In this episode of On the Edge of Breakthrough: Voices of Cancer Research, Anna Wu, Ph.D., Chair of the Department of Immunology and Theranostics at City of Hope, joins host Monty Pal, M.D., for an engaging discussion on how innovations in antibody engineering and imaging are improving clinicians’ ability to visualize tumors and guide more effective treatment strategies.
Dr. Wu shares insights on her team’s development of engineered antibodies and fast‑clearing mini‑body fragments. These fragments can initially be used for PET imaging and then later paired with therapeutic radioisotopes to precisely target tumors, which help clinicians see where the treatment is going and how well it may work.
She also talks about two exciting initiatives at City of Hope: CEA‑directed agents (targeted cancer therapies) that are being used in clinical imaging and therapy; and PSCA‑targeted radiopharmaceuticals, which are entering first‑in‑human studies for pancreatic and prostate cancers. These new approaches use imaging to zero in on the tumor target, confirm safety, then deliver the radiation therapy directly to cancer cells.
Dr. Monty Pal:
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 everyone to On the Edge of Breakthrough: Voices of Cancer Research. I am so delighted today to have Dr. Ana Wu with me. She's the chair of Immunology and Theranostics Research here at City of Hope. Anna, thanks so much for being here.
Dr. Anna Wu:
Yeah, it's great to be here, Monty. It is a great program.
Dr. Monty Pal:
So we've actually had a chance to talk shop on a couple of different occasions and we've collaborated together. But I have to say, I've only skimmed the surface with your many, many accomplishments. But before we get into that, you went to college at Harvard, did your graduate work at Yale, and then came out to the West Coast. Where are you from originally?
Dr. Anna Wu:
I was born in Virginia, but really grew up in upstate New York.
Dr. Monty Pal:
So
Dr. Anna Wu:
Near Albany, outside of Albany.
Dr. Monty Pal:
I really do think you've been sort of a pioneer in this area of theranostics. You've done so much, you're a household name in the field. What was it that sort of led you down this path? Was it your time at Harvard? Was it your graduate work at Yale? Tell us a little bit about that story.
Dr. Anna Wu:
It's interesting because it's really such a cross-disciplinary field. To make a long story short, it all had to do with where I was going to try to go to graduate school and a GRE exam.
Dr. Monty Pal:
Oh, okay.
Dr. Anna Wu:
So I was always interested in biochemistry from a young age, and I majored in biochemistry in college. But when you come to take the GREs, there's a biology exam and there's a chemistry exam. And I hadn't had enough biology to take the biology GRE. I hadn't enough chemistry to take chemistry GRE. So I only applied to programs where it was not required. So that's why I ended up going to graduate school in a department of biophysics and biochemistry.
Dr. Monty Pal:
Interesting. So you can kind of get around needing to take either one of those examples.
Dr. Anna Wu:
And actually I took it and I did fine, but at the time I was worried. So the point being that I was interested in biochemistry, but I was force-fed biophysics. So I had to learn all these approaches like mass spectrometry or x-ray crystallography and fourier transforms and inverse space and all this physics in terms of how you apply it to study biological materials. But we're talking proteins, small biological materials. So that all just kind of got stuck in the back of my head. And then by coincidence, when I did a postdoc at UCSF, it was also in a biochemistry and biophysics program. So all of this physics stuff is kind of seeping into my head, even though I was really interested in biochemistry, molecular biology, how do cells work, what goes wrong. So I think that was all there in the back of my mind so that when I first came to City of Hope, and actually I had some joint projects in the pathology department when I first came here.
It really was the early days of molecular biology. We started to do molecular diagnostics. We were taking patient specimens and extracting DNA and doing PCR. This was like bleeding edge at the time.
Dr. Monty Pal:
Sure.
Dr. Anna Wu:
And there's another story that goes with that. So let me circle back to that later because it all ends up being connected in the end. All these little bits of exposures I had all kind of came together
Dr. Monty Pal:
In the end. I love hearing about the journey. And you got to City of Hope in 1984, is that right?
Dr. Anna Wu:
84. Right.
Dr. Monty Pal:
Tell us about what the campus was like then.
Dr. Anna Wu:
I think one of the other beauties of being of City of Hope then and now was that the clinicians here were very accessible and interested in the research, the potentials, the basic research, but also the clinical research. I mean, they could have gone anywhere and hung out their shingles and practiced medicine, but here they are at an institution where research actually was a big part of our culture. So that was key because I came to City of Hope and I ended up joining the antibody program that was already here. So it goes back to art rigs. Oh gosh. Okay. Right? Yeah, indeed. Insulin, but also Mr. Recombinant antibodies. And I ended up in leading the engineered antibody program because art, of course, was onto something even greater. He was studying chromatin structure and DNA methylation and all that. And he kind of was losing interest in the antibodies right at a point where we were thinking, wow, this looks really promising.
