What’s Next in CAR T Cell Therapy

Our immune system possesses incredible cancer-fighting capabilities, but sometimes it benefits from a little boost. Imagine taking immune cells from patients, enhancing them outside the body, and then infusing them back into patients where they can seek out and eliminate cancer cells. No longer the stuff of science fiction, one of these adoptive cell therapy approaches—known as CAR T cell therapy—has already achieved success in the clinic and appears to have a promising future in cancer treatment.

In this webinar for patients and caregivers, Michel Sadelain, MD, PhD,  of Memorial Sloan Kettering Cancer Center (MSKCC), discusses CAR T cell immunotherapy, an approach he helped pioneer. By taking patients’ own immune cells and equipping them with chimeric antigen receptors (CARs) that enhance their ability to target and eliminate cancer cells, CAR T cells have already provided immense benefits for patients with leukemia and lymphoma, and now are being explored in solid tumors. In particular, Sadelain discusses how these powerful “living drugs” are created, how they work once in the body, and how recent discoveries and advances are leading to next-generation CAR T therapies including off-the-shelf varieties with the potential for enhanced effectiveness for more cancer patients.

At MSKCC, Dr. Sadelain serves as the director of the Center for Cell Engineering, the director of the Gene Transfer and Gene Expression Laboratory, and the Stephen and Barbara Friedman Chair. In addition, Sadelain is a member of the CRI Clinical Accelerator leadership, a former member of the CRI-SU2C Dream Team, and the recipient of the 2012 William B. Coley Award for Distinguished Research in Tumor Immunology.

Sadelain’s work provided the foundation upon which the first two FDA-approved CAR T cell immunotherapies were developed. After demonstrating the effectiveness of CD19-targeting CAR T cells in mice, this strategy was applied in the clinic, where it’s provided great benefits so far for both adult and pediatric patients. More recently, Dr. Sadelain has continued to advance our understanding of CAR T cells and reveal important insights that are being used to improve their activity. These include the development of novel strategies to overcome the resistance that can occur as well as efforts aimed at increasing CAR T cell survival and persistence in patients, so that they can provide long-term protection.

The "Cancer Immunotherapy and You" webinar series is produced by the Cancer Research Institute and is hosted by our science writer, Arthur Brodsky, PhD The 2019 series is made possible with generous support from Bristol-Myers Squibb, Cellectis and Celgene.
 
Browse our Cancer Immunotherapy and You Webinar Series playlist on YouTube or visit the Webinars page on our website to see other webinars in this series.

TRANSCRIPT

Arthur Brodsky, PhD: Hello. Welcome to the Cancer Research Institute “Cancer Immunotherapy and You” Patient Education Webinar Series.

Today’s topic is ‘What’s Next in CAR T Cell Therapy” and will highlight the remarkable benefits, important concepts, and incredible potential of this promising immunotherapy approach.

Before we begin, I’d like to thank our generous sponsors who have made this webinar series possible: Bristol-Myers Squibb, with additional support from Celgene and Cellectis.

I’m Dr. Arthur Brodsky, senior science writer at the Cancer Research Institute.

Today’s expert speaker is a pioneer of CAR T cell immunotherapy, Dr. Michel Sadelain of Memorial Sloan Kettering Cancer Center. Thank you for joining us today Dr. Sadelain!

Michel Sadelain, MD, PhD: Well, thank you, Dr. Brodsky. It's certainly a pleasure to be here today to introduce everyone to the wonderful world of CAR therapy. And I would like to start with some introductory slides to explain to everyone what are T cells, what are CARs, and what makes really this therapy work.

First, on the first slide here. Just a reminder, by way of introduction, the immune system is a complex system in our bodies that makes use of a number of different cell types, which all work together, and in coordinated fashion lead to powerful immune responses. For example, those that protect us against the common viral infections.

Now there are two main layers in the immune system. One that is a very short lived, but rapid response force known as the innate immune system. And a second layer, that is known as the adaptive immune system, which comprises two main cell types that many of you will have heard about before. One are the B cells, which produce antibodies. And the other one are T cells.

T cells are, as the slide says, critical foot soldiers of the immune system. They can directly kill infected cells. Virally infected cells, for example. And sometimes, at least, cancer cells. Now to recognize their target, these T cells make use of a receptor, which is on the cell surface of those T cells, which you see here, depicted in dark green. This receptor is known as the T cell receptor. We have billions of these in our body, which recognize different antigens. They are highly specific, which is why they may recognize one target or one virus, or one cancer cell but not another.

