CRI Speaks with Dr. Steven A. Rosenberg, Winner of the 2020 AACR-CRI Lloyd J. Old Award in Cancer Immunology

On Wednesday, June 24, Steven A. Rosenberg, MD, PhD, receives the 2020 AACR-CRI Lloyd J. Old Award in Cancer Immunology from the American Association for Cancer Research (AACR) and the Cancer Research Institute (CRI) during the AACR Annual Virtual Meeting II.

Dr. Rosenberg is being honored for the numerous contributions he has made over his five-decade professional career, including many important advances related to cellular immunotherapies involving T cells.

Currently, he is chief of surgery and the head of the tumor immunology section at the National Cancer Institute (NCI) of the National Institutes of Health (NIH), as well as a professor of surgery at the Uniformed Services University of Health Sciences and the George Washington University School of Medicine and Health Sciences. In 2011, he received the William B. Coley Award, CRI’s highest scientific honor.

Recently, I spoke with Dr. Rosenberg about his career in cancer immunotherapy and his thoughts on the future of the field.

Arthur N. Brodsky, PhD:

Congratulations on this well-deserved award, Dr. Rosenberg! Like Lloyd Old, you’re really one of the founding pioneers of cancer immunotherapy, and I assume your paths had to have crossed at some point. Did you two interact much?

Steven A. Rosenberg, MD, PhD:

We certainly interacted, especially in the earlier days when it was looking like these immunotherapy approaches might be useful. We probably talked a dozen times over the years just to catch up on what was happening. He was a very special person and certainly had an enormous impact on the field.

Arthur N. Brodsky, PhD:

Those conversations must have been pretty profound. You both seemed to recognize very early, before many others, that the immune system could be important against cancer. When did you first start to appreciate the immune system’s potential and what led you to devote your career to tapping into its power?

Steven A. Rosenberg, MD, PhD:

I became very interested in this when I was a resident in surgery at the Peter Bent Brigham Hospital in Boston, where I ran into two extraordinary cases that had a considerable impact on me.

One was a fellow with stomach cancer that had spread to his liver and other places. He was operated on, but beyond that there was no treatment for him. Miraculously, 11 or 12 years later he was completely disease-free. He had undergone one of the rarest events in medicine and that is the spontaneous regression of metastatic cancer. At the time, this was only the fourth reported case of a stomach cancer with spontaneous regression in the absence of treatment and it seemed to me that the immune system was the likeliest suspect for having caused that.

The second was a patient who had been treated several years earlier and had undergone one of the early kidney transplants at the Peter Bent Brigham Hospital. It turned out that the kidney that was put into the patient inadvertently and unknowingly harbored cancer. Kidney function returned after the transplant, but the patient then developed widespread renal cancer.

When he was taken off of immunosuppressive drugs—which were preventing the transplanted kidney from being attacked and rejected by the immune system—his cancer disappeared. Of course, he also lost the kidney, but it demonstrated that even advanced, widely metastatic cancers could be eliminated with a strong enough immune reaction. Although it involved reaction against tissue from another person, this case showed that it was possible, that the immune system was powerful enough to cause cancer regression.

Those two patients profoundly influenced me in my pursuit of immunotherapy. Those efforts then continued in 1974 when I moved to the National Cancer Institute at the National Institutes of Health.

Arthur N. Brodsky, PhD:

As I was listening to your story, in particular the one about the person whose tumors spontaneously disappeared, I couldn’t help but think of William B. Coley, CRI’s grandfather and the “Father of Immunotherapy,” and when he first encountered the same phenomenon back in the late 1800s. Although Coley knew even less about biology, when you encountered those patients, we still knew very little about the immune system and almost nothing about its role against cancer. In fact, right before you started at the NIH, there was a landmark study that essentially closed the case on the immune system’s ability to protect us against cancer.

I read that before you wanted to be a doctor, you wanted to be a cowboy. And I couldn’t help but think about how you—armed with doctoral degrees in medicine as well as biophysics—ended up in the Wild West of the cancer world. What gave you the confidence as you were charging forward into this unknown?

Drs. Philip Greenberg, Steven Rosenberg, and James Allison at the 2011 CRI Awards Dinner, where Drs. Greenberg and Rosenberg received the 2011 William B. Coley Award for Distinguished Research in Tumor Immunology.

Steven A. Rosenberg, MD, PhD:

After medical school, I realized that if I wanted to do innovative research, I needed more education and a broader base of knowledge in many areas of modern science. That turned out to be very important in my ability to pursue these studies, which were based on an intuition about how biology works. That’s a critical aspect of doing research. The more you study science, the more intuitions you gather and it’s those intuitions about how these systems work that leads one to clues as to what to pursue. Those early cases influenced me a great deal and it was all percolating in my mind as to how one might use the immune system to manage cancer.