Dr. Monty Pal:
And just for our audience, they may not know art rigs, but his reputation really precedes him. It's incredible his contributions to the field. He really is the brains behind recombinant DNA technologies, having a small team at the time. And that's really led to the genesis of, as you'd mentioned, many monoclonal antibodies that we now use in clinical practice. You of course have become expert in their use in diagnostics and out theranostics. Humanized insulin obviously comes to these same technologies as you'd already alluded to. Just major, major contributions to the field.
Dr. Anna Wu:
I ended up joining the engineered antibody program and also in part because I was at a point in my career that I was learning that the research that we were doing was actually practical. And to come here and have the potential of doing something that could be brought into the clinic as a PhD basic scientist, this was, to me, extremely exciting. So I was working with, and of course it's a team. I ended up working with Jack Shively.
Dr. Monty Pal:
Who's still here?
Dr. Anna Wu:
Who's still here. In fact, we got the team back together when I came back to City of Hope, and then a surgeon named David Beattie. And Jack had this really, really beautiful antibody that recognized CEA, carcinoembryonic antigen. It's kind of the classic colorectal cancer target. And actually that's the antibody he gave one of these antibodies he gave to Art Riggs, and that's what they expressed in E. Coli, and that was the source of the patents and all the recombinant antibody technology. They expressed that antibody in bacteria. So one of his antibodies was really, really good at recognizing very specific target on colon cancer, but this antibody had no biological activity.
Dr. Monty Pal:
It
Dr. Anna Wu:
Sprinkled on cancer cells and to say, ha-ha, lunchtime and nothing. It didn't kill cells. It didn't recruit immune cell, nothing. So I think he and David Beattie decided to try to put to arm it somehow. And so they went to radioisotopes. So they had already started this program and it actually had put the muring monoclonal intubations and we're moving into now with arts leadership generating chimeric antibodies. And that's where he got bored. And I joined the group and we'd started doing humanized antibodies. And that really was how I got into this role in the engineered antibody program.
Dr. Monty Pal:
And you make it sound so easy, but that transition from mirroring antibodies to humanized antibodies, tell us about that.
Dr. Anna Wu:
It was a step by step. Now you just kind of ... AI will do it for you.
Dr. Monty Pal:
ChatGPT
Dr. Anna Wu:
Will humanize your antibody for you. But back then, we were still cloning and sequencing. We were still physically working with pieces of DNA and sequencing them and trying to figure out what made things look human and what made things look mouse and how to splice them together. So it was very much a hands-on process. Now it's routine. But I mean, that's one of the things that's been very exciting for me to see over, and I hate to admit it, decades, is how mainstream these technologies have been become and how scalable and translatable and common they are now. Because back then, we were doing everything by hand, truly.
Dr. Monty Pal:
It's amazing. I love that picture of City of Hope back then. It explains a lot where we are now in terms of scientific innovation and discovery and so forth. Tell us a little bit more about the CEA program because my recollection when I joined City of Hope, and this is about 20 years ago, is you actually took that really from bench to bedside.
Dr. Anna Wu:
We did, and we're still doing it. And back then, we actually, we meaning the team, not me personally, we had to manufacture these antibodies ourselves and make them a way that was suitable for clinical use. And this was before the Center for Biomedicine Genetics was built. But yeah, we basically had to do it all by hand, just engineering the genes for these proteins and producing them, purifying them, scaling up, radio labeling them. And now actually, because of what we did then, the program has grown and grown and grown. So that actually now it's very straightforward for us to do this now. But back then we had to basically build everything and invent everything. But it was a true team effort across disciplines and just a lot of people just excited about the potential of delivering targeted radiation therapy.
Dr. Monty Pal:
Amazing. And I do want to get to the status of some of the other clinical programs that you've really helped build, but tell us about where the CEA program sits right now.
Dr. Anna Wu:
Oh, right now we have humanized antibodies that are actually in the clinic for immuno PET imaging. And we should talk a little bit about the imaging in general and antibody fragments, but immuno PET for imaging. And then we have therapy studies using actually alpha particle emitters. We have an Actinium 225 alpha particle emitter study that's open now. And then another wrinkle is that my collaborators at JAK and then Paul Yazaki have developed an immunocytokine. So they've taken the anti- CEA antibody and fused it to interleukin IL-2
Dr. Monty Pal:
So
Dr. Anna Wu:
That you can also get targeted delivery of cytokines and immunostimulants directly to the tumor environment. And again, the beauty is that you get localized treatment, you don't get the systemic side effects. And that's really the point of antibody targeted therapeutics is to really get that localized, highly specific, targeted delivery.