There are two main functions borne by this T cell receptor, as depicted in this slide. On the one end, the extracellular end, to the right here, the T cell receptor recognizes a potential target. And on the intracellular part, which here, is on the left end of the molecule inside the cell, the T cell receptor instructs the T cells to start an attack. It is what Dr. Brodsky here has called the ignition switch.

When a T cell approaches a cancer cell, its receptor must recognize some molecular structure on the surface of that cancer cell. The molecular structures that are recognized by our natural T cells are a complex of molecules that you see here in dark red. There are two parts here. One is called an MHC molecule, which we have on all of our cells. And whose chief role is to present little bits and pieces of putative targets. And that's the red triangle that you see here.

So for example, this red triangle may represent a piece of protein—which is called a peptide—which is embedded within this HLA molecule. And together, those form the structure that the T cell receptor—on the right in green—may recognize.

When the T cell makes contact with the cancer cell, it binds to this HLA peptide complex. And through the ignition switch, tells the T cell, hey, we found a target. Let's do something about it. And in the case of a killer cell, that doing something about it, that action, is to now kill and destroy the cancer cell. It does so by secreting or releasing an array of different molecules that killer T cells are specialized in producing.

The next slide, again, is a recap here. Where you see the MHC to the left bearing the peptide. And to the right, the T cell receptor. Now what happens if a cancer cell, for example, did not have an MHC molecule? Well if that were to be the case, the T cell receptor could no longer recognize it, because this HLA peptide complex that we reviewed earlier, is no longer there. Is this a mechanism that can occur in patients? Yes, it is. It is in fact, one of the escape mechanisms that tumors can take advantage of to elude an immune response taking place in the patient.

There are other mechanisms of escape, but this is one notable one since it implies that even if you have a good T cell with the T cell receptor recognizing the tumor, it simply could no longer start step one, the recognition of the tumor. So this has led scientists to start exploring different designs for a potential receptor in T cells. And the one that we are discussing today, is called a chimeric antigen receptor.

Now known as a CAR receptor, or a CAR molecule, if you like. And that is the structure here, that you see in yellow, at the center of the graphic. We will get to, in a minute, to how it functions. Now these are synthetic receptors that some years ago, we named CARs because they are chimeric in nature. Now chimeric, of course, is a word that goes back to the ancient mythology. Animals are part lion, are part goat, are part bird. And these molecules are chimeric in the way that scientists build them. They assemble different parts that are borrowed from natural molecules, such as antibody or activating receptors or yet other molecules. And assembled together into a single receptor, an artificial receptor, which as we will see in the next slides, serves multiple purposes.

As this slide implies, it is necessary to introduce the CAR into a T cell, such that, as shown here in the right, the CAR is now positioned to guide the T cell to the cancer cell and to induce its function. This means that the CAR needs to be genetically engineered into the T cell, such that the T cell can produce this CAR as if it were one of its own molecules.

So here's, to the right now, a T cell, which has of course, its own T cell receptor. And additionally expresses a CAR. And to the left here, Dr. Brodsky has shown a cancer cell that no longer has an MHC molecule, and therefore could not be recognized by the T cell receptor. However, the way that CARs are designed, the portion of the CAR that recognizes the antigen does not require HLA. And that is why a CAR molecule can be useful to recognize cancer cells that would not otherwise be recognized by a normal T cell.

And so, similar to a T cell receptor, when the CAR finds the target and binds to that red triangle that you see here on the tumor cell, the CAR molecule will activate again. The critical next step, tell the T cell, hey, you found the target. Let's start working on it. And that is sufficient to initiate the killing, now, of the cancer cell.

Now there's an important step that took place in the early research and the evolution of these CARs. And that's the addition of another compartment on the internal side of the CAR. Borrowing now from a category of molecule known as a co-stimulatory receptor. Our T cells normally have costimulatory receptors. Those are very important to amplify immune responses, or in some cases, to terminate immune responses.

Again, it is the T cell receptor that recognizes the antigen, and provides the early activation, or the ignition switch. But that alone, as critical as it is, is not enough to produce a durable, and therefore, protective or therapeutic immune responses.

So what we did some years ago was realize that the CAR molecule, even though it could recognize antigen and ignite an activation, because it doesn't quite work like the normal receptor. It was, let's say, kind of naked and lacked access to the costimulatory support that the T cell would need to produce an effective immune response. And so, a critical step in the evolution of these CARs was the incorporation of a piece of a co-stimulatory receptor—depicted here in purple—into the CAR itself.

So the CAR is a fairly complex machine. You can see one end recognizes antigen, even in the absence of MHC or HLA. Another segment initiates the activation. And yet, another part of it fuels the immune response, supports it through these so-called co-stimulatory signals.

