Decoding the Tumor Microenvironment, ft. Dr. Drew Pardoll

Dr. Patrick Hwu speaks with Dr. Drew Pardoll, a pioneering leader in tumor immunology and director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. Dr. Pardoll reflects on his early path into immunology and the scientific discoveries that helped establish immunotherapy as a transformative approach to cancer treatment. The conversation explores how tumors suppress immune responses within the tumor microenvironment and how understanding these immune “brakes” led to the development of immune checkpoint inhibitors, including anti–PD-1 therapies.

Dr. Pardoll discusses the importance of learning from early clinical failures, the promise of combination therapies, and advances in engineered T cells. Looking ahead, the episode highlights emerging technologies such as single-cell analysis and artificial intelligence, which are accelerating discoveries across cancer research and beyond. Dr. Pardoll also shares insights on mentorship, collaboration, and the importance of sustained investment in science to continue reducing cancer mortality. 

What You’ll Learn from Dr. Pardoll

• How early clinical observations from bone marrow transplantation helped reveal the curative potential of T-cell–mediated anti-tumor immunity

• Why many early cancer vaccines failed clinically, and how those failures directly led to the discovery of immune checkpoint pathways

• The critical role of the tumor microenvironment in suppressing effective immune responses, even when tumor-specific T cells are present

• Why combination therapies (immunotherapy + chemotherapy, targeted therapy, or cell therapy) are essential to overcoming tumor escape and resistance
  
  
• Emerging advances in engineered adoptive cell therapies, including logic-gated T cells designed for improved specificity and safety
  
  
• How single-cell and spatial transcriptomic technologies are transforming our ability to dissect the tumor ecosystem
  
  
• The growing role of AI in analyzing massive immunologic datasets and accelerating discovery

Podcast Transcript

Patrick Hwu, MD:
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 and challenges in the science driving this life-saving innovation.

Today, we have with us Dr. Drew Pardoll, director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins and one of the earliest pioneers in tumor immunology. For decades, Dr. Pardoll has worked to decode how the immune system interacts with cancer, particularly the mechanisms tumors use to suppress immune attack. He’s led influential work on antigen presentation, myeloid cell behavior, and the tumor microenvironment. His scientific insights have laid the foundation for immunotherapies used across a wide range of cancers today, and his leadership has helped transform Hopkins into one of the top immunotherapy centers in the world.

Welcome to the ImmunoVerse, Dr. Pardoll. Thanks so much, Patrick.

Drew Pardoll, MD:
It’s great, and an honor, to be one of the early participants in this very important podcast about a field that both of us have been really committed to for many, many decades—longer than we’d probably even want to admit.

Patrick Hwu, MD:
Wonderful. And tell us, Drew, how did you initially get interested in immunology?

Drew Pardoll, MD:
So immunology is just a very addictive science. The beauty of how we have a system that percolates through our body that doesn’t know what attackers it’s going to be faced with over our lifetime, and 99% of the time it’s figured out how to actually handle those very diverse viruses, bacteria, and everything.

I got excited about immunotherapy for cancer really when I was a fellow on the bone marrow transplant program, where the bone marrow transplants brought in T cells with them that could cause difficulties for the patient called graft-versus-host disease, when they would attack the normal tissues. But we could tell our patients that if you survived your graft-versus-host disease, your leukemia would never come back—you would be cured—because those same T cells could actually focus on identifying and eliminating your tumor cells.

And so it seemed to me that if we understood the way the immune system worked better, we could enhance the anti-cancer activity of the immune system within each patient’s own body while mitigating the side effects.

Patrick Hwu, MD:
So I remember you telling me that some of your early mentors were discouraging you from actually looking at tumor immunology.

Drew Pardoll, MD:
That’s true. I had two mentors, Don Coffey and Bert Vogelstein—a cell biologist and a molecular biologist—and I used to say they had very different styles. The only thing they agreed upon with regard to my career is that I would ruin it if I went into cancer immunotherapy. They were both very happy to see that. That was one of many pieces of advice that I did not follow.

Patrick Hwu, MD:
Yeah, sometimes it’s what you follow and what you don’t follow that’s important. And while you were clinically trained—you went through the internal medicine residency program at Johns Hopkins just like me—

Drew Pardoll, MD:
As you.