Dr. Monty Pal:
I love it when people bring up IL-2 because as a renal cell treating physician, when I started my training, I remember heavy amounts of use of high dose- Hydosiotin. Just wasn't probably the best way to give it. So I think that all these methods of targeted delivery are so innovative and might actually be another path forward decades later giving IL-2 to patients.
Dr. Anna Wu:
To make a long story short, one of the things that we realized when we talked about putting radioisotopes on antibodies for therapy was that antibodies have a long circulating half-life. And so you've got this radioactive agent circulating your blood for literally days while you wait for it to localize and slowly clear out. And you're exposing all your normal tissues and especially your bone marrow to that radiation. So we thought that maybe we could do better than that, especially because coming with ART's background and antibody engineering, what could we do to make it better? So we came up with a series of engineered antibody fragments, the idea being, let's just keep what we need, the two binding sites and throw away the rest and let's give it a little extra mass so that it'll clear through the liver instead of the kidney, whatever. But what we did is we engineered the antibody down so it targets fast, clears fast, clears either through kidney or liver, depending on what your application is.
But the point is for therapy, now we can reduce the exposure, the radiation dose exposure to the bone marrow, and then theoretically get a higher therapeutic ratio, target to background ratio, and deliver more of the radiation to the tumors without damaging the patient's bone marrow.
Dr. Monty Pal:
And am I right in saying this is the so- called minibody? Is
Dr. Anna Wu:
That right? This is the minibody platform. Okay, got it. Got it. We have smaller ones, diabetics. We have bigger ones, single chain FEFCs. And actually one of my goals is that my goals in the work was to have a whole spectrum, a whole family of engineered antibodies so we can pick the format depending on what our application is. And then in parallel, to get back to the imaging, even in the early days of before we had the humanized antibody against CEA, we had a chimeric antibody. And even in the very early days, the team, the clinical team would label it with Indium 111 first in the patients and do planar and SPECT imaging to see where the agent was going in the patients. And then they'd flip the isotope to Itrium 90 or beta emitter for therapy. So that was theranostics 30 years ago. Oh, wow.
We just didn't have a fancy name for it. Perhaps I should back up, and this goes back to the whole physics side of it. I've always been drawn to working with radioisotopes for a number of reasons. And the main one being you can find them, you can count them, you can measure them. So you actually know where it's going, what it's doing, and they go away with a defined half-life. So antibody drug conjugates, on the other hand, scare me to death because you don't know where that drug is going and when it falls off the antibody and what kind of side effects you're going to get unexpected. But with the isotopes, the radionuclides, you can find them and you can follow them. So they would image first and then they would do therapy. And so I developed the minibody originally for therapy, but we realized along the way that this would be pretty good for imaging too.
Dr. Monty Pal:
Kind of the rapid-
Dr. Anna Wu:
Same idea
Dr. Monty Pal:
Because
Dr. Anna Wu:
Vascular, fast, low background, you could image your patients same day or next day rather than waiting a week or so the way things came together to become theranostics.
Dr. Monty Pal:
I wonder if you could give our audience a quick two, three minute primer on the various isotopes. Is that possible or is it too much to squeeze in? How do you pick indium versus orconium versus copper versus yitrium?
Dr. Anna Wu:
Yeah. Well, we like radio isotubs because they come in so many different flavors and it's evolved in terms of what we pick, but I think a lot of it had to do with availability because back when we first started this work, all there was Indium Itreum 90. PET imaging hadn't been invented or had just been invented, but really was not broadly used.
So that's been an interesting evolution to see. So in terms of what isotope we pick for imaging, I think the field has moved to positron emission tomography because it's so much more sensitive and quantitative compared to older imaging with technetium or Indium, for example, which are still used clinically now, Indium for infection imaging and then technetium for cardiology and all sorts of applications. But I think people, when they can, have moved to positron emission tomography. So that's where you have Fluorin 18, gallium 68 you may have heard a lot about, but then we use some of the longer lived positron isotopes such as zirconium 89, top of 64 because we're working with antibodies and they don't move as fast as those small molecules. Those first two I mentioned only have half lives of one or two hours,
Dr. Monty Pal:
So you
Dr. Anna Wu:
Got to work fast. And so this has also been one of the parallel developments that has allowed us to do what we can do has been greater availability of these PET imaging isotopes with longer physical half lives. So the copper is 12 hours, zirconium's three days. And when you have an antibody that takes 12 to 24 hours to get there or a few days to get there, this is what makes it feasible to do this kind of work.