So when the CAR T cell now sees the tumor and is activated, not only is it activated to kill the tumor cell, but thanks to the incorporated co-simulatory signal—that further fuels again, this T cell—it now divides and amplifies. And you see here, one cell becoming two T cells. And each daughter cell giving rise to two more cells. This means that the immune response is amplified. And as long as the CAR T cell is activated, which means that it has found antigen, which means that there still is cancer to be eliminated, it continues to divide.

And so, this design with the integrated activation or ignition switch and costimulatory design is really the key to developing what we called some years ago, a living drug. We use this term because these T cells, even though they start from a T cell that is collected from the patient, they are modified with the receptor. And the receptor is not a natural receptor. It is a synthetic receptor. And this synthetic receptor not only guides the T cell to recognize and kill the cancer cell, but it also amplifies, which means that the number of T cells fighting the cancer may be greater after the infusion of those T cells, than what was administered originally.

This is very different from any drug, which from the second that you take it, it becomes degraded, requiring that you take the drug again. But this T cell is a living drug, if you like, capable of expanding as long as there is tumor antigen to be found. So this brings us really to where we are today.

There are CAR T cells—The first CAR T cell therapies were approved by the Food and Drug Administration in the U.S. in 2017. Both of them target the molecule that we, at Sloan Kettering, had proposed to be a potential CAR target some 15 years ago. That molecule is called CD19. And so, the CAR therapies that are approved target the types of cancers that in which CD19 can be found. And those are essentially leukemias and lymphomas. And of course, we hope that these first initial successes in the realm of leukemia and lymphoma will next be applied to many other cancer types.

Now, as in any therapy, there are a number of questions and even challenges to resolve. Today has seen the first approvals of this very novel form of medicine. Again, the drug is not a chemical, or is not an antibody, or not a vaccine. It's a cell. And now, we have demonstrated—the work of several groups has demonstrated—that this can be effective in some cancers. But there are safety issues. For example, in some patients, the response of the T cells can be overwhelming. Not too little, but too much. And the production of molecules called cytokines that come from the T cell or other cells in the body of the recipient, can have detrimental side effects.

Also, the living drug, the CAR T cell can divide and persist. But in some cases, not long enough. In some cases, maybe, they persist too long. The cancer is gone, but if the T cell is still producing a side effect, why would you want that T cell still to remain in the body of the patient? So we need to learn how to better design these T cells to control their persistence.

Another issue that is today very much at the forefront is with all the excitement that we now have a new class of drugs coming into oncology. Everyone is starting to look at the cost of these drugs. And as well as the very novel way of manufacturing these drugs. These are not chemicals manufactured in a plant somewhere and shipped to pharmacies. The T cells have to be collected from each and every individual patient, processed, and then reinfused to the same patient.

So that means that there is a certain novel mechanics of how to produce a drug such as this one. And with it comes a certain cost. And we agree that, at least for the early days, these costs seem to be too elevated. And lastly, we need to apply this and extend the use of this very exciting technology to more cancers. And to do that, one of the key questions to address is to find targets that would be suitable for those other cancers.

CD19 has proven to be quite amazing for lymphoma and leukemia. But we now need to identify other molecules that would be suitable for prostate cancer, breast cancer, or glioblastoma. So it's a wonderful world that's opening up, rife with challenges and opportunities. And from the perspective of the scientists in this field, as well as the clinicians, it is an incredibly exciting time with many of these challenges to resolve, but many exciting opportunities that lie ahead. Dr. Brodsky, I think it is now back to you.

Arthur Brodsky, PhD: Thank you, Dr. Sadelain for that very interesting presentation. I think it kind of set the stage really well. But I'm sure our audience has some more questions about it, which we will be able to dive into now. So you touched on it a little bit during your presentation, but for the sake of simplicity, the visuals kind of just showed the CAR receptors being added to the T cells. But obviously, there's more to it than that. So how are these CAR T cells actually made? And where do those natural T cells come from that are used to make them?

Michel Sadelain, MD, PhD: OK. Thank you, that's a great question. As I did allude to the production or manufacturing, if you like, of these drugs, is unlike any other medicine that existed before, because they are not chemicals. Most drugs are chemicals that you can put into pills. And they're not antibodies either, which today, the pharmaceutical industry is so expert at producing.

They start from a cell. And the cell comes from the patients. So these cells have to be collected. Now one of the very facile or favorable attributes of this, is that it's easy to get T cells from any human being, because we have plenty of T cells in blood. So it starts with collecting blood. The amount of blood that is needed requires more than what you would collect for say a transfusion, for example. And so, the patients have to sit on to a chair, an apparatus to go through a procedure that is called an apheresis.

