January 13, 2026 | How has immunotherapy evolved in the last decade? In this episode of The Chain, Laszlo Radvanyi, professor of immunology at the University of Toronto, discusses his years-long research on cancer immunotherapy, including his time at MD Anderson, with host Rakesh Dixit. He shares his thoughts on agonist antibodies, the true breakthroughs that are moving the needle for patients, reducing the CD-28 pathway so that it doesn’t produce cytokine toxins, and what is the next frontier in immunotherapy.

GUEST BIO 

Laszlo Radvanyi, Ph.D., Professor of Immunology, University of Toronto
Dr. Laszlo Radvanyi has over 30 years of oncology research background in academia and leadership experience in leading a large cancer research institute as well as leadership positions in international pharma and biotech. He is currently a professor in the Immunology Department at the University of Toronto where his research focuses on the role of non-coding regions, including retrotransposable elements and human endogenous retroviruses, in cancer development and as modulators of the immune response in cancer patients. Dr. Radvanyi served as President & Scientific Director of the Ontario Institute for Cancer Research from May 2018 to November 2024 overseeing all aspects of running the research institute, including its administrative functions its scientific research strategy and programs, and building national and international collaborations. Prior to this, Laszlo worked at EMD Serono (Merck KGaA) was senior vice president global head of the Immuno-Oncology Translational Innovation Platform and senior scientific advisor for Immunology and Immunotherapy (2015-2018). Prior to this, Laszlo was a professor in the Department of Melanoma Medical Oncology at the University of Texas, MD Anderson Cancer Center in Houston from 2004 to 2014, where he ran an integrated clinical and basic cancer immunotherapy research program focusing on adoptive cell therapy. He left MD Anderson Cancer Center in 2014 to become the founding chief scientific officer of Iovance Biotherapeutics (2014-2015), a pioneering company commercializing tumor-infiltrating lymphocyte (TIL) adoptive cell therapies for melanoma and other cancers which recently got its first TIL therapy product (lifileucel) approved by the U.S. FDA in February 2024 under the product name AmtagviTM. Laszlo led the company in filing its first INDs and built its research and development team. Laszlo also sits on several national and international grant review panels and biotech advisory boards and is a sought-after expert in cancer biology and immunotherapy and a thought leader in the field of oncology research strategy.

HOST BIO

Rakesh Dixit, Ph.D., DABT, President & Founder, Bionavigen Oncology, LLC and Regio Biosciences  
Rakesh Dixit is an accomplished executive, inventor, and scientist with over 35 years of success with top biotechnology and pharmaceutical companies, including Merck, Johnson & Johnson, and Medimmune - AstraZeneca. Currently, he is president and CSO of Regio Biosciences and Bionavigen, LLC. He is a board member of Regio Biosciences and a key member of multiple scientific advisory boards. Rakesh is also a chief adviser and consultant for more than 20 companies worldwide. His biopharmaceutical peers selected Rakesh as one of the 100 Most Inspiring People in the Pharmaceutical Industry by PharmaVOICE in 2015. Rakesh received the Most Prestigious Award of Long-Standing Contribution to ADCs by World ADC (Hanson-Wade), 2020. From 2006 to 2019, Rakesh was a global vice president of the biologics R&D at MedImmune - AstraZeneca. Rakesh has unique expertise in developing biologics (e.g., monoclonal antibodies, bispecific biologics, antibody-drug conjugates, fusion proteins, peptides, gene and cell therapies, etc.) and small-molecule biopharmaceuticals. His areas of expertise include discovery, early and late preclinical development, safety assessment, DMPK, and translational sciences. Dr. Dixit conducted extensive graduate and post-graduate training in pharmacology/toxicology–biochemistry with both Indian and USA institutions (e.g., Case Western Reserve University, Medical College of Ohio, University of Nebraska) and is a diplomate and board certified in toxicology from the American Board of Toxicology, Inc. since 1992.

TRANSCRIPT

Welcome to The Chain, the podcast exploring the lives, careers, research, and discoveries of protein engineers, scientists, and biotech professionals. We look at the impact their work is having on the field and where the industry is headed. Tune in to stay up to date on the newest advancements and to hear the stories that are impacting the world of biologics.

