After graduating from Hamilton College as a Chemistry major, Richard Edelson received his MD from the Yale School of Medicine (YSM). He then sequentially trained in Internal Medicine at the University of Chicago, Dermatology in the Harvard Program and Cancer Immunology at the National Institutes of Health. Before being recruited back to his alma mater as Chairman and Professor of the YSM Department of Dermatology in 1986, he was Director of the Immunobiology Group in Columbia University’s Comprehensive Cancer Center, Associate Director of that institution’s General Clinical Research Center and Professor and Director of Research in Columbia’s Dermatology Department.
While on the Yale faculty, he served continuously as Chairman of the Department of Dermatology (1986-2022), and at overlapping times, has also been the Director of the Yale University Comprehensive Cancer Center (2003-9), YSM Deputy Dean overseeing all Clinical Departments (2000-3), Leader of the YSM Cancer Center’s Lymphoma Research Program and the YSM Faculty Representative to the Yale New Haven Hospital Board of Trustees. On October 1, 2022, after serving as departmental chairman for 37 years (the longest duration of any Yale University departmental chairman in University history), he resigned the position, while remaining a full-time Professor of Dermatology.
He was recently announced as the recipient of the first Advanced Research Projects Agency for Health (ARPA-H) grant in the United States, which is an outgrowth of President Biden’s Cancer Moonshot program. The nearly $25 million award, titled “Curing the Uncurable via RNA Encoded Immunogene Tuning,” aims to train the immune system to better fight cancer and other diseases by educating specific immune cells with mRNA technology. Philip Santangelo, PhD, of Emory and Georgia Tech, is the principal investigator, who will provide designer mRNA and Dr. Edelson s a co-principal investigator on the project.
Welcome to Yale Cancer Answers with Dr. Anees Chagpar. Yale Cancer Answers features the latest information on cancer care by welcoming oncologists and specialists who are on the forefront of the battle to fight cancer.
This week it’s a conversation about the development of anti-cancer vaccines with Dr. Richard Edelson. Dr. Edelson is the Anthony N. Brady Professor of Dermatology at the Yale School of Medicine where Dr. Chagpar is a professor of surgical oncology.
Anees Chagpar: So Dr. Edelson, maybe we can start off by you telling us a little bit more about yourself and what it is you do.
Richard Edelson: So I’ve been a professor at Yale School of Medicine for a long time and held several positions. I’ve been chairman of dermatology for the past 37 years until I finally left to concentrate more on my research, that we’ll discuss.
I’ve also at different times been director of the Yale Cancer Center, deputy Dean for clinical Affairs overseeing the clinical departments. My clinical care and my research are tightly wound together. I specialize in a malignancy of lymphocytes called cutaneous T-cell lymphoma, and I’m a cancer immunologist trying to develop treatments that take advantage of the properties of those cells else.
AC: So let’s dive in a little bit more into treatments that involve lymphocytes, and presumably, we’re talking about immune-related treatments and cancer vaccines. Can you tell us a little bit more about your research and what’s been going on in that realm?
RE: Sure, and I’m happy to report that the President Biden Moonshot program is trying to make progress in very significant potential advances. Our group was a key part of the first one awarded, which is just starting and is between $5 and 6.5 million.
That project is intended to enable us to start to move towards patient specific cancer specific therapeutic vaccines. Those vaccines take advantage of selective markers on the malignant cells, and since everybody’s cancer is actually unique to that individual, it would seem at first that it’s prohibitively difficult to develop a personalized vaccine for everyone, particularly cancers that generate immune reactions.
In fact, this is all built out of a longstanding program where we, particularly for the longest period of time, myself, developed a worldwide therapy that actually does that for cutaneous T-cell lymphoma, the cancer that I specialize in.
We need now to figure out how to use the burgeoning skill sets of mRNA that really came to the fore in the anti-COVID vaccines and apply that to treatment of cancer. We’ve made major inroads. We are collaborating on this grant with Dr. Philip Santangelo, a world-class expert in mRNA designs, and together with a cell that we have highlighted and found to be the key trigger for these reactions, called a dendritic antigen presenting cell. That’s a mouthful, but call them dendritic cells.