A major step forward in the field was the description of a molecule that we now call interleukin-2, which supports the growth of T cells and enabled us to begin to handle and manipulate human T cells outside the body. That was a crucial finding that enabled me to begin more intensive scientific work in immunotherapy.

Arthur N. Brodsky, PhD:

I’m glad you mentioned interleukin-2. Obviously, it’s been an important molecule throughout your career, including early on as you headed some of the first pioneering immunotherapy studies that led to the first FDA-approved immunotherapy against cancer, aldesleukin, in 1992.

How did the discovery of interleukin-2 fuel your work after it was discovered?

Steven A. Rosenberg, MD, PhD:

The very first indication we had that immunotherapy could work was a patient that I treated in 1984 with interleukin-2. My team, of which CRI fellow Dr. Eitan Shiloni was a part, thought we might be able to stimulate immune cells in the body that were actively recognizing tumors, but none of the first 66 patients we treated with interleukin-2 or with interleukin-2-treated cells responded. But the 67^th patient, a young woman who hadn’t responded to standard treatment, had a dramatic regression of her metastatic melanoma after being treated with interleukin-2.

Dr. Steven Rosenberg and patient in 1984. Photo courtesy of NCI

Up until that time, I didn’t know if immunotherapy would ever work. But after treating this young woman, I saw that immunotherapy could indeed work. Her success was a major turning point for me. I always had a strong intuition that it could work, but until you see the first case you don’t know that it ever will.

We ended up treating over 600 patients with interleukin-2 at the NCI, and these results played a big role in its eventual FDA approval. Only 15 to 20 percent of patients had responses, but about a third of them were complete responses, meaning their tumors were entirely eliminated. The first patient ever to respond after we treated her, is still alive and thriving disease free 30-plus years later.

We came to realize that this could be curative. That immunotherapy could potentially eliminate the last cancer cell. And as we explored how interleukin-2 was working, we studied immune cells called T cells, specifically ones within tumors called tumor-infiltrating lymphocytes, or TILs. After all, what better place to look for a cell doing battle against the cancer than within the cancer itself?

In 1988, we showed that these TILs could be grown in large numbers outside the body and then reinfused into patients and attack their cancer. We treated almost 200 patients that way and 56 percent of melanoma patients had RECIST objective responses, with almost 30 percent of patients having complete and durable tumor elimination. This was further evidence that the immune system was powerful and a direct demonstration that T cells mediated these immune responses against cancer.

Arthur N. Brodsky, PhD:

The precision and power of these T cells is truly amazing. Of course, when you first started this work, there wasn’t a way to determine what these T cells were actually targeting. So, you had to grow and re-infuse all of the T cells within a tumor, presumably even some that weren’t really equipped to recognize and eliminate the cancer cells.

More recently, you’ve refined this TIL therapy by developing a way to enrich for the T cells that target cancer-specific markers known as neo-antigens. Then, only these cells are expanded and re-infused into patients.

Can you take us through that journey?

Steven A. Rosenberg, MD, PhD:

I wish I could say there was an absolutely linear development in our knowledge about this, but that was not the case. In retrospect, I can construct a narrative that adds order to it, but there were many, many side areas that we explored in a great deal of detail that were not effective.

Our more recent findings, which you alluded to, highlight what I believe is the “final common pathway” of all available immunotherapies, and that is the immune system’s recognition of the unique neo-antigens found in an individual’s cancer that arise from somatic DNA mutations.

Now, in trying to find targets for immunotherapy, it’s important that one not destroy normal, healthy cells, too. We realized early on when we gave TILs to melanoma patients that there was no damage due to recognition of normal tissue. What is unique about cancer, compared to normal tissues, is the accumulation of mutations that ultimately lead to cancer formation. If it’s these mutations that are causing the cancer, then they’re not present in normal healthy cells.

That realization led us to develop techniques so that we could do analysis on a patient-by-patient basis, which enabled us to identify every mutation present in an individual’s cancer as well as whether or not they had T cells targeting their tumor’s neo-antigens. We found that about 80 percent of all cancers contain mutations that have already been recognized by the body’s immune system. We then developed a way to isolate those T cells and use them for treatment, which has led to tumor shrinkage in a variety of cancer types.

In 2014, we showed that you could treat patients with defined TILs that target the specific patient’s neo-antigens. The first patient with a metastatic bile duct cancer had widespread cancer in her lungs and liver and after treatment with enriched mutation-reactive cells underwent a dramatic regression of her cancer and, she is living normally now, well over five years later. This therapy also worked for several other patients, including Judy Perkins, whose breast cancer had spread to her lungs and soft tissues. After she received an infusion of her own T cells that recognized four different neo-antigens found on her cancer cells, her tumors were completely eliminated, and she’s now disease-free three years later.