My name is Rakesh Dixit. Today we are joined by one of the most influential voices in modern immunotherapy, Dr. Laszlo Radvanyi. From the work he has done on tumorpreting lymphocytes, leading to major uh cancer ecosystems like OEC OICR MD Anderson. You know, he has dedicated his career in turning deep immunology knowledge into real-world work through for We are thrilled to explore uh his journey into the science and his vision for the next area of the cancer treatment. So just very quick background about him. He's a, as I said, he's only recognized cancer immunotherapy leader. He has served with the full president and scientific directors of the Ontario Institute of Cancer Research, also led the immuncology programs in MD Anderson. Today he's continues to drive innovation as a professor of ecology at the University of Toronto and visiting scientists at Princess Margaret Cancer Center, advising biotech companies and leading cutting edge research into cell biology. So, Dr. Laszlo, let me get started before I start my question. Would you like to describe very quickly within a few, within a minute or so, about your interest in this area and what prompted you to get into immunology?

Sure. Thank you very much, Rakesh. It's a real pleasure to be doing this interview and to share my knowledge and my career and hopefully inspire um scientists, both young and old, to go into research and specifically go into immunology and cancer immunology and immunotherapy. I think it really holds a secret and a lot of the future successes into really solving the cancer problem. Briefly, I've been interested in working on tumor immunology for almost probably 25 to 30 years right now. Initially, my interest was sparked when I was a graduate student at the University of Toronto. I was doing a PhD in clinical biochemistry, but my research project was really hardcore immunology at the time. I was studying what is called programmed cell death with T lymphocytes as a mechanism of self-tolerance to prevent autoimmunity. So back then, the whole area of apoptosis or programmed cell death became very, very well known and very popular because of the, you know, our knowledge of the molecular pathways regulating this program form of cell death became known. Um, and then it was applied to immunology. I kind of got interested in tumor immunology from a number of reasons, because one, I'm a rebel, I'm always trying to do something different to challenge the dogma and challenge the norm. Back then in the early to mid-1990s, tumor immunology was not a very much of an accepted field.

And I remember going to my first international conference in Budapest, Hungary, the International Immunology Congress. And during one of the poster sessions, there was these a row of posters in the back in the corner of the of the auditorium where a bunch of a few of these uh uh scientists were huddling around their posters, not many people were looking at them. And then they were all on about tumor immunology, and there was like hardly anybody looking at them because those were the big HIV research days and things like that. And I really looked at those posters and really thought, hey, maybe this is this is something that's really been untapped.

And also, you know, how T cells get activated and proliferate and how they can be potent killers and some of the initial data that has that came out at the time that, you know, indeed T cells can infiltrate tumors. But we didn't know about the molecular pathways back then that regulate a lot of T cell activation and why tumors suppress immune responses in cancer. And as you know, then you know the T cell checkpoints came in. And one of my one of a part of my project at the time, and we were probably the first to discover this during my PhD, was that toe stimulation through molecules like CD28 on the T cell uh prevented activation-induced cell death. And then several researchers, such as Jeff Bluestone, Jim Allison, and others, Gordon Freeman, etc., in the US started researching on some of these co-inhibitory molecules, such as CTLA4 and PD1 PDL1 axis. And then with the knowledge that C D28 is is very important in co-stimulating T cells, and then how these pathways began blocking T cells and avoiding or suppressing C D28 co-stimulation, I really became very interested in well, there's got to be a way uh in in which T cells do play a role in in uh fighting cancer.

And, so overall, I think I kind of got into tumor neurology kind of indirectly through sparking my interest, wanting to do something different and challenging the dogma and knowing that it was an unsolved problem. I think back then, and to a certain extent, even now, tumor immunology and how to fight the cancer with the immune system is still one of the major problems in human biology and biomedical research. Although we've made headway, there's a long way to go because, as you know, only a fraction of the patients respond to the most powerful immunotherapies, including cell therapies, as well as checkpoint blockade and other immunomodulators. So I'm always a person that likes to tackle top problems where you need really to think out of the box and be creative. And, you know, I think the harder the question, the more profound the answer, and the greater the impact.

Yeah, so I think you are you touched a very important point, you know, that I tell you that about maybe about 10, 10, 12 years back when I was working on the lots of immunotherapy like molecules in my previous role at Medimmune AstraZeneca. You know, there were there were oncologists, clinical oncologists, they really didn't believe in immunotherapy. They said, Yeah, we have tried IL2, they're just so toxic, you know, blah, blah, blah. You know, they have more toxicity. This chemo environment, microenvironment is so rigid, it won't let T cells or any of the things that will kill them. Why you're wasting your time, go back to you know, chemotype drugs and all that stuff. But then CTLA4 antibody came from BMS, and that totally changed the approval of that antibody, totally changed the entire field. And now it's created a gold rush, you know, if you want to say that way.