Patrick Hwu, MD:
Yeah. And it seems like those clinical experiences were what influenced you. At the same time, I’ve always seen your work as being very lab-focused and very mechanistic, in terms of you really helping us understand the mechanisms of how an immune response happens in the tumor itself.

Drew Pardoll, MD:
Yeah, so I’ve always worshiped two altars. One is the altar of basic immunology, and the other is the altar of therapeutics. I, for the first number of years that I was on the faculty, did see patients but also kept a basic research lab that was devoted to studying mechanisms of how, in particular, T cells were regulated—turned on and turned off.

Eventually, I decided that if I had cancer, I wouldn’t want myself as my doctor, because the laboratory piece just got larger and larger, and the sophistication of clinical oncology got greater. But I don’t ever regret a minute of the training and time I spent in clinical oncology, because when we work in the lab to define new molecules and new pathways that regulate the immune system, I’m always thinking about how those can be translated.

And it also makes it easier for me to interact with my clinical colleagues who are so critical when we do our clinical trials to bring these new agents into early-stage clinical trials to give them their best shot.

Patrick Hwu, MD:
I was always impressed by the insights that you provided through your work. For example, what exactly was going on in that tumor microenvironment? How did the immune cells recognize the tumor in the first place? The cross-presentation, and then the different kinds of immune cells—CD8 cells and CD4 cells—coming together at that tumor site and in the draining lymph node. How has that influenced your approaches to designing clinical trials for patients?

Drew Pardoll, MD:
We were interested in how a particular cell type called a dendritic cell was involved in presenting tumor antigens to activate T cells that could recognize tumors. This came out of work on a genetically modified vaccine, which ultimately, when tested clinically, did not pan out.

But it got us very interested in the question of why it is that those vaccines could be activating T cells that we knew could recognize the tumor, but that didn’t translate into tumor regressions. And so, if this is true, what does it imply? It implies that there have to be signals within the tumor microenvironment that are turning off T cells that have the capability to recognize the tumor, but whose activity and ability to actually execute the killing program has been put to sleep or somehow turned off within the tumor.

The immune system is imbued with checks and balances, and it turns out that what we learned is that tumors activate some of these parking brakes on the immune system right within the tumor. So you can have T cells that are sitting in the tumor that have the capability of recognizing the tumor, but they’re all essentially put to sleep.

The immune system is imbued with checks and balances, and it turns out that what we learned is that tumors activate some of these parking brakes on the immune system right within the tumor. So you can have T cells that are sitting in the tumor that have the capability of recognizing the tumor, but they’re all essentially put to sleep.

And the amazing thing is that sometimes you find a few of these pathways, and it can take as little as one antibody to block that, to release that very important parking brake, and then the patient’s immune system does the rest of the work.

Patrick Hwu, MD:
So it’s a great example of how even if something doesn’t work when tested clinically, if you really look mechanistically at why it didn’t work—by examining the molecular nature of the immune response at the tumor site—you can then come up with something that does work. And so you really helped to lay some of the groundwork for the anti-PD-1 approach, which has saved so many lives.

Drew Pardoll, MD:
Well, we’re certainly proud of that. There are many people, many groups, that contributed to understanding that pathway and to the clinical development of antibodies that block that pathway. When you go into clinical trials of completely new agents in cancer patients, you never know what’s going to happen. But at least if the science is sound, then it has a chance. Then you just have to give it its best shot with a good clinical trial. And occasionally, you succeed.

When you go into clinical trials of completely new agents in cancer patients, you never know what’s going to happen. But at least if the science is sound, then it has a chance. Then you just have to give it its best shot with a good clinical trial.

And of course, we still keep in touch with patients from 10, 15 years ago on those earliest trials, where we were seeing some miraculous responses that were durable because the immune system has memory—and that’s obviously incredibly fulfilling.

Patrick Hwu, MD:
So I guess you have to ask yourself: what are the emerging technologies now, even outside of the field of immunology, that are going to be tomorrow’s groundbreaking work to help patients with all diseases? And what is percolating and incubating right now in our academic institutions?