These T cells, this blood, and then the T cells contained in that blood are then processed in a facility in academia. And those centers that have spearheaded CAR therapy, there are facilities that process these T cells in the cancer center. And then, in the industry, today, well you would have to collect those cells, and ship those cells to a manufacturing site of the concerned company.

At that point, the T cells need to be genetically modified, such that they will now express the CAR molecule. As mentioned earlier, the CAR molecule becomes a protein made by the T cell, like any of its own. It's made from a gene, it's just that this gene was introduced into the T cell at the manufacturing site.

The transfer of the gene itself takes place in a matter of hours. Having said that, there is the need to expand these cells and to do some testing to make sure that they are sterile and that everything proceeded as one would want to be. So overall, the process often takes nine to 10 days, sometimes a bit longer, and sometimes possibly less than that.

And then the cells have to be, if they are in academia, they are just kept until the clinician requires, requests—I'm sorry—the infusion of those T cells. Or if they come from industry, they would have to be shipped back to the hospital. And so overall, this process could take, therefore, from a week or so to several weeks.

The way that the gene encoding the CAR is introduced into the T cell may vary, and that's because we have more than one way of doing that. One may use what is called a "gamma retroviral vector," or a "lentiviral vector," or a "transposon." All of these are genetic tools that scientists have developed over the last two decades, really, to facilitate the transfer of genes into T cells. And they are much used because they are efficient, do not damage the cells, and have very few side-effects.

Emerging today is another approach that is very exciting for the scientists because it might open new opportunities for creating even better and more sophisticated T cells. And those used gene-editing technologies, such as CRISPR-Cas9. But the bottom line is that there are multiple ways to safely and efficiently introduce the gene into T cells.

Arthur Brodsky, PhD: Great. So you mentioned the safety just now and during your presentation. And it's great that these cells are helping patients in the clinic, but sometimes they're too powerful. And they can cause that excessive inflammation through a process called "cytokine release syndrome" or a "cytokine storm." Could you talk a little bit more about how this happens, and more importantly, some of the strategies that you and others are working on to address this issue and make the CAR T cells safer for patients?

Michel Sadelain, MD, PhD: Sure. So the starting point for the production of this drug—this living drug—for each and every patient is their own T cells. So this is one of the many unique facets of this therapy.

And you wouldn't be surprised to know that not all of our T cells are equal. Some individuals will have T cells that maybe produce a very strong immune response. Others may be more sluggish. Also, if the tumor burden in a patient is elevated, it may, in some cases at least, not all, lead to a stronger activation of the CAR T cells because there's more tumor to be found. And so following the infusion, there's much more activation.

So between the intrinsic quality of the T cells that are different for each lot of cells, because each one of us is a bit different, and also, because of the differences in the tumor burden in the patient, there's quite a bit of variability in what ensues following the infusion of these T cells. And so in those instances, where the response of the CAR T cells is not only very good, but excessive, the patient can develop what is called the "cytokine release syndrome."

And so this is not intrinsically a bad thing. It's actually a good thing, and it's certainly a normal thing that, when T cells see their targets, they become activated, as we reviewed in your slides, and they produce cytokines. They also recruit other cells that play a role in the immune response, including cells that are known as myeloid cells, and maybe some of your listeners have heard about macrophages before. And those accumulate in the vicinity of the tumor. They're often there before the CAR T cells were infused, and even more of them may come there when the inflammation begins.

But the sum total of all that is that in some instances, there's too much cytokine that is produced. And that can lead not only to fevers, but high fevers that lasts for several days. The fevers are linked to cytokines. It can also create hypotension—a drop in blood pressure—and particularly, in patients who have, for example, a preexisting cardiac condition, high fever and hypertension can pose a threat. And it is for that reason that the CAR T cells have been approved in a very particular way—approved by FDA, I meant—meaning that they can be infused, but only at certain centers under the oversight of unexperienced or well-trained medical team, where the physicians, and the nurses, and their support staff are ready to provide the right treatment if a CRS (cytokine release syndrome) develops that's too strong.

Now luckily, today, patients are well—I'm sorry—the physicians are well informed of this. And while in the beginning, this had been a surprising and unexpected toxicity, today, everyone is well informed and prepared for it. But because of that, the administration, the infusion of CAR T cells, is limited to a certain number of centers.

Now, the good news is there are drugs that can control the CRS. And if you intervene early, you can abate it very quickly. So that's the good news. But we want more than that. We really want to prevent it. Actually, we would want to make sure that it never happens.