And now, you know, CART cell therapies, a huge number of therapies that actually trying to bring the immune system to kill tumors, you know. Uh, and yes, we we all know not all patients are still responding because your immune system is so beaten up, they can't they cannot, you know, they cannot get activated as much. But still, I do think that our best defense is too is our immune system, you know, no matter what people say. So I think what the point you were making earlier makes a lot of sense. So, one question that I have, you know, you have been working in this field for a long time, even when people did not believe in immunotherapy as much. So, if from your perspective, how the field of immunotherapy has evolved over the last decade, last 10 years, and what do you think the true breakthroughs that are moving the needle for the patients? You know, where we we are giving a lot of hopes to patients to live longer.

Yeah. First of all, I think one of the major impetuses or driving forces um that really drove the initial successes and are sort of breaking through the ice, so to speak, of cancer immunotherapy and launching, you know, our knowledge and how to drive successful immune attack against tumors was supporting basic research and basic immunology. I'm a big believer in this, and I think right now, with all the push towards translational research and you know, immunotherapy, biotech, it's it's all great. Of course, we have to apply and translate what we know. But I think a lot of the initial successes and which led to where we are now in immunotherapy, is because we did basic research and curiosity-driven research. So I'll give you a perfect example. At the time when I was doing my PhD, I think back on the some of the serendipitous uh observations that I made, because I was studying program cell death and how co-stimulation may inhibit activation-induced cell deaths of T cells.

And I really have to credit, you know, really inspirational scientists such as James Allison, for example, when he was at Berkeley, who was an amazing scientist and mentor there, but also a person who's always shared his knowledge and shared his reagents. So I asked him for his antibodies against anti-CD28 and anti-CTLA4 at the time when he was still at Berkeley, and he just openly shared an incenton. And next thing you know, a vial shows up in my lab in our lab. And it's really collaborations and open collaborations and open thinking and really support by people like Jim Allison and other really great immunologists that really has spurned the field. And a funny observation I made is one of the antibodies that I tested in my activation in due cell death assays was his anti-CTLA4, which I thought was an agonist antibody because back then we didn't know whether it was a costimatory molecule or an inhibitory molecule. And then when I added it to my cultures of T cells that were getting activated, um, all of a sudden the T cells went crazy and started to proliferate like crazy.

Wow.

And of course, they didn't undergo activation into cell death. But I didn't make that link, that intellectual leap at the time. And, you know, you kick yourself when you look back about, oh, you know, oh, these cells now are proliferating like crazy. Maybe if we do that in a cancer model and add an antibody, will the T cells proliferate like crazy and get activated, maybe fight the cancer. But Jim's lab in Berkeley and his his amazing team there made that intellectual leap. And it's these chance intellectual leaps that really have catapult to immunology. And so we have to really be cognizant of you know of that fact. And so, but of course, there's been tremendous headway made in now applying, you know, this knowledge into the development of new novel reagents. And so, really, what has driven the field forward in the last several decades is really this a fantastic collaboration and interaction between bench basic researchers that are still uncovering all the secrets of the immune system and how the immune system can fight cancer and why it's suppressed in cancer with translational and industry scientists and that take that knowledge and really make those reagents and those molecules that can actually be clinically actionable.

It's one thing to do something in a mouse and do something in vitro in a human situation in a human culture. It's another thing to actually generate a druggable molecule, be it a small molecule or a biologic. And I think one of the amazing things we've seen over the several decades now in the biomedical field, especially in cancer immunology, is this amazing interaction and close working together of basic immunologists with translational immunologists with industry to more seamlessly translate really what the discoveries from the lab into the clinic and then making those really sometimes hard decisions about what not to pursue and what to pursue, because sometimes not everything is really realistic in terms of translating it and into the clinic, and towards clinical trials, towards an actual drug for a patient.

So I think I was really happy to see this transition over my career where not only industry really has embraced, you know, academic institutions, cancer centers, et c., to more seamlessly bring these discoveries out and then help academic centers develop them. But also there's been a shift in terms of uh philosophy of academic centers, especially in the United States and now also now in Canada, of you know, researchers thinking in a more translational way, you know, not just, well, I want to get my nature paper or my science paper or make that big, beautiful, amazing new mechanistic discovery, but okay, how is what I'm doing applicable to a patient? How am I going to get it into a patient? How do I integrate patients into my research so I make it more applicable to humans? And I think this, these shifts um have really helped a lot in translating over the years.

And also, of course, we can't argue that these initial successes with anti-CTLA4, tumor infiltrating lymphocyte therapy by Steve Rosenberg, and all the amazing things that the National Cancer Institute has done under Steve Rosenberg, who really has single-handedly not only revolutionized tumor immunotherapy because he has done so many different things, not only cell therapy, cytokine therapy, CAR T cell therapy, vaccines, but he's also trained the most brightest and best tumor immunologists and clinicians in the world that have now gone out into the world and have disseminated this knowledge and and all these uh applications. And so we really owe him and the NCI, you know, a huge, huge thank you. And, you know, I, for one, being in Canada, hope that, you know, the US government continues to support the National Cancer Institute to the utmost because we wouldn't be where we are now without them.

