Could CAR T-Cell Therapy Be a Cure for Some Cancers?

Dr. Diane Reidy-Lagunes:

CAR T-cell therapy: This immunotherapy strengthens the power of a patient's own immune system to attack tumors. It's one of the most exciting and promising treatments out there today and has captured national attention because of the remarkable results produced in some patients – patients who had previously exhausted all treatment options. But what exactly is this therapy, and does it work for all cancer patients? Can it really be a cure for cancer as some say? Let's talk about it.

Hello. I'm Dr. Diane Reidy-Lagunes from Memorial Sloan Kettering Cancer Center and welcome to Cancer Straight Talk. We're bringing together national experts and patients fighting these diseases to have evidence-based conversations. Our mission is to educate and empower you and your family members to make the right decisions and live happier, healthier lives. For more information on the topics discussed here or to send us your questions, please visit us at mskcc.org/podcast.

We are so pleased to be joined today by Dr. Michel Sadelain and Dr. Jae Park. Dr. Sadelain is a leader in the field of immunology and a renowned physician-scientist here at MSK. He's the guy that helped pioneer the development of CAR T-cell therapy, a treatment in which a patient's own cells are modified to target and kill cancer cells. That research then gets translated, as we say, from bench to bedside. Dr. Park is the guy who runs the clinical team that delivers this brilliant technology directly to our patients. He's the Chief of the Cell Therapy Service and specializes in patients with leukemia. Michel and Jae, thank you so much for joining us today. We are super excited to discuss this game-changing treatment.

Dr. Michel Sadelain:

It's a pleasure to be here.

Dr. Jae Park:

Thank you for having me.

Dr. Diane Reidy-Lagunes:

It's really an honor. Michel, you were awarded the 2024 Breakthrough Prize in Life Sciences for your role in developing this innovative technology. For those listening and aren't familiar with this prestigious award, this is literally like the Oscars of the science world. Before we delve into the ins and outs of CAR T-cell therapy, can you share the backstory about your original idea and the years of work that you spent developing it before it became something we have today?

Dr. Michel Sadelain:

We have to go back in time then, some 30, 35 years ago. It was known that, on occasion, the immune system can successfully fight cancer but loses in most instances. At the time, there was a hope that vaccines might elicit a response. Vaccines take time to kick in and you also need to identify what are called antigens, the molecular structures that the immune response could identify on the tumor cell.

The idea underlying CAR T-cells is to bypass a vaccine and go directly to T-cells. T-cells are major players in the immune system and they're the ones who can recognize the tumor and then destroy it. And to guide those T-cells would require a receptor which, on the surface of those cells, tells what the T-cell should recognize, followed by an instruction to kill.

But to do that, you first need it to learn how to educate those T-cells, which requires a genetic instruction; and then design receptors that would be capable of performing all those tasks; and then identify an antigen that could serve as a first model should this therapy one day come to patients; and then figure out how to manufacture this new type of medicine which is not a pill, which is not an antibody, but has to be manufactured in personalized fashion for each and every patient.

Dr. Diane Reidy-Lagunes:

And so just to recap, you're taking the patient's white cells, specifically their T-cells, to manufacture, modify, and then put them back so that those T-cells will attack the cancer?

Dr. Michel Sadelain:

That's exactly correct. That is the process.

Dr. Diane Reidy-Lagunes:

How did you even think of such a thing?

Dr. Michel Sadelain:

Our immune system is very well suited to protect us against invaders to our body such as viruses, bacteria, or parasites, but it's not as well suited to tackle cancers. Cancers originate from our own cells. They're really a variation of our own cells, and normally our immune system avoids attacking our own cells. That is a process called immune tolerance.

And to snap out of this immune tolerance, one concept was that if you introduced new receptors into the T-cells – synthetic receptors that we later named chimeric antigen receptors, or CARs – that you could overcome this limitation of the immune system. For that purpose, you needed to work out the technologies that would enable you to directly modify the patient's own T-cells.

Dr. Diane Reidy-Lagunes:

They say the pioneers in this world have an imagination to do things that others just never see, and it's just absolutely remarkable that you and others thought that you could figure out a way to modify that T-cell and put it back into a patient so that it could see that cancer cell, which it wasn't able to do before.

Dr. Michel Sadelain:

You're absolutely right. And in fact, if you go back two decades or so, many thought this sounded more like science fiction than science. And I have to say the idea wasn't immediately embraced by the scientific community. It took some time to demonstrate, first in mouse models, that this could indeed be accomplished. And later, it took some time to show that we could do the same thing with human T-cells.

