LIVE from the 2025 SITC Annual Meeting, ft. Dr. Sandra Demaria
Dr. Patrick Hwu welcomes Dr. Sandra Demaria, Professor of Radiation Oncology and Pathology at Weill Cornell Medicine and a global leader in cancer immunology. Dr. Demaria shares her pioneering research demonstrating how radiotherapy can transform tumors unresponsive to immune checkpoint inhibitors into responsive ones—a discovery that has reshaped cancer treatment strategies worldwide.
Recorded live from the 2025 SITC Annual Meeting, this episode highlights the emerging science shaping the future of immunotherapy, including late-breaking abstracts and press program findings presented at the conference. As the current vice president of SITC, Dr. Demaria discusses the evolving synergy between radiation and immunotherapy, insights from studying the immune microenvironment and the translation of her discoveries into ongoing clinical trials. She also reflects on the collaborative energy that defines SITC and continues to drive the next generation of combination immunotherapies.
Podcast Transcript
Hwu:
Welcome to the ImmunoVerse, a podcast that brings the ever-expanding universe of immunotherapy to life through the voices of those advancing this groundbreaking field. I’m Dr. Patrick Hwu, president and CEO of Moffitt Cancer Center and a career immunologist. In each episode, I sit down with pioneering experts who have shaped the past, present, and future of immunotherapy, uncovering breakthroughs, challenges, and the science driving this lifesaving innovation. Today, we’re coming to you live from the 40th Annual Meeting of the Society for Immunotherapy of Cancer, or SITC, the world’s premier gathering for those at the forefront of immuno-oncology. And I’m thrilled to be joined by Dr. Sandra Demaria, professor of radiation oncology and pathology and laboratory medicine at Weill Cornell Medicine and vice president of SITC. Dr. Demaria is internationally recognized for pioneering studies demonstrating how radiation can synergize with immunotherapy, showing for the first time that focal radiation can help overcome resistance in poorly immunogenic tumors. In this special bonus episode, we’ll be discussing some of the most exciting science unveiled here at SITC — from new insights into tumor-specific antigens and immune cell heterogeneity to groundbreaking first-in-class therapies that could reshape the field. Welcome to the ImmunoVerse, Dr. Demaria.
Demaria:
Thank you very much, Patrick.
Hwu:
It’s wonderful to have you here, and thanks for your leadership of SITC. How many people are here at SITC this year?
Demaria:
It’s a little over 4,200 people, so it’s a great crowd.
Hwu:
Wow. It’s really grown every year. It’s one of the largest immunotherapy meetings in the world, right?
Demaria:
Yes.
Hwu:
And it’s a special occasion for SITC this year, right?
Demaria:
Yeah. We have our 40th anniversary, and it’s just amazing how the field has grown and changed. We kind of remember even just 20 years ago, when it was just a few hundred people who were enthusiastic about the potential power of the immune system to control and actually maybe cure cancer. And although there was some sporadic evidence that it could happen in patients, there were no approvals for any immunotherapy at the time. And so the field has grown so much.
Hwu:
Yes, absolutely. And as you pointed out, 40 years ago almost no one believed the immune system could fight cancer. And certainly even 20 years ago it was a very small society. It’s exciting to see it grow.
Hwu:
This large event has both biotech, big pharma, investors, academics and the government all together trying to move toward a really ambitious — but I think feasible — goal: another hundred approvals in the next 10 years. Think of how many lives we would save.
Demaria:
Yes.
Hwu:
Absolutely.
Demaria:
That is the goal. And I think we had a bit of an inflection point this morning with the Smalley Awardee, Dr. Ira Mellman, giving his talk. And he called it the “renaissance of cancer immunotherapy,” pointing out that indeed — well, it’s such a new field, why do you call it a renaissance? — but because we are at an inflection point with a lot of really completely new concepts that can become effective agents in cancer patients. There are a lot of new bispecific T-cell–engager antibodies. We are really understanding in depth how the tumor microenvironment functions and how different it is in different tumors and different patients. We know that many patients respond to the current immunotherapies, but there are a lot more who don’t. And this is a big challenge, and that’s what we really have to take on — to understand exactly what intervention is missing for the immune system of a patient to be able to work against the tumor.
Hwu:
Yeah, both Dr. Mellman this morning as well as SITC had a workshop on AI before the meeting, right? So tell us about that workshop.
Demaria:
So we had a great keynote presentation by Gary Nolan, who is one of the pioneers in developing single-cell analysis technologies. He has developed CyTOF and the MIBI approach and others. And basically, it’s a way to really understand how the cells interact in the tumor microenvironment and characterize not only the type of cells that are there but their function. And there has been all this technology that has produced a lot of data, but there are still a lot of things we don’t understand. And a quantum leap comes from being able to actually organize all this data in models — in large language models — that can help interrogate the data in a way that will bring out profiles of different immune microenvironments in different patients and different tumors. And he actually had this very nice stage about how the draining lymph node can really be conditioned by the tumor to become the habitat that causes systemic immunosuppression, or in some cases actually fights the tumor. So it is extremely important that we figure out what the molecular mechanisms and potential therapeutic targets are that lead to these different situations so that we can actually decide what to do.