We have coupled these key cells of the immune system with the Santangelo expertise.
AC: So tell us a bit more. I mean for our audience listening to this, many people may understand a little bit about an mRNA vaccine because we’ve all heard about the COVID vaccines—but those vaccines, our understanding is, they were really intended to reduce the severity of COVID, and many vaccines that we get on a routine basis we all think really prevents us from getting that disease to begin with.
But here you’re really talking about somebody who already has cancer. So how do vaccines work in that setting?
RE: That’s an extremely important point. Nobody can come to an immuno-therapist like myself with the cancer cells they’re going to get by the time we see those patients clinically, they already have the cancer, the immune system has already been overrun and now you’re treating, not preventing.
It’s important to realize that as potent and important, basically saving humanity, that these mRNA vaccines have been for the amelioration and sometimes prevention of COVID-19, they are never used as therapy. The vaccines are very good at softening the blow of COVID-19, but in cancer, just as you mentioned, you have to treat, and that’s a higher bar, and that’s where these dendritic cells, the master switch of the immune system come in. They have been elusive as a therapeutic tool. They actually were responsible for Ralph M. Steinman of Rockefeller University winning the Nobel Prize in 2011.
But what’s new is that from our past experience, we have reasonable confidence that we can turn them on to be therapeutic. When you get COVID-19, as an excellent example, the vast majority of the afflicted individuals like myself, probably many of the listeners, those individuals beat the virus not on the basis of the vaccine but on the basis of their own natural immune system.
It’s that natural immune system that these dendritic cells allow us to partner with.
AC: So is the idea that you figure out what the antigens are on the cancer cell, and somehow you use those with a vaccine to rev up the dendritic cells against that particular antigen? Is that how that works?
RE: Very close. It’s important to realize that these dendritic cells circulate through the blood as a common white blood cell a monocyte. What hasn’t been known until we discovered it is how monocytes get triggered to become dendritic cells. This master switch where and when you need them in the past, because it wasn’t known how the body does that procuring these dendritic cells had to involve some artificial intelligence.
What we discovered is that the actual way that the body makes these dendritic cells from monocytes is entirely different than what was guessed, and that is that platelets, these small pieces of cells involved intricately in clotting and wound healing in the absence of any growth factories, signal monocytes to become dendritic cells. That was the breakthrough that allows us to put these dendritic cells easily in our hands so that we can now teach them what to go after those antigens that are typical of characterizing the malignant cells.
AC: So what’s the difference between a vaccine and other therapies that might prime the immune system?
RE: Another great question. So as all oncologists know, major advances have been made in recent years with checkpoint inhibitors, so-called CAR T. These are ways to help the immune system catch up and potentially beat the cancer by attacking antigens that are group antigens, not absolutely selective for the cancer, which is why those treatments can be very effective, revolutionary in fact, but they don’t hit the very select specific antigen or marker on the cancer cell, which is why they also lead to significant side effects hitting other cells.
What we’re talking about is not artificial intelligence, but cellular intelligence. The cellular intelligence is coming from the dendritic cell doing its professional job, getting a bunch of antigens to select from and finding the right ones specifically for that person’s cancer, doing the big job themselves.
So the stars of this team is not the RNA. The RNA is more like a GPS. The RNA does nothing unless it actually gets into the right partner and the right partner.
Now, in our hands for anybody would be a dendritic cell. I don’t want to minimize the challenges ahead. So this is not absolutely ready for primetime playing, but that’s why we got the large grant.
AC: I was about to ask that question, which is, this sounds like it would be potentially revolutionary. But what are the challenges ahead? What are the potential toxicities to patients both from a physical as well as a potentially financial standpoint? Are there logistic kind of roadblocks that you can foresee?
RE: Yes, but there have been a lot of roadblocks that we’ve already passed through and overcome. So the ones that are remaining go back to what you suggested before, finding the right antigenic targets distinctive of that person’s cancer and then putting them to work.