But to do that requires that you have a good understanding of how it works. And as I mentioned before, this was an unexpected, unanticipated toxicity of CAR therapy. And then it's only recently that some mouse models have been generated that recapitulate this syndrome.

And what those mouse models have revealed is that it's not just that, oh, the CAR T cells sees the tumor through the CAR, and the ignition switch does its job, and it starts killing, and lots of cytokines are produced. Well, no, it's a more complex interaction. I already mentioned these macrophages and dendritic cells and other cells that all contribute to this.

So we're just starting to understand this. But already this understanding is yielding new clues as to where a drug could be given to prevent the cytokine release syndrome. So today, there is a treatment based on the administration of the IL-6 receptor or corticosteroids. But in the very near future, several new agents are going to be tested to control the CRS. For example, one of them is interleukin-1 receptor antagonist. Another one is dasatinib, a drug that is already approved for other purposes that was very recently shown this month to be able to curb the CRS in animal models of the disease. So I think there is reason to be optimistic that while the CRS is a very real issue today, that, in the upcoming years, hopefully, few years, this CRS will become less and less of an issue.

Arthur Brodsky, PhD: I think that's certainly welcome news. So now, I want to turn to the second challenge that you mentioned earlier during your presentation, dealing with the long-term persistence of these cells. So it's great that in a lot of leukemia and lymphoma patients—and I guess, still in clinical trials, multiple myeloma patients—is these T cells have worked pretty well a good amount of the time. But unfortunately, sometimes they can become what we call "exhausted." And then they stop doing their job, and then that allows the cancer to come back.

I understand, like you've mentioned in your talk, that the type of ignition switches, or co-stimulatory domains, can affect this long-term persistence and how quickly the T cells become exhausted, or if they become exhausted at all. Would you mind sharing with our audience some of your current work in this area to kind of help create CAR T cells that provide better long-term protection?

Michel Sadelain, MD, PhD: Yes. Yet another very important question for the future of this field. As you just said, the incorporation of these so-called costimulatory signals within the CAR molecule itself, which we just reviewed a few minutes ago, was crucial in making this engineering strategy become a therapy because these T cells now not only get activated when they see the antigen borne by the tumor cell, but they also amplify. Now cell division is good because you grow the size of the army that fights the cancer. But that's actually not enough.

Not only should these T cells increase in numbers, but they should remain functional, meaning they should retain the ability to kill the tumor cells. If they lose this ability, well, what good is it to have a T cell that's expanding in number or even lasting for a long time? By "long time" here, I could be, for example, referring to several months. What good is it if the T cell does not remain functional? And this is a biological issue that goes way beyond CAR T cells.

In what is called checkpoint blockade therapy that is also one of the big challenges that is being tackled by trying to reverse the state of T cells that have been trying to fight the cancer, might have had an effect, but eventually, diminished their function over time. And they're just there, but they're absolutely not in a position to eradicate cancer.

So we have this same issue in CAR T cell therapy of confronting the possibility that a T cell that is trying very hard to fight a cancer may become exhausted. This is the term used by immunologists to describe the poor functionality of a T cell. Sometimes it settles in progressively over time, and sometimes, it settles in rather fast. And an exhausted T cell is not helping the therapy.

So in the world of CAR T cells, the way to tackle that is through T-cell engineering because that is the foundation for this therapy. And that can be addressed through the design of the CAR or by introducing additional changes in the CAR T cell. While you're engineering the T cell, why not engineer two genes or three genes?

A few years back that seem to be not in the realm of the feasible, but today, introducing two genes or three genes is no longer technically prohibitive. And one can even imagine—and now I'm speculating, really— that in the not-so-distant future, it may be possible to even introduce several more genes. And I should add that not only would one have the opportunity of adding genes, but you can also remove genes. This is a process called gene ablation, which the gene-editing technologies can accomplish. And why would you want to do that? Well, you would want to, for example, remove genes that accelerate this exhaustion.

So there's a lot of research going on in this area. And one can anticipate several new CAR designs coming to the clinic in the near future starting to test, I guess, a next generation of CAR T cells, which will be designed to not only recognize and attack cancer, but to not exhaust—or to not exhaust too fast—to give more time to the infused T cell to get the job done.

We have a molecule—we call it 1XX—that we will be bringing to several trials at Sloan Kettering in the near future—I'm sorry, in the near future—which is an example of these new CAR designs that I think we will see many of in the years to come that, hopefully, will contribute to improve these therapies, increase the functional persistence of the T cells, and, in doing so, we hope, open up the application of CAR T cells to solid tumors.