Dr. Monty Pal:
That was really, really helpful. And just one other terminology thing that you could walk us through, alpha versus beta emitters. This is something that I've actually- I should get into
Dr. Anna Wu:
That because on the therapy side, we also have two general flavors of radioisotopes. The beta emitters, betas are simply high energy electrons. So they just kind of zap along and they destroy macro molecules and destroy cells and DNA along the way. A lot of it is through reactive oxygen species and other chemistries like that. Beta particles are high energy electrons with path lengths of one to a few millimeters. And back in the old days, that's all we had. Okay. So Itrium 90 was very popular. Now lutetium 177 is more mainstream. The alpha particles are completely different. They're actually helium nuclei, two protons, two neutrons. So they're massive. They're 7,000 times more massive than an electron. So they have high, what we call LET, linear energy transfer. They really pack a punch. All you need, I think is one alpha particle hitting one cell and you'll kill it because just wreaks havoc because it's like the MAC truck plowing through and it just creates double strand breaks everywhere and will kill the cell.
The downside of the alpha particle, the limitations, since they're so massive, they can only travel a few cell diameters, not one to 10 millimeters. Got it. Okay. So they're very different flavors, beta versus alpha. They're very probably complementary in ways. And again, a lot of the work we do is limited by isotope availability. And right now there's only, well, for a long time, there was only one place you could get Actinium 225, which is our most commonly used alpha particle emitter, and that was the Department of Energy, and there's a limited amount available. And early on, they weren't even making it available for clinical use. They weren't even making it. So all these things have to evolve in parallel. The ability to engineer the antibodies or even just humanize antibodies for just regular cancer therapeutics, the infrastructure you need to be able to scale that up and actually roll out clinical as well as commercial level products, the infrastructure in terms of the isotope supply, the infrastructure in terms of PET imaging and cameras to be able to see what we're doing.
Dr. Monty Pal:
So true. So true. Yeah. That was such a great primer. And our producers actually gave us license, didn't they, to sort of geek out a little bit and talk about the science and detail. No, this is terrific. No, no, what a wonderful primer for the audience and all these different technologies. So we talked about CEA. What was next for you after moving on from CEA as a tardin? And again, the CEA is still in development. It's
Dr. Anna Wu:
Still in development. We've actually, we have to go back to my timeline. So in 2002, because I had created these minibodies and diabodies and other fragments that looked ideal for imaging, I got recruited to UCLA. So they have a major PET imaging program there. And the goal was to be able to make based on antibodies, PET imaging agents. So that was my, first it was a sabbatical project, but then it
Dr. Monty Pal:
Stuck.
Dr. Anna Wu:
And so they recruited me there. I was on the faculty there at the medical school for umpteen years. So that's where I started a longtime collaboration with Rob Writer, who's a professor in urology.
Dr. Monty Pal:
Love Dr. Reiter. It's terrific. And he
Dr. Anna Wu:
Worked with Owen Witty early on and they discovered this protein called prostate stem cell antigen.
So we've been collaborating since then. He started with a mouse monoclonal. We humanized it. We turned it into engineered antibody fragments and it's taken a long time, but it's upregulated. Well, first of all, it has very low normal tissue expression, prostate, bladder, lumen of the stomach, I think ovarian placenta to some extent, but generally low level expression in normal human tissues, but it's upregulated in almost all prostate cancers and in significant majority of pancreatic cancers. So I've worked with Rob, he's urologist. So of course we've been pursuing prostate cancer related projects with him mostly preclinically. But then on our side, I also realized that if you look at unmet need, pancreatic cancer is like right up there at the top of the list of we really need better treatments. So what we've been working on in the lab has been to continue to develop PSCA engineered antibody fragments for imaging and therapy in pancreatic cancer.
So I'm really excited on the preclinical side. We've done therapy, we've done imaging with zirconium, we've done therapy with Lutetium-177 and now actinium-225. But in parallel, we've actually pulled the trigger funded by an NIH grant to go into clinical production and clinical evaluation. So I'm very,
Dr. Monty Pal:
Excited
Dr. Anna Wu:
That actually literally last month our manufacturing team head by Dr. Paul Izhaky, who's our antibody manufacturing guru, produced, purified, conjugated vialed. And so the anti- PSCA antibody is now in the vial in the pharmacy ready for us to think about initiating our clinical trials.