The way this would happen is to extract from the cancer itself all of the message mRNA that’s in the cancer cell, which will include many, many types of mRNA coding for things that you are not really interested in.
You have to find the needle in the haystack, and the best way we believe to do that is to rely on the dendritic cell itself. It knows in its bag of tricks how to find them, how to find those markers because we’ve already done it in cutaneous T-cell lymphoma.
By feeding the dendritic cell from that person the entire cancer cell, it digests the cancer cell it uses, it tricks to extract the right antigen, present it and stimulate immune reactions. What you want to do with mRNA is step it up, put all that mRNA from the cancer cell into a dendritic cell from the same person and let the dendritic cell sort it out. We have preliminary information that we should be able to do it, but it hasn’t been done.
AC: As you describe this phenomenon, it sounds a little bit like CAR T therapy. Is it close to that or is it completely different in terms of it not being cellular, but a similar concept?
RE: So the difference is the nature of the tight partnership that’s generated with the genuine immune system rather than with CAR T are trying to outsmart the system.
So, for example, CAR T was introduced as a way of treating I’m sure, as you know, very aggressive therapeutically resistant M malignancies of a particular kind of white blood cell called the B cell. In order for CAR T through the use of these engineered manufactured aggressive T cells that can attack B cells, CAR T attacked all of the B cells in the person.
It’s like having a criminal somewhere in Chicago and eliminating everybody in Chicago to eliminate the malignant person. This is enormously more selective. This is what the normal immune system does and we know that under optimal circumstances we can pick out precisely the cancer cell and leave every other cell alone. That’s different.
AC: Dr. Edelson, you had mentioned that you treat T-cell lymphomas. So can you talk to us a little bit about how that clinical interest developed and talk a little bit more about cutaneous T-cell lymphomas?
RE: Sure. So directly after my clinical training, I spent three years at the National Cancer Institute learning to be a new thing at the time, a cancer immunologist, someone who uses immunology to try to improve therapies, diagnosis outcomes for patients with malignancies.
Just while I was there as a particularly young person starting my career, the entire area of T cell immunity broke wide open and it was very natural for me since I was already trained as a dermatologist with a special interest in cancer.
It was very, very simple for me to apply the early T cell biology techniques to looking at malignancies of what turned out to be T cells. And I found, along with my mentors, something fantastically interesting that essentially shaped my career—and that is that malignancies of the cells called T cells, which normally are themselves a master effector cells of the immune system, when those T cell malignancies start, they extremely commonly start, clinically, as a rash in the skin, a rash that can be very difficult to distinguish at the outset from non-malignant rashes.
I became fascinated with why that was. What we found very quickly, and essentially shaped my career, was that malignant T cells come, of course, from normal T cells and it is those normal T cells that give rise to this cutaneous T-cell lymphoma that has a tendency to affect the skin, come from a normal T cell discovered because of the malignancy that itself circulates between the skin and the blood.
In fact, 15% of all of the T cells in normal human beings are cutaneous T cells that percolate between the skin, and lymph nodes, and blood, defending against infections and cancers of the skin. That’s how it started.
AC: So can you tell us a little bit more about what this looks like and how you distinguish between a cutaneous T-cell lymphoma and another benign rash?
RE: Absolutely. It’s extremely important in terms of the prognosis of the individual patient to make the diagnosis as early as you can because in the earliest phases, when it is difficult to distinguish it from let’s say, eczema or an allergic reaction in your skin, like poison ivy, that’s the time when it is easiest to actually beat it before it becomes aggressive, before it spreads internally and there are clues.
The unusual thing that distinguishes the rash of cutaneous T-cell lymphoma in his early phase is that it tends to occur in areas of the skin that are commonly shielded from the, because it turns out that the sun, as we later learned, interferes with the development of this cancer in a positive way actually can be used therapeutically to shining ultraviolet light on the skin and the way, because it tends to affect in its early stages what’s called the bathing suit area under a bathing suit skin that’s typically covered.