Absolutely totally agree with you. So on the follow-up question that I have for you, um, of course, we have now several checkpoint, immune checkpoint inhibitor antagonist antibodies, and they they have helped us a lot. But one of the things that I was when I was in at my previous role, hat's AstraZeneca Medimmune, we had several immune agonist molecules, like direct immune agonists, like Gitter, OX40, CD137. Unfortunately, it looks like the immune agonists, you know, have a hard time in really bringing up the T cell to versus the immune antagonist, you know, checkpoint antagonist, you know. What are you what are your thoughts on this? Why it's so hard to activate the immune system versus inhibiting a, you know, taking out inhibitory signal that activates. It's like, you know, pushing the pushing the brake is is is is is uh giving us good results, but accelerating the, you know the gas is not doing anything good. In fact, it has failed miserably a lot of you know quite often, you know.

Yeah, I mean, I think you can talk to many cell biologists, be it cancer biologists, molecular biologists, um, in who study various different organismal systems, be it um in humans or rodents or other single unicellular organisms such as yeast, it's always been much easier and much more direct and interpretable to knock out a gene or to modulate down regulation of a gene and inhibit a pathway, then all of a sudden putting on the accelerator through overexpression of a gene or a pathway, uh which you know sometimes you can't control by over-expressing a gene or turning on a particular pathway. Um, it's been even in, you know, in in mouse models, I mean, the classical transgenic knockout versus transgenic.

I mean, if you look just look at the whole trend in the literature and the science there, there's been a plethora of hundreds to thousands of knockouts versus very few, you know, transgenics. I mean, as opposed to TCR transgenics, B cell receptor transgenics, and things like that, because it's just naturally difficult to control the expression. Of course, tissue-specific promoters and inducible promoters and things like that have helped, but generally in the body, when you're talking about immunotherapy, uh, you know, and putting in an agonistic antibody against Gitter or 41 BB, which is another problematic molecule still that we're still trying to grapple with, or OX40, CD40 is another one that people have grappled with to try to activate dendritic cells. Um, and then, you know, that that fine line between activation and then toxicity, and where do you find that therapeutic window? So it's always been much more of a sort of a conceptual as well as uh molecular challenge, uh signaling challenge to knock out versus knock in or or or or turn on uh or accelerate a pathway.

But with that said, I think there are newer technologies out there that we can fine-tune uh these agonistic antibodies and and and really realize that we don't really have to activate these pathways so strongly, but we can sort of tweak them and activate them um it less strongly by modulating the uh features, the molecular features of the actual reagents, be it lower affinity, modulating avidity uh and things like that, and also dosing. I think you know dosing could be another area that we can take a look at. Now, these, of course, clinical trials are very challenging because sometimes, you know, just like when you titrated, you know, a pH, an acid with a base in their chemistry lab, you add one more drop and boom, you know, all of a sudden the the the the pH increases like crazy and you can't control. So it's been very difficult. But I mean there's been conditionally activated molecules that are now being developed that get activated in the tumor microenvironment by proteases.

There's been masking, you know, molecules that have masking uh subunits that sort of open up more, let's say, because of an acid microenvironment versus or a protease-rich environment. We can learn a lot from natural signaling, for example, how you know certain molecules in the tumor microenvironment change conformation and allow ligand binding, such as VISTA and PSLG1, for example, and things like that. But it has it has remained difficult. And I think we need to do more basic biology in order to understand when and where and how to use these agonistic antibodies. And I think it just goes to show you again, we have to go back. Sometimes industry and translational uh research and biotech has to just come to the realization with certain classes of molecules that we have to go back to the drawing board. We just can't be flogging the same horse, you know, like as people say, you know, the the definition of insanity is just trying to do the same thing over and over again and expecting a difference.