Arthur Brodsky, PhD: Excellent. I think it's very promising. The conceptual foundation has kind of been established. And now, as you mentioned with this new gene-editing technologies, it really it seems like the sky's the limit. It's just a matter of kind of exploring and seeing which combinations of changes might be the most beneficial.

So also, you mentioned during your talk the cost and the time to produce these CAR T cells. And right now, the two FDA approved CAR-T-cell therapies—each one has to be made from that—the T cells have to be taken from that patient and made individually for each patient. But I also understand that you're starting to use another approach that involves stem cells—that you kind of create what's being called an "off-the-shelf therapy" so that when a patient comes in, the doctors wouldn't have to bother with taking that patient's immune cells and manipulating those to create their CAR T cells. Could you talk a little bit about your efforts in this area to create these off-the-shelf products?

Michel Sadelain, MD, PhD: Sure—another wonderful question. As you just said, today's therapies are "autologous" is the scientific term, which means that the T cells that are administered to a patient come from that patient. Now there was a good reason why we and a few others who started this field used autologous T cells, because if they are your own T cells, engineered now with a CAR—because they are your own T cells, these T cells will not attack you when you reinfuse them, and you will not reject them because they are your own. So it made perfect sense to initiate the testing of this concept of a CAR-engineered cell in a living drug in the autologous setting.

And so now we know that it can work, at least in some instances. And we have to do all these improvements that you've been asking me about. But we also would like to reduce the cost of these therapies to broaden their applicability and make them available to more patients.

And so the way to do that would then [be] to make cells from a given source, and from that source, administer those cells to many patients. So it wouldn't be a one-on-one scenario anymore, my T cells made for me. It could be your cells, Dr. Brodsky, made for many patients.

But, while that sounds very desirable, there are some significant biological obstacles. If we take your cells and introduce the CAR into your cells, and infuse them into me to treat my lymphoma, for example, will your T cells armed with a CAR attack my lymphoma? Yes, they will. They will because the CAR is telling those T cells, go and attack that lymphoma because it has the CD19 molecule.

However things don't stop there. Your T cells will be in a different environment seeing all of my molecules. And there is a lot of your T cells that are going to react against that. In a transplant setting, this is what's called graft versus host disease. You would be the graft donor. I'm the host. It would be graft versus host.

And furthermore, my T cells will see your cells and say, wait a minute. That's not the cells we know. Those are different cells. And my T cells will start rejecting your T cells. So we enter T cell war. And the bottom line is that the toxicities, or the quick rejection of these T cells, would negate the benefits of a therapy.

So we have two big problems to solve here. How can we use your cells armed with a car, but prevent them attacking me? And how can we solve the issue of me rejecting your cells? Well, there are a few approaches that different groups are pursuing.

The first of the two challenges is the one where we are starting to already see trials emerging. And there are essentially two main ideas. Since it's the T-cell receptor of your T cells that will attack me, because all of your T cells—remember, each have their own T-cell receptor in addition to the CAR that we've introduced—well, there are two ways to prevent that attack.

One would be that we use virus-specific T cells of yours that only recognize a virus. Why is that? Well, if they only recognize a virus, they hopefully, will not recognize me. So we can keep that T cell receptor and add the CAR T cell, and the CAR T cell should do its job.

The other way is to not keep a T-cell receptor, even a virus specific T cell. Let's just remove it. Get rid of it. So it is to generate a T cell that has lost its essential attribute, which is the T-cell receptor. And gene-editing technologies allow us to do that today.

And so there are a number of groups, academic or industrial, that today are gearing up—and some trials have already started—to test this these two approaches on which there will be many variations. And we'll see who gets it right. And hopefully, some teams, and many of them, hopefully, will get it right.

The second part is more difficult to address. How do we change your cells so that I won't reject them? Although this is not a transplant, like a heart transplant or a liver transplant, still, there are cells from another individual from you coming into me, and I would reject them like anybody would reject a transplant. How is this usually managed in hospitals?

Well, immunosuppression. Shut down the immune response, and you give these drugs that slam the immune response. And in many cases, then, the patient accepts the kidney or another graft. But that's the last thing we want to do here because this graft is an immune response. That's the one thing we couldn't do. We want this immune response to continue.

So all of these—or maybe not all, but certainly, the main solutions of the transplantation field do not apply here because we want to keep T-cell responses going. So this is going to need a lot more innovation and inventiveness to make this work. And that is why the trials that have started today, where one uses a virus-specific T-cell receptor, or a T-cell receptor that has—in which the T-cell receptor has been ablated, only take place in patients that are severely immunocompromised, for example, after a transplant because they can't—or at least they're less likely to reject those cells. So that's a start.