Dr. Monty Pal:
Wow, congratulations. That's terrific. Tell us about the clinical program around that. Who are you working with here on campus to implement?
Dr. Anna Wu:
Well, for this one, it's pancreatic cancer. And so Vincent Chung and Lala Melstrom, of course, are. And of course, Dr. Jeffrey Wong, who's our head of theranostics overall, who we've been working together for a long, long time. So those are the clinical team that will be implementing this trial. It's going to be an imaging trial to start with. It's going to be a PET study with Copper 64 because this is a new format of antibody. We don't know what the pharmacokinetics are going to look like in people at all. So we want to at first evaluate the targeting, the PK dose estimation. Can we get enough into tumors? What does normal tissue absorbed doses look like? So it's a safety study, but it'll lay the groundwork for a therapy study.
Dr. Monty Pal:
Wonderful.
Dr. Anna Wu:
Wonderful.
Dr. Monty Pal:
Hoping to
Dr. Anna Wu:
Move that forward.
Dr. Monty Pal:
And I think you've made very clear for our audience that there is that sort of progression, isn't there, from diagnostic to theranostic within these programs that you've built. So does it always begin there with the diagnostic and then evolve into the theranostic approach, would you
Dr. Anna Wu:
Say? It depends. I think this is a brand new agent. So it really is nice to have the ability to evaluate it diagnostically first to just make sure to understand where it goes. We're not flying blind. We're not just empirically dosing up to a maximum tolerated dose. We actually can be a little more thoughtful and plan how to dose and where we need to start and how fast we can move up. So that's the beauty of the fact that you can find, count, quantitate these radioisotopes. So the imaging is just a very, very useful companion to, especially if you're going to do a radioactive therapy dose.
Dr. Monty Pal:
You know what I'm realizing as we sort of look across our CVs, yours far better than mine. I actually was at UCLA at the same time in medical school, finishing up my residency in 2006, and that's when I made the transition over here to City of Hope. So what was it that sort of prompted the transition back over here, if I may ask?
Dr. Anna Wu:
Clinical translation.
Dr. Monty Pal:
Okay. Okay. Tell me more.
Dr. Anna Wu:
Clinical translation. And I have to say that I love my colleagues at UCLA, but they're really much more focused on small molecules and peptides. And any translational work that we did at UCLA, actually things were made and labeled at City of Hope and couriered across town.
Dr. Monty Pal:
Oh, you're kidding. Oh, okay.
Dr. Anna Wu:
It really was the opportunity to get much more directly involved in clinical translation. I think that's one of the great things about being here is that you have access to that. And we as scientists really do need to understand what is the need and what are the practicalities of trying to move something into the clinic. I think if we really want to make progress, you've got to have that whole picture. We can't just be pushing. There's got to be pull on the other side and it clearly takes a team. There's no way to do this without a team.
Dr. Monty Pal:
Indeed, absolutely. And actually that brings us to a collaboration. I think that, I mean, you and I have had very effectively, and that's in the domain of these CD8 minibodies. For the audience, CD8 T cells or those T cells that are really doing the heavy lifting and work for the immune system as it pertains to cancer, infection, et cetera. And I think you've come up with a brilliant way to sort of image these entities, right?
Dr. Anna Wu:
Yeah. Yeah. And so there's a story that goes with that. And it circles back to when I first came to City of Hope and we were known for lymphoma treatment. And so Steve had the bone marrow transplant program. We had Henry Rapapor of the Rapaport classification of lymphomas, morphological classification of lymphomas. And when I first came and I told you, we were extracting DNA and doing southern blots on patient specimens. But the reason we were doing it, we were trying to classify lymphomas.
Dr. Monty Pal:
And
Dr. Anna Wu:
Back then, they were classifying lymphomas by trying to determine clonality. So you'd stain for Kappa and Lambda. Those are the two different flavors of light chains in human B cells and B cell lymphomas. But if you have a lymphoma, it becomes clonal. So it's all Kappa or all Lambda. So that was one of the diagnostic techniques that was being used then. We looked at, can you take the DNA out and look for rearranged antibody genes and see if you saw a clonal band. And if it was, you could see Kappa, you could see Lambda. If you saw a rearranged band appear in your patient's specimen, it meant you had a clonal population growing
Dr. Monty Pal:
Up. Sure. So
Dr. Anna Wu:
That was the first thing I was doing. But I was looking at all these slides and I learned a whole different set of names for what we now call the CD antigens. There was LU16 and T4 and whatever. They had completely different names, but now they're all the CD markers. But that kind of was one of those things that just kind of stuck with me. So I'm over at UCLA, Tony Rebas, right? Mr. Melanoma immunotherapies. And these were in the early days when they were just looking at the anti-CTLA-4 antibodies. And they were seeing a phenomenon in about 10% of patients called pseudoprogression, which you may be familiar with, where they'd start to treat the patients with these immunotherapies, these early checkpoint blockade antibodies. And they'd follow the patients with a standard imaging, either a CT or MRI or even FDG PET. And the patients would look worse, some of them.