There's a whole cohort of hurdles to overcome – some scientific, some technical, some regulatory, even some clinical. How do you deliver these T-cells to a patient? And I also should emphasize that until recently, there was no industry that performed this. This had never been done before and therefore it was up to medical centers like ours to roll up our sleeves and become manufacturers of genetically instructed patient T-cells.

Dr. Diane Reidy-Lagunes:

Absolutely. And so Jae, how is CAR T-cell therapy being used in the clinic? Can you share with us a little bit about what cancers that we're treating right now?

Dr. Jae Park:

Sure. I remember working closely together 15 years ago when this therapy was actually tried and put through clinical trials in humans, and it's certainly been an exciting journey from there on. Since then, this therapy has been approved for many cancers, mostly blood cancers at this time.

The one disease that we're currently using it is in cases of lymphoma – patients who have tried conventional or first line chemotherapy and they have failed to work, the cancers have recurred. It’s also approved for large lymphoma patients, mantle cell lymphoma patients, patients with acute lymphoblastic leukemia, types of blood cancers for both pediatric patients as well as adult patients, and lastly multiple myeloma patients. It's an approved therapy for all these types of patients so it is hugely exciting time.

And then obviously we're even more excited about the possibility of expanding to other cancer types too. The one key thing about this type of treatment, which I think made a splash, is that it is a curative therapy, meaning it could actually achieve that holy grail of what we as cancer doctors want to accomplish for all of our patients: a cure. Not a hundred percent of the time, but in some cancers we're able to do that, especially in the lymphoma and acute lymphoblastic leukemia, or ALL.

Dr. Diane Reidy-Lagunes:

Awesome. And Jae, can you just give us a step-by-step of what a patient actually has to go through?

Dr. Jae Park:

Sure. As Michel mentioned, this is a modification to their own immune cells – called T-cells, that we all carry in our body – that normally do surveillance for cancer cells and infection cells. So first, we have to collect the T-cells from the patients, and we call the leukapheresis or apheresis. That essentially looks like a donation of blood. You're sitting on this apheresis machine for about two hours or so, and they filter out the T-cells and the rest of the cells are returned back to you.

We take those collected white blood cells and then we isolate the T-cells. We then do genetic engineering and manufacturing so that the T-cells then express this chimeric antigen receptor or CAR, which is an artificial T-cell receptor that recognizes cancer cells. So these are essentially enhanced T-cells or immune cells that now have a capability to recognize and kill cancer cells. That takes about two weeks.

During that time, the patients may require additional therapy for their lymphoma, leukemia, or other cancers, in order to stabilize their disease or further treat their disease while their T-cells are being manufactured. Once the T-cells are manufactured, the cells are either frozen and then thawed, or they are infused immediately back into the patients.

Dr. Michel Sadelain:

I want to thank you Jae for daring to use the C word, the “cure” word. I think that's indeed one of the most remarkable aspects of this therapy; that in some patients, it can be curative.

But importantly, this is following the administration of this medicine only once. There's no reinfusion or long-term maintenance therapy.

Furthermore, the drug is not a chemical or protein or an antibody. It's a cell.

Thirdly, it's not just a cell, it's a genetically instructed cell. So there are many firsts embodied in this novel form of immunotherapy.

Dr. Diane Reidy-Lagunes:

As you know, I take care of GI cancers and I don't think there is a clinic that CAR T-cell don't come up from my patients who ask me if we can use it too, because like you said, Michel, it is absolutely remarkable that one infusion can be curative in some patients with blood cancers. But what's the magic bullet? And why can it be tricky that we can't so quickly extrapolate it to all types of cancers?

Dr. Michel Sadelain:

That’s a great question and often asked these days. Solid tumors are found in different locations in the body, and they also tend to organize themselves in a different way. What we call a tumor is not only made of cancer cells. It's a tumor plus supportive cells, immune cells, blood vessels, even sometimes neurons. So there's a whole microcosm there that feeds and protects the tumor.

So the good news is that, first of all, we know that T-cells can eliminate solid tumors. That has been shown in melanoma for many years, and also in another immunotherapy called “checkpoint blockade” where patients receive antibodies. It's actually their T-cells that eliminate those solid cancers. So we know very well that T-cells can do it. There's no mystery there.

Now, those T-cells are often blocked in the tumor. So in the context of CAR T-cells, we need to figure out which blocks are more important than others, and this approach allows us to adapt and modify the T-cell accordingly. So this cannot be done overnight.

I know a lot of people, including us, want to see this happening right away, but it takes some time to identify the most important resistance mechanisms, find the right targets, demonstrate that in animal models, establish the manufacturing, have it approved by the FDA, and then commence clinical trials. So I am very optimistic that this can succeed, but you have to give it a few years.