Drew Pardoll, MD:
Well, first of all, I would reiterate a comment that Jim Allison, one of our senior pioneers in the checkpoint field, always used to say, which is that all therapy is immunotherapy—and he wasn’t half wrong. You look now at patients treated with anti-PD-1, with anti-PD-1 antibodies being the single most commonly used therapeutic. Eighty percent of patients treated with anti-PD-1 are treated with anti-PD-1 in combination with something that was not developed as immunotherapy—combinations with chemotherapy.

A large number of patients do better with certain chemotherapy agents combined with anti-PD-1, and now we’re beginning to have some insights as to how chemotherapy can actually, in the right way, boost immune responses.

Our own work, together with actually my former thesis advisor, Bert Vogelstein, was targeting T cells to recognize peptides from oncogenes that are commonly mutated and presented to T cells. The most common oncogenic mutation is in this oncogene called RAS. And there are now some very interesting drugs that are targeting RAS. They work for sometimes six months, eight months, 12 months, but then resistance develops.

Similarly, we expect resistance to develop to our T-cell targeting, but because they’re different mechanisms, one tumor cell is unlikely to be able to develop resistance to both of them at the same time.

There are just so many really exciting things in the engineered adoptive cell therapy space. There are some of these so-called AND gates, NOT gates—these very sophisticated ways to engineer T cells to give them greater specificity for the tumor and to decrease their off-tumor toxicity, because T cells can be very potent at killing.

The opportunities now are really exploding, I think more so than ever, because of where science has brought us in the last 30 years and engineering technology.

Patrick Hwu, MD:
So it’s a great point, and you’ve really been a leader there—to know that when you see a cancer, it’s not just cancer cells. There are many different kinds of immune cells and fibroblasts and stromal cells. And if you understand those underpinnings and interactions, you can develop approaches and therapies to use all of those cells against the cancer.

Drew Pardoll, MD:
Absolutely. There are scientific platforms now—so-called single-cell transcriptomics, spatial transcriptomics. These are names, but what they are are technologies that did not exist 10 years ago. Just 10 years ago, they didn’t exist. They certainly weren’t available to immunologists studying something as complicated as the tumor microenvironment, which was hopelessly, impossibly complicated to dissect 10 years ago.

Now that’s not the case. We really can. We’re getting more and more powerful computers. AI is allowing us to mine these literally petabytes of data, once we teach AI how to do it. But again, the computational components of this dissection of the ecosystem were literally not imaginable just 10 years ago.

Patrick Hwu, MD:
So if we really understand this neighborhood that the cancer exists in, we can then develop the combination therapeutics that will not only synergize, but make it very hard for the cancer cell to escape.

Drew Pardoll, MD:
Absolutely. Cancer cells are very good escape artists, but it’s very difficult if you have to escape two or three simultaneous attacks. In general, a cancer cell should not be able to do that. And these combination approaches, based on our understanding of the tumor microenvironment as an ecosystem, I think are going to be the way that we can really increase the number of cures.

We can say now that for adults with solid malignancies that are advanced, that are not curable by local surgery and radiation, we are probably—using these combinations that engage the immune system today—curing between 10 and 15% of patients. That’s ten times what we were doing when we were fellows. I mean, it was almost unheard of.

We can say now that for adults with solid malignancies that are advanced, that are not curable by local surgery and radiation, we are probably—using these combinations that engage the immune system today—curing between 10 and 15% of patients. That’s ten times what we were doing when we were fellows. I mean, it was almost unheard of.

I think we can keep going. There’s no reason to think that we can’t ultimately eradicate cancer as we know it, including with screening and earlier treatment interventions. And I think really it’s going to be limited by the commitment and investment not only in university research, but also in biotech companies and collaboration with pharmaceutical companies.

Since 1990, where the cancer mortality rate plateaued, the cancer mortality rate—which is basically the number of patients diagnosed with cancer who ultimately die of the cancer they’re diagnosed with rather than something else—has gone down roughly one-third, about 33%. That’s pretty amazing when you look at those curves, and that’s still going down. Our job is to keep it going down and to have it go down with a sharper slope.