And so here I think with agonistic antibodies, we have to go back to more basic research and understand when and where and how um these agonistic signaling pathways play a role in the immune system, such as Gitter, and on what different cell types. Because one of the other problems, I'll I'll give you one example, ICOS. Okay. Now I don't want to be controversial here, but of course, ICOS became a big hit because of some of the data coming out of MD Anderson that, you know, it it was upregulated uh during anti-CTLA4 therapy on s on on effector CD4 cells, supposedly. And so then everybody went crazy and said, Oh, that's you know, agonistic ICOS antibodies, that's that's it, you know, and then all these animal models, and of course, jounce, you know, raised tens of millions of dollars. And at the at the same time, there were scientists like myself who were working at the time also on regulatory T cells and cancer, and that were finding that wait a minute, there's other subsets of T cells that also induce and express very high levels of ICOS and undergo ICOS co-stimulation, and namely very highly active, highly suppressive T regulatory cells. And we and others showed at the time that ounce for ounce, if you add an ICOS co-stimulatory signal to an effector CD4 or T reg, that T REG is going to get much more activated and has much higher levels of ICOS.

So in the tumor microenvironment, what's going to happen is if you have T regs there, the T regs are going to mop up a lot of an anti-icost and get activated. So you're just going to activate a bunch of ICOS positive T regs. And so unfortunately, a lot of people ignored that because of dogma and hype in the field. Again, this is an example where we all have to keep an open mind and not fall for the dogma. I'm not saying ICOS is not great to co-stimulate CD4 T cells. I'm not saying that. But I think we have to understand, again, it's a perfect example of finesse and more nuanced science where you have to figure out how and when and where you apply these types of molecules. And you need to have biomarkers, better biomarkers that would predict or tell you, okay, when I should use an anti-Icos agonistic, when I should use an anti-gitter, or when I should use an anti-ox40, or when I should use an anti-CD27, uh, you know, for example. I think these are the these we like I say, we still need to research these scenarios and uh figure this out. But with that said, there are molecules such as 401 BB that show great promise and um and even uh TNF receptor antibodies. And I think right now, I think what's really exciting and what's finally you know taken off is more targeted, you know, employment or targeted activation of these molecules in specific microenvironments by basically using bispecific molecules and and trispecific molecules, where we can now target co-stimulation to the rife cell, to the right tissue, or target it to the tumor. And you know, right now we have bispecifics with you know PD1, 41 BB, and and all sorts of things emerging where we can target, you know, co-stimulation, for example, to the activated T cell, or in trans by using biospecifics targeting PDL1 and then 41BB and things like that. So I think you'll you'll be seeing more and more of these types of molecules being tested in the clinic. And I think that could really um help uh improve the situation there.

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Yeah, so I think just to follow up on the agonist antibody question. In 2006, when the CD28 agonist was tried, it we know that it worked. It created massive cytokine release, massive T cell proliferation. So is there, so it's not that the immune system cannot get activated? It's like how do you touch that, what I call gas on, you know? And are there differences between different gas-on approaches in immuncology? And how can we tame down the CD28 pathway so it doesn't produce this massive cytokine release syndrome that almost killed six volunteers and still take the advantage of CD28? Because we know clinical inpatients are in the humans, it worked well. I mean, this is the only mechanism I've seen that created such a potent uh T cell activation, along with obviously all all the other bystand effects that came through with that uh pathway. Yeah.

Well, I mean, going back to that clinical trial, that unfortunate incident in that phase one trial, was that first of all, it's a very poorly designed trial.

Right, right.

It would never have passed ethical uh, you know, uh, you know, ethics board approval, um, especially blindly going in more, you know, just going into normal donors.

You never should run these trials in LDS.

Yeah, I mean, yeah. But with that said, you know, we learned a lot from that trial. And that is that you can't use such a high affinity agonistic antibody and and and you know you you know, you need to be careful. So it really was a wake-up call to the biomedical research community and the pharmaceutical biotech community that you we need to be really careful with agonists. We can't just, you know, go go and just use them willy-nilly. And it's sometimes very difficult to predict from preclinical models, animal models, in into humans. And so, because there are differences in uh these these pathways, these co-stimulatory and co-hibatory pathways between rodents and and and humans, where certain pathways are more active or more emphasized in the mirroring system and less emphasized in the human system, and vice versa.

And so Icos, for example, is a great example. CT, you know, B71 interactions between different molecules and B72 between C D80, CD86, CTLA4, there's slight, you know, nuances there too, as well. And some of the other co-signatory pathways, such as the CD2 co-signatory pathway. Um, there are there are nuances there. But yeah, you're right. I mean, I mean, CD28, you know, is is a is a great co-signatory pathway. And one of the ways that people have been tackling it right now is by making biospecifics by targeting CD28. So there's several molecules that are in development that in fact don't show that toxicity, as far as I'm aware. Correct me if I'm wrong, but there are some people making headways, there's several biotechs that are that are broaching that sort of arena, although very delicately and very cautiously because of the past history of CD28, for example. And unfortunately, like with you know uh gene therapy, when you know the original uh, you know, adenovirus uh uh or retrovirus or adenovirus therapies went in when there were a few deaths at the time. Um, these types of incidences set the field back um many years, sometimes, you know, even a decade. Um, and and because people are afraid of the risk and they don't want to do it anymore. And so it's it's unfortunate uh that one bad clinical trial or one ill-fated or ill conceived study can set a field back. And I'm and we've seen examples of this, right? In in in biotech and in therapeutic development.