Metastatic breast cancer veteran Judy Perkins in conversation with journalist Charles Graeber at IO360 in 2019. Photo by Arthur Brodsky

Arthur N. Brodsky, PhD:

Have you investigated if combining these cell therapies with other immunotherapies, such as checkpoint inhibitors, might make them effective for more patients?

Steven A. Rosenberg, MD, PhD:

That’s certainly one aspect we’re actively looking at in an ongoing clinical trial, to see if the two can synergize, or at least work in concert with one another. So far it seems that combining cell therapy with the checkpoints can improve responsiveness in patients with solid cancers, but it’s a small improvement, not the ultimate answer to the problem. A great deal more work needs to be done.

The critical aspect of our cell therapies is that the neo-antigens we’re targeting are unique to each individual cancer. That’s good news and bad news.

The good news is that since all cancers have mutations, we can potentially target mutations in many different cancer types. The bad news is that it’s a complex treatment because it’s very difficult to develop an off-the-shelf treatment when you have to target something different in virtually every patient. So that’s a big challenge, now.

Now, there are a few neo-antigens, such as mutated forms of the protein KRAS which can drive cancer as well as the tumor suppressor protein P53 that are commonly mutated in different patients. But because each is recognized in the context of the patient’s own MHC surface molecules, it’s still going to be highly individualized, even when targeting the shared mutations. Right now, we’re in the process of building a library of these T cell receptors against mutated KRAS and mutated P53. We have dozens of them now that we hope to eventually use as off-the-shelf products to treat patients, although it’s going to require a very large library because of the high variability from patient to patient.

Arthur N. Brodsky, PhD:

That is certainly important work, and I look forward to following the potential breakthroughs that come from it.

Now, I want to zoom back from the science for a minute. At CRI, we always talk about how proud Lloyd Old would be of how far the field of cancer immunotherapy has come. As someone else who was there at the beginning and has helped get the field to where it is now, what does it mean to you to get this career award named after Dr. Old?

Steven A. Rosenberg, MD, PhD:

Lloyd Old was a visionary. Clearly, a giant in the field who helped propel it forward in the early days. He was one of the first to champion the idea that immunotherapy could work. To be named in the same sentence as Lloyd Old is an extraordinary compliment.

Arthur N. Brodsky, PhD:

Like Old, I assume you also have an acute appreciation of how research into basic immunology, much of which has been supported by CRI, paved the way for today’s immunotherapy breakthroughs. How would you describe the impact of these investments in efforts to learn about the fundamentals of immune biology?

Steven A. Rosenberg, MD, PhD:

Everything we’re doing now is based on an understanding of how the immune system works, and funding from organizations like CRI has had enormous impact. None of this progress would have been possible without the support of basic immunology research. The cutting-edge treatments we’re using now are based on our understanding of the immune system’s ability to recognize tumor antigens via T cell receptors and our ability to sequence both tumor cells and T cells within patients.

Steven A. Rosenberg, MD, PhD, at the inaugural International Cancer Immunotherapy Conference (CICON) in 2015.

Arthur N. Brodsky, PhD:

These scientific achievements are remarkable, but ultimately the only thing that matters is saving patients’ lives. How does it feel to see immunotherapy actually making a difference—at least for some patients—in the clinic today?

Steven A. Rosenberg, MD, PhD:

Obviously, it’s gratifying to see patients with metastatic cancer recover. But I’m treating cancer patients every day, and everybody that we treat in the Surgery Branch of the NCI comes to us with metastatic cancer that has resisted all other therapy approaches.

The unfortunate reality is that most of the patients I take care of are not successfully treated. That’s a very humbling experience. Now, of course, it’s exhilarating to see the people who do respond, but when I lie awake at night I’m not thinking of them, I’m thinking of the people who have not responded and will go on to die because our treatments were ineffective.

When we make our rounds every day, it’s a rollercoaster of emotions. You go into one room and patients are responding, and they and their family are joyous. You go into the next room and patients are in tears and their families are standing by impotently, unable to help because our treatments didn’t work. It’s an emotional experience and one has to understand that we’re in the developmental phase of many of these therapies. We learn something from every patient, and we try to emphasize that to both those who respond and those who don’t. Certainly, I don’t feel as if we’ve come as far as we need to go in developing these treatments. It’s a start, but we need to understand that most patients, today, are not successfully treated by immunotherapy.

Fortunately, I think now we’re on the brink of some important developments. Again, the major problem we face is that many patients’ cancers are so advanced and resistant to therapy. But we have chinks in the armor, now, and I think within the next decade there’s going to be huge progress in developing effective treatments for those patients.

Read interview with 2019 AACR-CRI Lloyd J. Old Award Recipient, Dr. Cornelis ‘Kees’ Melief