Hwu:
That’s great. Yeah. So what you’re saying is now there are so many ways to analyze the data. We have so much data it’s actually hard to interpret it all. And so AI is helping us interpret, for example, in this case, the lymph nodes that drain the tumor — and how sometimes you would think they would be good because those lymph nodes make the immune cells to fight the tumor, but yet the tumor can release substances to actually make the immune system paralyzed against the tumor. And so it’s a complex interaction of cells. And so all of this data can be more carefully analyzed, more focused in the analysis using AI.
Demaria:
Absolutely. Another area that is very interesting in AI is designing or understanding really how the T-cell receptor, based on the sequence, can predict what antigen it recognizes. And this could be extremely helpful because we could design new TCR-engineered T-cell agents. So these are just two examples of the many things that have been discussed at the workshop.
Hwu:
Wonderful. And Dr. Mellman also mentioned that this morning in his Smalley Award–winning talk — where we’re at an inflection right now — we’ve had huge successes with immune checkpoint blockades such as anti-PD-1, Keytruda, Opdivo therapies, but now there’s a bit of a plateau, and just adding other immune checkpoint blockers has not really helped except in rare cases. And so he said maybe we need more immune T cells that can recognize the antigens, and one of the ways is AI potentially helping us design new T-cell receptors that we can use to fight the cancer. I think there were three papers in July in Science—
Hwu:
—looking at that, which is exciting. And he was also talking about using vaccines and careful vaccine design along with a combination of T cells plus vaccines to try to enhance the anti-tumor immune response.
Demaria:
Absolutely. There are a lot of antigens that are extremely difficult to predict. We don’t have, at this time, algorithms to predict them, but they could be very powerful targets for the immune response. So that’s another very important area. And also we need to understand all the other immune cells besides the T cells. There was a very nice session yesterday on the myeloid cells and B cells, and Tullia Bruno gave a very nice talk about how B cells may be activated or actually become kind of exhausted if not properly activated in TLS. So I think we have the opportunity to really figure out better how to target the myeloid innate immune compartment that is critical for the function of the T cells in the tumor. There can be dendritic cells — they are really important to be there for the T cells to function and get activated. But there are many other myeloid cells. Some of them can either be good or bad.
Hwu:
So what you’re saying is that there actually is a very complex interaction of cell types in that tumor. We often think of the T cells because they can directly kill the cancer, but yet there’s macrophages, there’s B cells, and any of these other cell types can be both helpful to the T cells and harmful. So it’s really exciting that we’re seeing a lot of work here talking about the B cells and the macrophages and many of the different subsets of macrophages. And so as we determine and understand more of these subsets, we can then manipulate them to enhance the ability of the immune system to destroy the cancers.
Demaria:
Absolutely. And I think we have to put into the picture — and that’s what makes it really complex — also the metabolic state of different areas in the tumor microenvironment that affects the immune cells and the lymphatic circulation. So all these factors and the nerves—the exciting session yesterday was about how the nervous system can crosstalk with the immune system. And I think it’s a really new emerging area that is going to dig deeper into the physiology of the tissues and how this is disrupted in tumors to sort of create an environment that enables tumor growth and can suppress the immune system. So that’s another point of intervention that has never been considered before. We didn’t think that we had to worry about the nerves in the tumor. As a pathologist, I do see them sometimes — we see the cancer cells invading around the nerves — but that’s about all that has been done for many years in terms of thinking that they can directly have an effect on supplying the immune cells. It is not something we previously, as a field, paid that much attention to. And now I think there are really exciting data emerging on that side.
Hwu:
Yeah, it’s a really new area, right? Because cancers — we’ve known for a while — can use the nerves as highways to get around, but now we’re saying the nerves actually can innervate the tumors, and nerves are everywhere. We think about tumors as being a simple collection of cells, but it’s a very complex collection of cells, and nerves actually connect to these tumors. And these nerve endings can cause growth of the tumors directly and can also cause immune suppression. So the more we can understand the interaction between the nerves and the tumor microenvironment, the more we can block the harmful signals and help the helpful signals.
Demaria:
Absolutely. And I think it’s also — we are at a time when bioengineering is really exponentially growing and capable of designing new agents. We mentioned bispecific, trispecific T-cell engagers — a lot of different agents. There are some exciting new agents, particularly targeting PD-1 and VEGF, that are actually in the clinic and are giving an important signal. And some data presented here really support the value of this agent, particularly the Harmony clinical trial EGFR-TKI therapy. So EGFR-positive non-small cell lung cancer is known to not respond to checkpoint inhibitors, but there is a targeted therapy. However, when the targeted therapy fails — when the tumor becomes resistant — it’s a tough situation. And now this bispecific agent seems to be able to overcome immunotherapy resistance in this subset of tumors. So that’s super exciting.