Yeah, you you are absolutely correct on that. Well, I think you know, in the RD business, there will be some accidents and we need to learn from those. Yeah, you know, but if you look at the number of trials that have been run with the immune modulating molecules and the safety problem, they're still very, very rare. There's few much.

Yeah, and also keep in mind that we haven't really investigated natural ligands as well as we should. We've jumped on the antibody bandwagon because you know, antibodies, you can make antibodies now very easily. Anybody can make an antibody by screening a single chain FB human library or a CAMOLID library or whatever for a VHH or whatever. I mean, you just go to a a CRO and you can make an antibody now, and then you know, they'll send you a really good set of antibodies. You can test them and away you go, cars, you know, agonist antibodies, defector antibodies, et c.

But I think we've been avoiding the natural ligands. I mean, the immune system developed its its all these processes and amazing ways of fighting off infections and fighting cancer through natural ligand receptor interactions, right? And which are generally low affinity and really rely more on the avidity effect more than anything. Whereas antibodies generally rely, at least in the past, on affinity effects and not so much avidity effects. And now we're getting a little bit smarter by generating different kinds of antibodies that can, you know, utilize uh avidity effects through hinge hinge region changes and things like that, and biospecifics, for example, and and biotropic antibodies and and and things like that. So um, but I think going back, um, there are several biotechs that are kind of still struggling in the ligand space, um, and you know, making trying to make multimeric ligands, I think there's still some room for development there. And I think we should still pay attention to that area um as opposed to you know just using antibodies against everything.

Again, you know, the field, unfortunately, you know, because of who we are too, because science is a social institution, biotech is a social institution, we like quick fixes as humans. We want quick uh solutions to problems, you know? And you know, I think sometimes we're not careful enough in drug development to um cater the technology to the science and to the biology. We we try to uh put round pegs in square holes by trying to make the biology conform to the technology. And so, you know, we try to solve a biological problem or a disease problem by using a particular technology, a particular type of drug uh formulation like biologic antibodies, and then we try to apply it to all the diseases, as opposed to sitting back and saying, okay, what, you know, and making better decisions up front and spending the time and money a little bit more to say, okay, but what is the molecular uh kind of structure? What is the type of molecule we should be targeting this pathway for this particular situation or this particular patient or this particular type of types of patients, rather than just using one, you know, one-shot solution for everything. So I think we need to get better at doing that, uh, especially making biologics. And I think we'll find perhaps that, you know, some ligands that have been sort of fallen by the wayside may come back and say, well, this might be a better way of activating some of these pathways versus agonist antibodies. And so yeah, I think I think that, and there's some and and there's examples of that, you know, emerging right now uh in in the field, uh especially in innate biology, uh activating NK cells. There's, you know, the VEGF trap was originally a molecule, you know, a ligand. There are trap molecules uh such as TGF data trap and things like that um that are now emerging. But I think we can use that for agonism too as well.

So I think this is the one of the more important questions for me, at least, and also for the audience, is that what do you think uh is the next uh frontier in immunotherapy? If you have to, I mean if you had a crystal ball, I mean, of course, there are other till therapy, engineer T cells, biospecific. We have seen a lot of progress in biospecific, cytokine, and also anything which is well beyond people's imagination, where we say, you know what, we haven't tried this. Let's see if we can push the boundaries a little bit more, you know, and to bring bring bring our immune system a lot more active in killing tumor cells because, as you know, in the solid tumors, still we have problems, you know, treating solid tumors with uh immunotherapy because of the resistance process, tumor microenvironment so rigid, and it's still, you know, we have made a lot of progress, but still there are several tumor types where these these immunotherapies don't do squat. You know, I mean you talk about pancreatic cancer, colorectal, and I can just name, keep on going on this list. There are only a few cancers that are responding so well to immunotherapy, but then there are several of them don't respond at all, especially solid cancer. So I think what I would like to hear from you where you think the field could improve on, uh and and of course use the biology and and the knowledge of immunology to make it better. Yeah.