The localization of the rash helps raise the possibility, and then there are now a number of laboratory tests that could be run on simple skin biopsies, very small pieces of skin that can pin it down. So, it’s important, if an individual has a rash that persists, is resistant to classical therapies that dermatologists use all the time, localizes in those areas of the skin, ask for a biopsy and ask for the possibility that this disease can be ruled out.
AC: Dr. Edelson, one of the things that you just mentioned is kind of confusing. Many people who listen to the Yale Cancer Answers may really try to protect themselves from the skin oftentimes because we know that exposure to UV light increases your risk of melanoma.
But if I heard you right, you just mentioned that it can actually be protective against a different kind of cancer, that being cutaneous, T-cell lymphomas. So can you give us a clue as to whether we should be avoiding sunlight or not avoiding sunlight, or is it particular to particular people?
So for example, if you are at increased risk of a T-cell lymphoma, you may want to spend more time in the sun, whereas if you have other risk factors that put you more at risk for melanoma, you might want to avoid that.
RE: Thank you so much for protecting me from making the wrong statement. So I wouldn’t suggest that people increase their exposure to the sun in the hope of preventing this, but just to try to stay with me briefly as in the simplest way I can I explain the answer.
There are cells in the epidermis, they go by a fancy name and I won’t bother the audience, but those cells are very sensitive themselves to ultraviolet light. They come from the bone marrow like other white blood cells often do, and they localize in the skin in a way that helps protect the skin, for example, from infections and even cancer of different types.
When one gets ultraviolet exposure of the skin, those cells temporarily disappear and when they disappear, even though they will be replaced in a month or two, they make it very difficult for the malignant cells of cutaneous t-cell lymphoma, which are dependent on those cells to grow.
So I’m not suggesting that people go out willy-nilly to nudist beaches. I am simply suggesting that you use the localization of the rash in those areas of sun shielding as a warning sign.
AC: Okay, so let’s suppose somebody does to the show and they see that they have a rash in the bathing suit area and they go and they advocate for themselves and they get a biopsy, and lo and behold the biopsy comes back positive for a cutaneous T-cell lymphoma. What happens next? Is this something that would then mandate further imaging? Do patients go on to get treatment? What does that treatment look like or feel like? Can you tell us more about the next steps?
RE: Sure. In the earliest stages, which is what we’re talking about, a kind of non-sunburn ultraviolet light called narrow band ultraviolet light, which you can get exposed to for a reasonably long period of time therapeutically without getting a sunburn. It’s the kind of ultraviolet that passes through the window glass in your car when the window is shut and you’re in traffic on the way to the beach.
Narrow band ultraviolet light is a very effective treatment as we discovered for early cutaneous T-cell lymphoma limited to the skin. It eliminates the cells we were referring to temporarily and the skin lesions go away. They may come back if you don’t continue periodically using the ultraviolet light.
But since it’s not a particularly dangerous kind of ultraviolet, it’s easy to do that is the treatment which is very effective for the earliest stages of cutaneous T-cell lymphoma. I’ve watched, in my career, that simple treatment, the exposure to that kind of ultraviolet light completely revolutionized the early care and evolution of this disease. So now, a high percentage of patients with the early cutaneous T-cell lymphoma live completely normal lives, which they didn’t before. So don’t underestimate the sun.
When the disease, however, gives rise progressively to more and more aggressive, called subclones or subsets of these malignant T cells, like cancers, naturally evolve. Then what happens is the disease becomes prone to spread throughout the body and becomes very dangerous for those patients.
That’s where the immunotherapy comes in and a treatment that we developed, which is the grandfather, you could call it, of the vaccine approach that we’re taking now—that treatment called, abbreviated because it was a long name introduced by us, ECP, is now in virtually every medical center in the United States and Europe for the advanced stages of the disease and patients who have an intact immune system.
Eighty percent of those patients respond to that initial vaccination very well. The patients who have a compromised immune system, which happens because of the disease progression or even chemotherapy that the patients may receive, they don’t respond because they don’t have an immune system. They can respond to the vaccine.