Patrick Hwu, MD:
So your point is, if we continue to focus on the science—what exactly is going on in the tumor microenvironment—and translate that to patients, we’ll continue to see a decrease in cancer death rates.

Drew Pardoll, MD:
I think there’s no question. I’ll also remind the listeners that these same concepts that we’re learning in cancer are applicable to autoimmune disease, to infectious disease treatment and prevention, and to better vaccines.

One of the exciting areas—if you look at the success of the COVID vaccines—they came from vaccine technologies that were developed by companies that really got into the game making cancer vaccines, which now are being tested with some promising results. They look so different than the cancer vaccines I worked on 30 years ago at the start of my career, which were not successful.

One of the exciting areas—if you look at the success of the COVID vaccines—they came from vaccine technologies that were developed by companies that really got into the game making cancer vaccines, which now are being tested with some promising results

Patrick Hwu, MD:
And with so much technology and science in play, and so much data, you pointed out that using AI, you think we can continue to decrease death from disease across the world if we continue to use and integrate things with AI?

Drew Pardoll, MD:
Absolutely. AI—it is a buzzword that probably a lot of people don’t totally get what it is, other than maybe ChatGPT. But to me, what AI is is the ability to take massive amounts of information that our technologies accrue, that are just far too big for us to look at and deconvolute, and to find the nuggets—literally needles in haystacks.

AI is is the ability to take massive amounts of information that our technologies accrue, that are just far too big for us to look at and deconvolute, and to find the nuggets—literally needles in haystacks.

AI allows you to go through data that normally, 25 years ago, would take computer space that would fill up this whole convention center just to store the data. AI now allows that to be mined in maybe a couple hours, and two years from now, maybe even a couple seconds.

Is AI going to replace us scientists and investigators? I absolutely don’t think so—certainly not in my lifetime. But it’s an incredibly powerful tool for us to be able to use. We use AI programs all the time. We could not analyze the data that we generate without them.

Patrick Hwu, MD:
The other fun thing is, in an academic environment, we get to meet many colleagues at big meetings, and we get to know new people. And you actually met your spouse—who also is going to be a guest on the ImmunoVerse—at a science conference, right?

Drew Pardoll, MD:
That’s absolutely true. We met over a slide projector—literally—at a meeting that, Patrick, your colleague Mike Lotze was a co-organizer of. And it may have been love at first slide, but it was a lot of fun. And you were there.

And actually, it was a great opportunity for me to get to know some of the great folks in the surgery branch that Steve Rosenberg really created into the first immunotherapy juggernaut. And that turned into—we’re coming up on our 32nd wedding anniversary.

Patrick Hwu, MD:
All right. In our last minute, you have mentored many people in the field of tumor immunology, being one of the original tumor immunologists. Tell me about your approach to mentorship.

Drew Pardoll, MD:
You’re making me feel very old, but that’s okay. My approach to mentorship is a balance of advice, promoting rigorous scientific evaluation of your data, and some very fundamental principles—like, if this is true, what does it imply?

We shouldn’t go into the analysis of the results of our experiments with a preconceived notion. We should let the data—the results of our experiments—tell us what’s going on. And in some ways, the most important novel concepts come from the experiment that didn’t turn out the way you expected it to. Keeping an open mind to that is critical.

In some ways, the most important novel concepts come from the experiment that didn’t turn out the way you expected it to. Keeping an open mind to that is critical.

So those principles, as well as remembering that your students and your fellows are people, and they have lives, and they’re committing their lives to a very noble mission. You have to pay attention to their personal fulfillment and happiness in addition to how many experiments they pump out. I think that’s also a very important principle. And I tell all the students when they graduate: you may be leaving the lab, but you’re not leaving the family.

I tell all the students when they graduate: you may be leaving the lab, but you’re not leaving the family.

Patrick Hwu, MD:
And you always had the best parties at your house with your lab. And so I’ll note those a little bit.

Drew Pardoll, MD:
But still, we take a lot of pride in our holiday parties.

Patrick Hwu, MD:
That’s great. Well, we want to thank our guest, Dr. Pardoll, for joining us today. And thank you for joining us on this journey through the ever-expanding universe of immunotherapy. To hear more episodes of ImmunoVerse, make sure to subscribe on your favorite podcast platforms.