Yeah, well, that's a huge question, a lot of question. I'll try my best to answer that. It it really is a multifactorial problem, a multifactorial uh solution that would be involved in this multidisciplinary solution. And it'll it'll it's gonna, you know, we're not anywhere near to solving the cancer problem with immunotherapy. So a note to the young scientists who may be listening uh to us here right now, you have plenty of work to do. Don't worry, we're not gonna solve cancer and immunotherapy anytime soon. So, you know, there's a lot of plenty of work for you guys left and you girls left. So, you know, please come and explore the most exciting field of biology and of cancer and and therapeutics. It's it's an amazing maze, you know, how to apply the immune system. So so in answer to your question, I think, well, it's it's it's a multifold answer. Let me start by saying, you know, making some specific points. Number one, in order to really realize the tremendous, you know, power and potential of the immune system against cancer, I uh is is we need to start diagnosing and detecting cancer much earlier, especially for unmet need uh cancers such as pancreatic cancer and other types of cancers where, you know, in in in lung cancer, where uh you know you detect it, you know, 20 or 50% of cases at the metastatic stage when it's already there's also local regional spread or metastatic uh widespread spread.

So you know, there's a lot of headway being made into you know uh screening, liquid biopsy-based cancer detection and early stage, especially in high-risk individuals, such as you know, hereditary gene carriers such as BRACA, Paul B and Lynch syndrome, et c., P53, leafraumania, et c. So I think that's a whole parallel area that's really developing and rapidly evolving, you know, the Grail tests, the, you know, methylation tests, et c., you know, extracellular vesicle-based tests and things like that. And I think that has to communicate with the immunology, and the immunologists have to communicate with these people. So it really is going to require a multidisciplinary, collaborative convergence approach where the immunologists can't be sitting in one room, the cancer detection people and the molecular biologists and the next gen sequencers in another room, and the targeted therapy people in another room, and then they every once in a while come to a meeting like AACR or ASCO, and then they, you know, give a few talks and then they talk about a few ideas and then back they go.

I think we need to start forming more convergent multidisciplinary teams. And I think a lot of major funding organizations across the world, such as Cancer Research UK through Grand Challenges, AECR, Stand Up to Cancer, NCI, et c., have really recognized that you have to really bring together multidisciplinary teams of researchers. And so early detection, early intervention is going to be one key. That then links into how do we then activate the immune system in cancer patients as soon as possible. Well, one of the things that I've been pushing and really advocating for for many years is we have to really push neoadjuvant therapies for cancer. If I may be so bold, I think we should be treating almost all cancers through neoadjuvant immunotherapy right after diagnosis to activate the immune system as soon as we can. Because even in the colder tumors, there is some immune component, either functioning or non-functioning, that we can impinge upon to stimulate a non-existing immune response or enhance an existing immune response.

And so we have to also take into consideration that surgery and chemotherapy are immunosuppressive. We finally have come to that realization. Clinicians are finally accepting that, and they have to be used in a very smart way to combine with immunotherapies. And then when you do apply chemotherapy and surgery, we have to be very um attuned to how that is modulating the immune system. We now know that, and it's finally being accepted after you know, certain surgeon scientists and some of my colleagues, such as Rebecca R. at the Ottawa Hospital Research Institute, have been advocating for years that surgery is very immunosuppressive. We cut out the tumor, but these patients are very immunosuppressed, they get immunosuppressed. So if we can activate the immune system in a neo-adjuvant setting, even if it's one or two doses of anti-PD1 or a vaccine or something, and then we go to these traditional therapies and where we don't delay that standard of care, I think that's very important. Kickstart that immune response in the neoadjuvant setting, detect cancer as earlier as possible, and then follow up.

You know, I used to joke with my friends at MD Anderson, too, my colleagues, that, you know, who were talking about adjuvant cancer vaccines, because there was a whole, you know, phase or era, and it's still being researched, you know, of adjuvant tumor vaccines, which are now being tested in several scenarios, such as melanoma, pancreatic cancer, et c. But I always sort of reminded my colleagues, especially my clinical colleagues, is that by removing uh the source of the antigen, which is the tumor, you're relying on those effector memory cells, those short-lived memory cells, which uh effector memory cells that really are the most of the antigen tumor-specific cells to survive in the absence of any antigen. A lot of those cells are gonna fall by the wayside. And if you then start vaccinating a month or whatever later, that that's not that's not gonna you what are you reactivating, right? Unless you're reactivating a naive T cell population or a young, younger central memory or stem memory population. So, so there was these sort of misnomers in how we applied immunotherapy like vaccines in the adjuvant setting. And I think now we've learned those lessons and now we know that we need to apply immunotherapy and also applying immunotherapy in healthier patients.