But if you kept treating them, then those tumors would resolve. And if you waited like six months or a year or even longer, you'd find out that these patients actually were responding. And what it was, it was the immune response. The tumors are getting bigger because they're getting infiltration with the good guys, the CD8 T cells, et cetera. So Tony Rebus one day comes to me, this is while I'm working on CEA and PSCA and HER2 and ALKAM and all these other cell surface markers and tumors. And he says, "Anna, is there any way we can distinguish tumor cells from immune cells?" And I said, "Well, of course." Because when I'd previously been at City of Hope, I'd been looking at all these slides stained with all these antibodies for all these markers for immune cells. I said, "Well, there's all those CD targets
Dr. Monty Pal:
And
Dr. Anna Wu:
There's all those antibodies. So of course we can distinguish them." So we took anti-CD8 antibodies and turned them in an immuno PET agent so that we could look at image the immune responses in vivo.That's where it came from. All those pieces kind of fell in place. We started in mice. And then as you know, I co-founded a company called Imaginab because really to ultimately translate your ideas to really get them out beyond what you could do on an NIH grant, which is usually just a small phase one study, you need to find a commercial path. So through Imaginab, they developed the human specific anti-CD8 minibody for imaging immune responses in patients. So that's where we end up collaborating because you were one of our phase two investigators.
Dr. Monty Pal:
Right, right, indeed. And I was just fascinated by the technology. I think the data's out there so we can talk about it now. And you looked at this technology and cohorts of melanoma and some of my patients with renal cell carcinoma, and I thought it was such a cool way to interrogate this thing that has really become envogue in immunotherapy research, which is, is a tumor hot or is it tumor cold as it pertains to the immune system? And I really think that that's where this technology comes into play, right?
Dr. Anna Wu:
Exactly. But I think it's very complimentary to what our current standard technologies are because right now the only way to tell if a tumor is hot or cold is by biopsy, usually done at baseline. And sometimes you'll do a follow-on on treatment biopsy, but not routinely, usually in the context of a clinical trial because somebody's really trying to understand that immune response to a particular therapy. But the beauty of PET imaging, it's whole body and it's non-invasive. So we're not sticking needles into people everywhere. And there are places you can't biopsy, and there are risks with biopsy. This way we can scan the entire body, including if there's metastatic disease, the different lesions, because we know there actually can be differing responses lesion to lesion. And actually, I think some of the work that you've done comes back to something I was always interested in as well, because we're not just looking at what's happening in the tumors and are they hot or not, and are they changing?
Are they getting ... You can look at the whole immune system. It is a system. And so you can look at the spleen or you can look at draining lymph nodes, and is there anything interesting going on in there? So we have a new way of looking at just getting new information that were never able to access previously. So that's what's been thrilling to me is we can look at the whole immune system in a live person.
Dr. Monty Pal:
I'll share with you a cool story. I actually had one of my fellows who we've mentioned on this podcast before, Peter Zhang, brilliant guy. He's going to be joining our faculty in fact next year. Oh,
Dr. Anna Wu:
Fantastic.
Dr. Monty Pal:
Which I'm super excited about. He really poured through the data for this CD8 imaging modality and he came up with this premise that actually that uptake in benign nodal tissue, that CD8 uptake there may actually correlate with response. And I was blown away when I saw that that maybe just as well as tumor related imaging really played a role in dictating immunotherapy response. When you think about it, it actually makes perfect sense, doesn't it?
Dr. Anna Wu:
And then you go to some of these meetings now where people, because we're learning it, there's a lot of action going on in those draining lymph nodes. And in fact, that's where your T-cells go to get reeducated. Yeah. So are we making a mistake by taking out that sentinel lymph node?
Dr. Monty Pal:
Okay, you're making me think now.sections.