But that does not address the bigger problem that I was discussing just now because it's only a tiny subset of all cancer patients that are so immunocompromised that they could accept and not reject foreign T cells. So something has to be done.

And this brings me to an additional approach that you alluded to in your question, which is an even more radical idea. The idea of going using donors—the scientific term is "allogeneic donors," meaning somebody that's not genetically identical to you—as the source of T cells is a provocative idea that is, again, starting to be tested in the clinic today. And there's an even more provocative idea, which is the following. And it takes advantage of stem cell technologies.

As you know, in other fields of medicine, there have been great advances in the generation of cells that are called "pluripotent," which can self-renew, which can multiply themselves for a long period of time. And not only can they do that, but from those cells, you can learn how to generate different cell types, perhaps heart cells or neurons.

A few years ago, we reported that we could make our favorite cell from one such stem cell—a CAR T cell. So this CAR T cell is not made by collecting the blood of an individual and introducing the genes for the car. This T cell is born in a dish. It is born in a tissue-culture vessel, and it is derived from a stem cell.

So in the first report, we show that these T cells could recognize tumors and could somewhat eliminate cancer cells. And we continue to do this today. This is still the object of—I can tell you—very intense ongoing research. But this is another possible future for the field.

What if we could generate living drugs in culture from stem cells? What that would do is it would open up the possibilities of engineering, once again, the stem cells in ways that scientists deem to be most efficacious and safest for therapeutic purposes, and have, in the laboratory, a source of T cells that you can always go back to and that would, under the right culture conditions, spin off, or produce, these T cells ready for infusion.

So if this works one day, then we will have what you called "off-the-shelf” therapy. We will have reservoirs of stem cells or the CAR T cells derived from those stem cells, perhaps in pharmacies, that, like today, are the storage area for conventional medicines. Perhaps we will have T cells banked, ready to be used, whenever needed. And the hope here is that, were this to materialize, be effective, be safe, and be cost effective, that this would contribute to lowering the cost of cell-based medicines.

Arthur Brodsky, PhD: Excellent. Yeah. I think that would be obviously very crucial. And I hope that your work continues to proceed and create breakthroughs in that area.

So lastly I’ve got one final question. We've mentioned several times so far that these CAR T cells have worked great in blood cancers mostly. In leukemia and lymphoma, they have—that almost all of the cells express the CD19 marker, so CAR T cells that target CD19 are fairly effective against these cancers. And not quite as advanced—multiple myeloma—a lot of these blood cancers also express some of the same—express their marker called BCMA, which is being targeted. And that target can kind of help the CAR T cells detect and eliminate all the cancer cells.

But with solid tumors, there's not really a single marker like there are with blood cells. And so I wanted to ask you, what kind of targets are being explored with respect to solid cancers that haven't really worked thus far? What targets are being explored that you think might help make CAR T cells more effective for patients with brain cancer, breast cancer, or lung cancer?

Michel Sadelain, MD, PhD: Another great question. So the principle of CAR technology is applicable, in principle, to any cancer. The field was born in the realm of hematology—or I should say hematological malignancies—for a number of reasons we don't have time to go into. But that is just a starting point.

Sometimes people ask, could CAR T cells be effective against solid tumors? Well, there's certainly no reason why they could not be. I mean, T cells are effective against solid tumors.

I remind everyone that when, for example, checkpoint blockade therapy—antibodies that target molecules such as CTLA-4, or PD-1 PD-L1—are given to a patient, it's their T cells that actually deliver the blow to the tumor. So there you are. You've got proof right there that T cells can do a very fine job against solid tumors, at least in some patients.

Another form of T cell therapy uses tumor-infiltrating lymphocytes, which are collected from cancer patients, expanded in culture, and then reinfused, has also shown responses in a fraction of patients, which is another way of showing that, yes, T cells can be, at least sometimes, active against solid tumors. So based on this, there's certainly no reason to think that CAR T cells couldn't be, likewise, adapted for their use against solid tumors.

Having said that, there are additional modifications to this CAR design that have to be brought to this approach. As you said, you have to identify targets. CD19, the best-known targets in current CAR therapies is applicable to lymphomas and leukemias, but not to other cancers. You need to identify other molecules for other cancers.

And there is a challenge here in tumors that are more heterogeneous. And what do I mean by that? Well, it turns out that in leukemia and lymphoma, when the tumor expresses CD19, the target, it often tends to be present on virtually all cells. So that makes it a very good setting for advancing a CAR T cell therapy. In fact, this is one of the several reasons why we chose CD19 long ago.