Hwu:
That’s a really exciting study — randomized. So patients with this oncogene-driven lung cancer, very hard to treat if they progress after getting the targeted therapy — you got chemotherapy plus this antibody that blocks both vascular endothelial growth factor and PD-1, and they did better than the chemotherapy alone. So that’s very exciting that we’re helping this subset of lung cancer that was thought to be poorly immunogenic, but it seems like we can get them to respond. So that was a really nice, nice study. So new agents coming out to help with cancer patients. There’s another agent that’s new that hits a T-cell receptor and also provides interleukin-2, a growth factor. Right? Isn’t that an exciting new agent?
Demaria:
Well, it is. I think the concept is really novel because instead of — we always think of T-cell therapy as having to target a tumor antigen. In this case, the T cells get into the tumor and they activate tumor-specific T cells by getting the signals — they become activated — but they have… it’s a very creative way to deliver an activation signal in the tumor for the anti-tumor T cells that are there. It’s almost like sending in some support, some cheerleader into the field so that the players that are there become activated and can actually eliminate the tumor. I think it’s a very interesting, very creative approach. They did see responses — there was an overall response rate of 21% and a disease control rate of 80%, and patients included colorectal cancer, bladder, lung, gastric, gastroesophageal junction, bladder, and head and neck squamous cell carcinoma. So this is a very encouraging result for the early-stage agent.
Hwu:
So we’ll have to see with larger studies where this holds up. But it’s exciting. It’s a new way — stimulating the T cell through the T-cell receptor—also adding interleukin-2, and we’re seeing some clinical responses, which is very exciting. And then yesterday’s keynote was also very exciting by Dr. Jen Wargo about the microbiome. What did you take away from that?
Demaria:
Oh, well, I think she provided a beautiful overview of where the field is right now. So what we have learned is that the gut microbiota is really important in determining our immunological fitness. It really plays a very important role. It’s affected by lifestyle and particularly by the food we eat — particularly if you follow the high-fiber diet — it is the most likely to help you keep a very healthy microbiota. We know that use of antibiotics can have effects. She discussed something which is really important, because I think patients sometimes think that taking probiotics may be a good way to get a good microbiota, but current studies don’t really support that — it may actually have detrimental effects. But I think the concept that we can prescribe — actually during cancer immunotherapy — patients may be prescribed a diet as part of their treatment that can help restore a healthy microbiota and increase responses to cancer immunotherapy is really exciting.
Hwu:
Some really exciting concepts — that you can have fiber in your diet and that can fuel the kind of bacteria in your gut that will help patients respond to immunotherapy. And it was small numbers still, but a big difference — like 75% versus 25% response in the fiber plus immunotherapy compared to immunotherapy. And that fiber is 30 to 50 grams of fiber. So she also mentioned some other lifestyle areas, including getting the COVID vaccine, because there are some studies out of MD Anderson and other institutions that if you get the RNA COVID vaccine, patients with cancer did better.
Demaria:
Yes. That’s fascinating data, actually. I think we don’t really know yet the mechanism. People are fascinated because it looks like the signal is real. But talking with both Jen Wargo and also talking to other people around, they think we need a prospective trial to actually really demonstrate rigorously this connection. But it is certainly a very intriguing and exciting connection
Hwu:
Speaking about stimulating the body’s immune response — your own work uses radiation to combine with immunotherapy. So talk about that and what’s the best way to give radiation to the tumor to get the best anti-tumor immune response.
Demaria:
So radiation does a lot of things, but one that can have the biggest benefit in combination with cancer immunotherapy is the fact that it does activate a viral-mimicry response. It does activate an immune pathway leading to production of type I interferon. And that really creates the environment where the T cells and the antigen-specific T cells that are attracted become activated, at the same time that the tissue makes the cancer cells so much easier — more tasty (kept because it’s the speaker’s original wording) — for the dendritic cells. They uptake irradiated cancer cells a lot faster and more effectively than they do non-irradiated ones. And so basically loading the antigen-presenting cells with tumor antigen, providing activation signal, and so you can actually really generate what we call an in situ vaccine. Well, we try to not guess or predict what may be the important antigen in the tumor, but to actually let the tumor tell — let the antigen be just simply properly cross-presented by antigen-presenting cells that are there.
But that said, we have been able to see in clinical trials a lot of signals that it can happen — that in some cases radiation can convert a tumor unresponsive to checkpoint inhibitors into a responsive one. However, we still lack enough evidence that this process is reproducible or consistent enough in different patient populations. And I think where the field is going — and needs to go — is to understand, for the given tumor type, what you combine with radiation, how you really sequence it, and how you do what radiation does as you apply it to achieve this in situ vaccination effect. But other studies suggest that it can actually improve the activity of CAR T cells, maybe in solid tumors, making the tumor more accessible to CAR T cells.
Hwu:
So what you’re saying is in some patients — and we’re still trying to figure it out — giving radiation can destroy the tumor, activate the immune system, and act like a vaccine at the tumor site.
Demaria:
Absolutely.
Hwu:
Well, thank you for being here with us today, and thank you for your service to SITC and to the field and helping to bring us all together for this incredible conference and also your mentorship of so many people in the field. So we want to thank our guest, Sandra Demaria, for joining us today. And thank you for going on this journey with us through the ever-expanding universe of immunotherapy. To hear more episodes of The ImmunoVerse, make sure to subscribe on your favorite podcast platforms.