Dr. Anna Wu:
I mean that question is starting to pop up. Are we taking out the key immune
Dr. Monty Pal:
Tissue? Well, not only that, the other observation we had in going through this data, so again, just to paint a picture for the audience, we'd get a scan back on a renal cell patient, for instance, and we saw that there were these pockets of mild uptake in the lymph nodes, as we've already mentioned, that might dictate responsiveness to immunotherapy. We also saw a lot of heterogeneity in where the CD8 was sitting, right? Yes. And I thought that was another curious finding because it's so common that we'll treat a patient with immunotherapy and we might get a great response in a lung tumor, no response in a bone tumor, might get a great response to the liver, no response in the lung, vice versa. So this technology I think also lends itself to understanding that intrapatient heterogeneity,
Dr. Anna Wu:
Right? Yes. Yeah, absolutely. And I think Tony Rebas at one point was doing things where he'd see discordance in the FDG response to immunotherapy and he wanted to, I don't know how far he got with it, but to biopsy those lesions to see what's different about them. So it can help you understand where to look to try to understand better why some lesions are responding and some aren't. So theoretically you could something similar to CD8, although I'm not a big fan of biopsying everything, but we're able to see things that we're not able to discern before. And I think it is changing our thinking in different ways, which is good.
Dr. Monty Pal:
I love it. I think out of all the projects I've been involved with the City of Hope and many, many really interesting ones, I think that this was really thought provoking and really strongly hypothesis strategy. So thank you for getting me involved.
Dr. Anna Wu:
Yeah. And you could also see though what a simple idea it was.
Dr. Monty Pal:
But
Dr. Anna Wu:
It only triggered in my mind because I'd already been, first of all, exposed to all this biophysics stuff at a young age. So for me to step into radioactive isotopes and into the imaging, which is all four year transforms and inverse space and all that same stuff, it didn't scare me because I kind of got it. But then to see how my early work just with pathology, just looking at lymphomas led to the CD8 imaging, it all just came together. And it's such a simple idea, but to be in a fertile environment where I'm learning about all these clinical things and all of a sudden it's like, duh, this is what we should do. That really, I think is a product of being in this environment.
Dr. Monty Pal:
Now, I won't ask you to explain to our audience 4A transforms. I think that might go beyond- I
Dr. Anna Wu:
Don't think I can experiment them anymore either.
Dr. Monty Pal:
Let me ask you, you've talked about so many cool projects that you've done over the years, CEA, PSCA, CD8. What's really exciting to you in pipeline right now?
Dr. Anna Wu:
And it's all coming back together.
Dr. Monty Pal:
Yeah. Tell us about the pipeline and what's in the
Dr. Anna Wu:
Opera. The scientific and clinical west I'm most interested in right now is the effects of low dose radiation on the immune system.
Dr. Monty Pal:
Okay.
Dr. Anna Wu:
So people have seen that external beam therapy for high dose, of course, kills tumor cells, but it definitely kills the immune cells. They're highly radiosensitive. But people have also noted that lower doses of external beam radiation may actually trigger ... It's like an inciteuve vaccine. It kills tumors in a way that induces immunogenic cell death, provokes the immune system to come in and there's new antigens exposed. And so you can get ... And this is the theory, and there have been certainly animal models and some hints from patients that this can happen as well, that you provoke a productive immune response. So people are starting to looking at, have been looking at it formally for external beam therapy more and more. And I'd also like to look with our targeted radiopharmaceutical therapies if we administer them at low dose, can we see interesting immune responses?
So this is something we could maybe image with CD8. And in fact, we actually have an ongoing study with Cevida Donapani.
Dr. Monty Pal:
Okay. I
Dr. Anna Wu:
Love
Dr. Monty Pal:
CVDA. She's wonderful. Which actually
Dr. Anna Wu:
Has been doing external SBRT and imaging pre and post with the CD8 immunopat.
Dr. Monty Pal:
Actually, she's doing that in a lot of my renal cell patients. Yeah. We had a couple of great experiences with that.
Dr. Anna Wu:
So I think that's a really interesting combination where are we provoking an immune response? Can we visualize it non-invasively through PET imaging and then use that tool to help us tailor how we deliver the radiation therapy more effectively? But also I think combination therapies, for example, with radiation and immunotherapy or these immunocytokines, I think that ultimately we've got to harness the immune system if we're really, really going to have long, durable, curative responses in cancer. The immune system is the only thing that can run fast enough to keep up with a tumor that's trying to evolve and escape. So we've got to find ways to boost the immune system. And I do think that there's potential for radiopharmaceutical therapy, targeted radiation therapy to be part of that if we can figure out how. And so that's one of the things we're exploring now is how we can use these radio-labeled antibodies at low doses.