Like one of the things that and again, learning how to use immunotherapy in the right setting at the right time. Like we uh one of the areas that of course I became known for and you know, we developed was tumor infiltrating lymphosite therapy for melanoma, and we started developing it for other uh areas such as triple negative breast cancer and and other things. But you know, even when I was at MD Anderson 15 years ago or so, we were advocating for uh till therapy to be used in for first-line metastatic melanoma treatment and not after the patient failed multiple lines of therapy, especially checkpoint therapy, which which still doesn't generate as good of T cells than if you would um grow those T cells out before checkpoint and then use till therapy in the primary, you know, metastatic setting as a first line and then add checkpoints to it. I think again, we need to start being smarter in which how we use different therapeutic modalities to in in in combination for the best you know uh outcome for the patient.

And then, of course, keep in mind, you know, this personalized or more precision um kind of approach for immunotherapy that one one size doesn't fit all. And so for one patient, maybe a vaccine is needed to kickstart an immune response because it's a colder tumor, the patient didn't have any music, then you do a checkpoint, then you do kills, and then on top of that, other things. So I think we just need to get smarter at how we apply and when we apply immunotherapy, the earlier the better, the healthier the patient, the better, the earlier detect cancer, you know, the better. And of course, combination therapies are going to be, you know, the norm. Now, another area that I think, you know, car T cells are are are gonna still continue to be a mainstay. I think people are gonna be, you know, developing newer and newer CAR T cells to target more and more different antigens using and or gates, uh, et c., better co stimulation, better endodomains. So, but I think even T cell therapy, I think, and I've argued this too uh for many years, even TIL therapy, TCRT cell therapy, CAR T cell therapy, we have to view them as adjuvants, not as, well, they're going to be the sole drug and they're going to eradicate every single tumor cell. I think we have to start to really conceptualize this more in a broader sense, that these types of T cell therapies are going to inflict damage, they're going to kill tumor cells, they're going to release antigens.

And then we then need to say, okay, how what can we do to then augment uh the antigen presentation and the priming of that secondary immune response that's triggered by the damage done by these cell therapies, be it vaccines, be it checkpoint blockade, be it activating dendritic cells, and that that is going to be very important. And with that said, I mentioned dendritic cells. This is another area that I think has not received enough attention. Um, you know, myeloid-derived suppressor cells, tumor-associated macrophages. We've been like, you know, huge area, a lot of talk, and of course, T cells, and how do we activate T cells? How do we get into the tumor, et c.? But I think we haven't talked enough about dendritic cells, you know, um, and and you know, I'm sure that, you know, Ralph Steinman will be saying, yeah, yeah, yeah, because we need to better understand how dendritic cells get activated, where they can get activated, how do we can activate them better? And I'm pleased to see that, you know, areas such as the tertiary lymphoid structures that can prime tumors is now part of the cancer immunity cycle uh as well, that Ira Melman recently presented. I think really kind of identifying how we can activate dendritic cells better is going to be very important.

And thirdly, I think, you know, tailor-making these molecules to activate dendritic cells versus reprogramming myeloid cells and activating T cells in the right order could be really useful. And lastly, antigens. I mean, we we we went through a whole, you know, kind of a whole um evolution of cancer vaccines and tumor antigen targeting from overexpressed antigens to tumor-specific antigens, where we have to break tolerance and things like that now to neoadjuvants because of huge advances uh of next generation sequencing of cancer. Um, but I think one of the areas that you know is going to make a huge impact is is you know what is called the dark proteome or the dark genome. We now know that most antigens are actually probably not being presented, um, emanating from coding regions, and probably will be actually generated from non-coding, either because of truncated proteins, fusions, breakpoints, and things like that. But also my area of research, I think, will make a huge impact in the years to come, and that is starting repeat retrotransposable elements and human endogenous retroviruses. We now know that practically in every single type of cancer, because of this embryonic programming or or dedifferentiation that occurs in cancer, it turns on due to the epigenetic modifications, DNA methylation changes, loss of epigenetic regulation, turns on uh expression of things like line elements, sine elements, alluelements, and in human endogenous retroviruses. And we now know that this can happen actually very early on in cancer and continues uh to later stages of cancer, including metastatic disease. And so I think there's been an increased amount of activity in identifying um actually targets that uh of this uh retrotransposable elements and how we can you know intervene early against cancer, but also they represent new antigens that we can target along with other antigens, the multi-antigen vaccines. And I think we'll be seeing a lot of uh a lot of uh progress in that area soon.

Yeah, I fully agree with you every point you made. And thank you so much for the great insight in your therapy, and and I'm pretty sure the audience will learn a lot from your from our discussion. Thank you again.

Okay, thank you very much, Rakesh. And thank you everybody for uh inviting me to do this.

Okay, thank you again. Bye.