Dr. Diane Reidy-Lagunes:

Absolutely. It's very exciting though. Jae, what are some of the potential side effects?

Dr. Jae Park:

So there are some acute toxicities, and the short-term toxicity happens shortly after the T-cell infusion. As Michel said, this is a single infusion of the CAR T, but it's done in combination with some chemo. The purpose of the chemotherapy is to enhance these infused T-cells to grow and expand as best as they can, and then successfully eradicate and eliminate the cancer cells. So part of the process is our immune cells being reactivated and replicating, trying to kill the cancer cells.

As a result of this immune activation, patients can experience first what's called Cytokine Release Syndrome, that essentially is a reflection of the hyperactivation of immune cells. It's very similar to how our body fights infection – you get fevers, your heart rate goes up a little bit, you may have a little difficulty breathing. So Cytokine Release Syndrome happens usually within the first week of cell infusion. These are very well recognized side effects. These are very well managed and even prevented in some cases with the “cytokine blockade” or corticosteroids.

The second side effect is what's called neurotoxicity, or neuro side effects. It doesn't happen with all CAR T-cell infusions. We see it mainly in lymphoma patients, and ALL or acute leukemia patients. This happens a little bit later, 7 to 14 days after T-cell infusion. Again, transient reversible side effects and these are also manageable and preventable.

The other side effect is more recently recognized, which is an infection or “myeloid immunosuppression.” It can happen from the chemotherapy as well. Some patients who need more time to recover their full cell count may need some transfusions. It doesn't happen in all patients but seeing as patients usually travel to our center to receive the cell therapy, they may return to their treating doctors for subsequent follow-up one or two months later. During that time, it’s just important for referring doctors to be aware of what things to watch out for.

What we are really getting better at now is actually predicting who's going to be at high risk or more likely to develop these side effects. There are very low risk patients who we know can actually coast through this therapy without any fever any side effects at all. It's very possible that some patients can do that.

Dr. Diane Reidy-Lagunes:

Absolutely. And along those lines of being mindful of the side effects, is it generalizable? You beautifully explained the play-by-play of what's expected from a patient, but in the backend, what's going on in terms of the folks that know how to provide the pheresis to take out the T-cells and then to modify them and put them back in? Is this something that you envision most centers will be able to do, or will it be unique to certain centers that have the capacity and capability of doing this?

Dr. Jae Park:

That's a very good question too. So I think for right now, for a couple reasons, it's limited to the centers who have done traditional bone marrow transplant, which is another type of cell immunotherapy where you get donor T-cells. So the transplant centers who've been doing this for years have the capabilities and resources for T-cell collections and so forth. So it’s somewhat limited to these major cancer centers or transplant centers, and that does put some barrier to the access.

The reason that it is limited to those centers is not just because of the T-cell collection process, but also because of the side effects we talked about. They’re manageable and in some cases preventable, but not 100% of the time, so they do require very close monitoring. So you do want to be at the center, for now at least, with the current products that we have where the doctors and nurses, or whoever is taking care of these patients, know what to do when the side effects happen and can anticipate them and proactively manage them.

Once we make this therapy much safer so that most patients do not get those side effects and they don't have to be in the hospital, I think at that point we will feel comfortable – as a clinician myself – to deliver this type of therapy to other centers since they won't have to be monitored as closely. So it will be just like any other infusion, like an antibody-based therapy, which is typically done in smaller centers because side effects are much more manageable. I think that's exactly where we want to go, and I think it's very possible that we can get there.

Dr. Michel Sadelain:

If I may add to Jae's comments – going to the mechanism that underlies some of these toxicities that Jae described are the consequence of a very strong immune response. It's because there are so many T-cells that, in synchronized fashion, are attacking the tumor that you get the release of these molecules and these side effects. So why can we not predict whether a patient will develop these responses accurately, or at least not yet?

Well, it's because this is a personalized medicine. Your drug, which is this CAR T-cell, is different every time because it is made from the patient's own T-cells. And so we don't yet have a way to precisely anticipate the degree to which these T-cells will multiply in the body of the recipient, and whether the attack on the tumor will be violent and synchronized or more spread out over time. Our clinical colleagues are learning a lot about how to manage these complications. And as Jae said, in due course, we will be able to produce T-cells that never proliferate too much, but rather just enough.

Dr. Diane Reidy-Lagunes:

Let's talk about cost. Right now, it needs to be done in specialized cancer centers but we're talking about a therapy that's potentially curative. Is there a potential to actually bring those costs down?