What do they do to the tumor microenvironment? How can we combine that with immunotherapies? And the beauty of the radiopharmaceutical therapy is that it's systemic administration. External beam, you have to know where the tumor is to aim the beam, right? But if you've got disseminated disease, and we also know that some of those lesions can be very immunosuppressed. We've seen it in CAR-T studies sometimes, that you put the CAR-Ts in, but they can't do anything because where they're trying to go with such an immunosuppressive environment, maybe with the systemic administration of targeted radiopharmaceuticals, we might be able to modulate those environments. So it's new. There are a lot of people who are very interested in looking at this. We have nothing to report yet, but I find it really intriguing and it really does bring everything together, the radiopharmaceutical therapy, along with the immune responses and being able to put them all together and optimize and get more effective treatments overall.
So that's what is inspiring me these days. How can we best put all of these treatments together?
Dr. Monty Pal:
I love that. I have so many conversations with Savida Dondapani, brilliant radiation oncologist in our group here, Rose Lee, who I believe you've met as well. We have such a talented group of young investigators in that radiation oncology group. One of the things that I've been sort of stuck on is a paper that Rose recently shared with me that actually looks at low dose radiotherapy, believe this nut administered to the benign colonic epithelium. And the premise there is that we have this huge institutional focus now in the gut microbio. The thought is that maybe that creates maybe a small site of leaky gut, if you will, allows for permeation of short chain fatty acids, some other bacterial bryproducts into circulation. But again, that whole premise of low dose radiotherapy, perhaps to tumor is in the case of SEVIDA study, perhaps to benign areas. I do think that it's got to foster the immunologic response to some extent.
And I think your technology is a great way to look at it.
Dr. Anna Wu:
It's a different way. It's very complimentary. I
Dr. Monty Pal:
Won't
Dr. Anna Wu:
Say it's the only or the best way to look, but it does offer a unique view of the whole organism, the whole system that can compliment what we can do because the flip side of that is all these incredible omics type studies we can do and the vast amount of datas we generate there, but only on very small specimens.
Dr. Monty Pal:
Exactly. I
Dr. Anna Wu:
Think we need to find a way to put all of that information together intelligently to figure out what works, what doesn't work, what went wrong, how to fix it. But it is a very exciting time. It really is.
Dr. Monty Pal:
The wheels are totally spinning right now, but I'm going to shift gears nonetheless and just ask you perhaps a broader question. You have achieved such success in science and collaborative science and translational medicine. This is a difficult time, obviously, for folks entering into the field. What's your advice to the junior investigators that are out there that really want to make a difference in translational medicine?
Dr. Anna Wu:
I always encourage them to talk to people at the other end, the clinicians who are treating patients, the patients to understand what the need is. Because if you find a challenge and a need and you're working towards addressing that, it doesn't matter what else is going on financially, politically, whatever, persistence is important, but also persistence toward a real goal, not just, "Oh, your next grant. Oh, I want to see this in mice." To really leap ahead and also think about what is the final goal? What is the final reason you're doing what you're doing? So it takes a long time. So we've gone through cycles, economic cycles and political cycles even across our careers. And to stay the course, if this is your passion, absolutely you've got something to contribute and stay the course because we go through these crazy cycles
Dr. Monty Pal:
Out there. I love that advice. Just keep the blinders on, stay focused, come up with that end goal, if you will, and work towards it. That makes a lot of sense to me. One of the things that we always ask folks on this program, and it's a tough question, it relates to the title of this program, which is On the Edge of Breakthrough: Voices of Cancer Research. What does on the edge of breakthrough mean to you, Anna?
Dr. Anna Wu:
To me, we make a lot of advances, certainly in the laboratory or animal models. When I think about clinical trials, we do a lot of small trials and we'll see promising results and we'll follow up on those. To me, the real breakthrough comes when you can offer those treatments more broadly to patients. It's not good enough to just influence the people in front of you. I think that the true breakthrough is when these treatments become available to large chunks of the population, larger numbers of patients.
Dr. Monty Pal:
I love that principle. And we've obviously seen that here at City of Hope with, as we started with at the top of this program, Art Riggs's contributions to monoclonal antibodies. And now of course we have rituximab and trastuzumab and all these amazing life-changing technologies that have been born out of this campus. I love the focus on another thing you alluded to, which is that end goal of seeing the clinical translation of things makes a lot of sense to, again, a broad swath of patients. That makes a lot of sense. Yeah,
Dr. Anna Wu:
That's why I came back.That's why I love it here, because that's really the mindset here.
Dr. Monty Pal:
Yeah. Well, thank you, Anna, for joining us. And I definitely want to have you back again in the coming years to talk about all the amazing progress that your program's making.
Dr. Anna Wu:
Okay. Sounds good.
Dr. Monty Pal:
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.