring together, um, those in the field, um, that are doing cancer immunotherapy, and we meet twice a year and present our research. And then, you know, the Parker Institute also facilitates, um, trials, uh, collaboration, science. It has been amazing. It really has transformed sort of that sharing of data and advancing what's possible in cancer immunotherapy. I think it was really visionary, uh, of Sean to put this together. And, you know, it's been a real privilege to be part of the Pisces organization. I've learned so much and, you know, just in brain tumors and sharing our clinical results and talking to collaborators, you know, I think it's advanced, um, CAR T-cell therapy for brain tumors based on their support.
(33:41):
And that's just one example. That's just one example.
Dr. Monty Pal (33:43):
I- Indeed. I mean, I always see the postings from, from PIC, um, and, and I see this bringing together your team and Carl June's team and all these amazing, like, forces around the country and CAR T-
Dr. Christine Brown (33:54):
Absolute who in the Q cancer immunotherapy
Dr. Monty Pal (34:15):
Right. No, indeed. Indeed. Absolutely. And, and, you know, I'm sure that, you know, some great clinical trial ideas have, you know, evolved from this. Um, I know you yourself have a couple of studies that are either just recently launched here in the CAR-T space or just about to launch. Anything you'd like to share with our audience on some of those new trials?
Dr. Christine Brown (34:33):
Yeah. So last, in 2024, we published our phase one clinical trial evaluating IL-13 receptor off of two CAR T-cells in high grade glioma. And this was one of the largest studies ever published to date. And we learned so much about how to deliver these cells, what, how the cells function in the CNS. And so our goal since then has been to build on that. So even in that study with a CAR T-cell targeted to a single antigen, we've seen impressive clinical benefit in a handful of patients, but many patients didn't respond or didn't respond with a, as durably as we would like. Um, in fact, one patient today remains disease free six years after treatment with no other therapies. Six years. Yeah. Wow. Amazing. Okay. This was a individual with an oligodendroglioma. So we know these cells have activity, but we need to make them more durable, more potent.
(35:33):
And so our new trials that we're opening really are trying to address that. So we have two trials. One has just opened, and that is the first CRISPR-modified CAR T-cell product that we've tested at City of Hope. Um, so what we did is we, uh, made our IL-13 receptor off two targeted CAR T-cells TGF beta resistant by knocking out a receptor that binds TGF-beta. So now, TGF beta does not suppress the immune cells. And this is because we learned from the patients we treated that those patients with high TGF beta levels in the CNS actually responded more poorly to our therapy. And so now by making, um, our T-cells resistant to this pathway, we hope to enhance their function. The next trial that we're, um, submitting the IND in January that I'm really excited about is targeting two antigens that are known to be expressed in glioma.
(36:29):
So that is IL-13 receptor alpha-2 that forms the foundation, but adding to that EGFR, because in many of our, not many, in a subset of patients where we saw antigen loss, we actually saw an upregulation of EGFR- Hmm. ... and when we queried a whole panel of GBM tumors, we saw, um, a co-expression pattern that would suggest that a high percentage of patients, uh, would get benefit to that combination approach. And so we're just about to open that trial after the first of the year. That's
Dr. Monty Pal (37:04):
So interesting. And is there sort of conditional expression of EGFR and IL-13 receptor, or is it, uh, are both expressed, you know, in a balanced fashion?
Dr. Christine Brown (37:12):
You know, each tumor's different. Okay. And I think these tumors are highly heterogeneous, but we're gonna ask that question- Sure. Sure. ... about the co-expression patterns and the response to therapy, but, um, we think this is a great combo. Got
Dr. Monty Pal (37:26):
It. Oh, that's super exciting. Wow. Uh, you know, these, these trials obviously require tons of investment from the institution. You've been incredibly, incredibly successful in grant applications to the NIH, to the SERM and other entities, but I, I have to imagine, just like my research, uh, you must lean to at least some extent on philanthropic support, right? Um, have you had some donors that have been quite critical in terms of, uh, getting these studies off the ground?