Dr. Michel Sadelain:

When the first CAR T-cell therapies were approved by the FDA in 2017, the companies that commercialized these CAR T-cells put out a very high price for a single infusion – somewhere between $400,000 and $500,000 for this single potentially curative, albeit not always curative, infusion. I think we can all see that this cost would break the bank, if I may say. It is not sustainable. We need to come up with ways to lower the cost.

I won't comment on the profit margin that pharmaceuticals deem to be sufficient to garner their interest. But I think on our end – as scientists, researchers, and clinicians – what we can do is improve the quality of the T-cells that we manufacture. Because if we make a better T-cells, we will need fewer T-cells, meaning we would lower the dose that has to be manufactured for each and every patient. We would also lower the cost of production if the production was shorter. Today, all our manufacturing protocols are 7 days, and we think that fairly soon, the manufacturing will be only 3 days.

There are also other approaches that are under development that may contribute to lowering the cost. If you made the cells from a healthy donor and could administer that one batch of cells to multiple recipients, it would lower the cost because it would be one manufacturer for many patients, not one manufacturer for one patient, as is the case today. There are efforts heading in that direction.

Another way, which is already in the clinic, is stem cells that can be cultured in bioreactors and from which scientists are learning how to produce T-cells, including CAR T-cells. So these would be T-cells that wouldn't be harvested from the patient or from a healthy donor, but they would be born inside a bioreactor.

A fourth approach that has come very recently to the fore, is to engineer the T-cells inside the body of the patient. Now this is even more remote but in theory, if it were to succeed, it could bypass many of the manipulations that today we perform in the laboratory, outside of the body of the patient.

So from a scientific and technical and clinical point of view, there are a number of things that we can hopefully implement in the years to come that will ultimately lead to a lower price for these therapies.

Dr. Diane Reidy-Lagunes:

Absolutely brilliant. Those innovative ideas – we all know in the world of science – they're really hard to get funded. Can you talk a little bit about how philanthropy has helped support some of the ideas you've had?

Dr. Michel Sadelain:

Philanthropy was critical in bringing this immunotherapy to the patients. When the research was more conceptual, we were successful in obtaining funding from federal agencies. However, as we wanted to develop this therapy for a first in-human clinical study, we now needed to accomplish different things such as building a facility that would meet production standards, what are called good manufacturing practices. These kinds of items that are not funded by typical agencies, and so I have to say that it's thanks to philanthropy that at MSK, we were able to accomplish all of these tasks.

I am both happy and sad to say that without philanthropy, this therapy would not have seen the light of day; happy because the philanthropy came through, and sad that the federal agencies support the research up to a certain point of concept and then fall through when you need to make this big transition to the clinic.

Dr. Diane Reidy-Lagunes:

Yeah, that's a powerful example of how challenging the world of science can be to get these ideas to fruition. Question for both of you: Where do you see us headed in the next five years as it relates to CAR T-cell therapy?

Dr. Michel Sadelain:

The big frontier is what you asked us about earlier, which is the solid tumors. In the next five years, I’m hopeful that we and others will come up with the demonstration that CAR T-cells can also be effective in solid tumors. The good news is that many of the key barriers have been identified, so at least we know where we need to focus our attention.

Dr. Jae Park:

In addition to what Michel just said, CAR T-cell therapy – even the ones that are curative and highly effective – is currently being used in patients who have failed two or three prior treatments. I really don't believe that's the best setting to use this effective therapy. This therapy is one of the most single most effective treatments that we have for some liquid tumors or blood cancers, and there's no reason we have to wait for two or three lines of chemotherapy fail to get there. As a clinician and ALL leukemia doctor, that's what I want to see in five years because that can actually make a huge difference in patients’ lives.

The second is access. I think we really have to do a better job as scientists and clinicians and institutions to increase access to this type of therapy to a wider population. I think that effort really needs to be made.

Dr. Diane Reidy-Lagunes:

Absolutely.Jae and Michel, thank you so much for coming on today. I learned a tremendous amount from both of you.

Dr. Michel Sadelain:

It's a pleasure to be with you today and with all your listeners.

Dr. Jae Park:

Thank you.

Dr. Diane Reidy-Lagunes:

Thank you for listening to Cancer Straight Talk from Memorial Sloan Kettering Cancer Center. For more information or to send us your questions, please visit us at mskcc.org/podcast. Help others find this helpful resource by rating and reviewing it on Apple Podcasts or wherever you listen. Any products mentioned on the show are not official endorsements by MSK. These episodes are for you but are not intended to be a medical substitute. Please remember to consult your doctor with any questions you have regarding medical conditions. I'm Dr. Diane Reidy-Lagunes. Onward and upward.