But then in many cancers there is heterogeneity, meaning not all tumor cells are identical. We know that. But that means that a given target may not be present on all of the tumor cells. And if a target is present on only a third of the cells, that's not good enough. So we need to either identify additional targets, or combine the CAR T-cell therapy with some additional piggybacked way, if you like, to expand the immune response in the patient beyond that one target that is only present on one-third of the cancer cells. So there's a whole piece of research that has to be done to identify suitable targets.

Now some of you may say, well, wait. There's been research for so many years on cancer. Don't we just have a list of these targets already? Well, not really, it turns out. Yes, a lot is known about cancer, of course. And a lot of mutations, for example, that give rise to what's called "neoantigens" have been identified. But the majority of these are what's called intracellular proteins. And the CAR T cell really scans the cell surface of the tumor looking for targets.

So there is a limitation there. And good news there, also, the limitation is that no proteins are present on the cell surface, obviously. So the realm of potential targets is more reduced. On the other hand, the antigen does not have to be a protein or a peptide. It could be what's called a "glycolipid", or a carbohydrate, or sugar, if you like.

But more research has to be done to look for that because this has not been, until now, examined with as much depth as have been those proteins that bear mutations. So there is work to be done. So this is one of the big challenges– by challenges" I mean just things that need to be done, really, today to adapt the CAR therapy approach to solid tumors.

The other second big issue that has to be addressed is that, as you know, a tumor does not consist in just cancer cells. In fact, there are several cancers where the cancer cells or a minority of all the cells that you find in that structure called a tumor. And the tumor is surrounded by a little microcosm that it really shapes as it grows, and known as the "tumor microenvironment." And that tumor microenvironment is composed of many cell types—many immune cells, stromal cells, blood vessels, even nerve tissue sometimes.

And in a number of solid tumors, this tumor microenvironment is highly structured and really quite adept at—guess what—shutting down immune responses. And the CAR T cell is an immune response. And so the CAR T cells will have to be combined with some of the agents, from checkpoint blockade to small molecules and others that many are investigating today, or the CAR T cell has to be further engineered to not only recognize the tumor through the CAR, but to resist the negative influence, if you like, of the tumor microenvironment.

So there's a lot of ideas out there. There is a lot of fascinating papers. I have to say the field of CAR therapy is one of the most creative and innovative fields in oncology. And I think it's because the genetic engineering opens up the possibilities to do things that go beyond what nature does.

If you remove a gene or introduce a synthetic receptor, like a CAR, you can start creating cells that have properties that are not quite what natural cells do. So it opens up new possibilities.

So which ones of these will work? We don't know. These are early days. But clearly, the issue of identifying suitable targets and further refining the design of the CAR T cell to overcome a not-very-friendly tumor microenvironment are sort of the two main lines of work that are going today in developing the CAR T-cell therapies for solid tumors of tomorrow.

Arthur Brodsky, PhD: Excellent. Certainly, as you mentioned, the challenges are formidable. But just thinking how far the field has come in the last decade, I think, it's still very hopeful that these are challenges that can be overcome, and hopefully, extend this promising immunotherapy for more patients.

Michel Sadelain, MD, PhD: Thank you.

Arthur Brodsky, PhD: So that is all the time that we have for today. Thank you so much, Dr. Sadelain, for your extremely informative and inspirational webinar.

For more of our webinars and additional resources we have for patients and caregivers as part of CRI's Answer to Cancer Patient Education program, we encourage you to check out our website at cancerresearch.org/patients. Here, you can read and watch stories shared by others who have received immunotherapy treatment across a wide variety of cancer types. You can register for one of our immunotherapy patients summits; browse our entire library of past webinars featuring the world's leading immunotherapy experts, such as Dr. Sadelain; access information on other resources, including treatment, emotional support, and financial assistance; and find help locating an immunotherapy clinical trial.

Finally, I'd like to thank our sponsors one last time for making this webinar series possible– Bristol-Myers Squibb, with additional support from Celgene and Cellectis. And I'd also like to recognize and thank BioRender, whose platform was used today to create the majority of the graphics that you saw. And again, you can watch this and all of our other webinars on our website at cancerresearch.org/webinars to learn more about the immunotherapy options and a number of cancer types.

Dr. Sadelain, I just want to thank you one last time for taking the time with us today and for the amazing work that you have done to create and advance these CAR T-cell immunotherapies for patients. We wish you the best of luck.

Michel Sadelain, MD, PhD: Thank you. It's been a pleasure to be with you today.

Arthur Brodsky, PhD: Thank you. Have a good one.

Michel Sadelain, MD, PhD: Thanks. You too.