Dr. Christine Brown (37:55):
Yeah, so these are exciting, new, novel therapies, and they take partnership to make, and they're expensive, right? Bringing these new therapies to patients are expensive. And, and so I'm thankful to the NCI and their funding, and it's important to, to support, um, NCI funding for cancer. CERM as a funder has been really important, but key to allowing us to move quickly and act on that idea immediately and make the most rapid impact for patients has been philanthropy. And so we've had amazing supporters that, uh, this program wouldn't be, have been able to do what it has accomplished without this support. So Catherine Ivy with the IV Foundation, she ha- is one of the largest supporters of brain tumor research outside the NCI. So amazing support from the IV Foundation. The Norris Foundation has, you know, been so critical in us being a, in our program being able to run these trials.
(39:08):
Um, we just got a grant from the phase one foundation, very, very important. Um, we just heard that we got a grant to look at some of our correlative studies from the Merck Foundation. The, um, the Marcus Foundation supported, um, a trial that we just finished. So really, um, it's amazing. Uh, it takes getting funding from many different sources to be able to bring this program together and to be able to learn from patients and hopefully, um, bring these novel therapies to patients in an accelerated manner.
Dr. Monty Pal (39:46):
It's, it's such a great point. You know, I have to say that, you know, the NIH grants and the other grants come with such scientific rigor that you apply to your work. I think the philanthropic funds, they really come with such a sense of trust, don't they? Trust from the donors that you're gonna do the right thing and push these therapies into, again, these, these unmet needs, right, that other folks may be unwilling to tackle.
Dr. Christine Brown (40:07):
Well, and, um, also, and I shouldn't leave out, the Mann Foundation just gave a very generous gift, um, to us. And that was more to bring the, to accelerate bringing novel ideas to patients. So more on the preclinical side, which is also very important.
Dr. Monty Pal (40:23):
Indeed, indeed, absolutely. So this is a common core question on this particular, uh, program to borrow a term from education. The title of this podcast is On the Edge of Breakthrough: Voices of Cancer Research. Uh, we've asked all of our guests- mm-hmm. ... what does On the Edge of Breakthrough mean to you?
Dr. Christine Brown (40:42):
So first, can I say, "I love the title."
Dr. Monty Pal (40:44):
Yeah.
Dr. Christine Brown (40:45):
Yeah. So who came up with that? I have
Dr. Monty Pal (40:47):
Nothing to do with it. There's, there's some brilliant person in our city of Oak Working Department that-
Dr. Christine Brown (40:51):
So anyways, I think it's a clever title. Yeah. Um, so, okay, what does on the edge of breakthrough mean to me? I guess when I think about that, I really think of hope and optimism. I mean, this idea that the next experiment we're doing in the lab or the next insight we have or the next clinical trial will really change someone's life, right? And, and then maybe we can rewrite what is possible for glioblastoma. I don't know. So I don't know if you've been up to our lab on the third floor, but as you walk to the, um, to the lunchroom, we have words, you know, there and it says, until we find a cure, our job is not done. And we have pictures of, you know, patients that have participated on our trial because it really is a partnership and you, it takes it from this sort of abstract setting to realizing it's a person, it's a family, it's, you know, it's how important what we're, what we're doing is.
(41:56):
And so for me, when I think of on the edge of breakthrough, it's, it's that hope and that scientific discovery that we can hopefully translate to patients here at City of Hope. I don't know.
Dr. Monty Pal (42:08):
I love that. I've got to take a field trip up to your lab so I can see these photos and that inspirational wall. That, that's terrific. Christine, this has just been marvelous. Thank you for everything that you do here at the institution, and I know we're gonna have you back in a couple of years to talk about even more breakthroughs.
Dr. Christine Brown (42:23):
Oh, thank you, Monty. Uh, you're amazing. I'm a big fan.
Dr. Monty Pal (42:27):
Thanks for tuning in to On the Edge of Breakthrough. See you next time for more insights from the front lines of cancer research and care.