CAR-T Cell Therapy: Advancements and Challenges

CAR-T cell therapy introduces synthetic receptors into T-cells to recognize and kill cancer cells, addressing challenges in safety, persistence, and targeting solid tumors.

### Advancements and Challenges in CAR-T Cell Therapy for Cancer Treatment
* Dr. Michel Sadelain from Sloan-Kettering Cancer Center explains the basics of CAR-T cell therapy, including its **mechanism of action** and the importance of **chimeric antigen receptors (CARs)**.
* 🩸 CAR-T cell therapy has shown **significant success** in treating blood cancers like leukemia and lymphoma, but faces challenges in solid tumors due to **heterogeneity and the tumor microenvironment**.
* 🏥 The current CAR-T cell therapy process involves collecting T cells from each patient, genetically modifying them to **express CARs**, and reinfusing them back into the patient.
* Ongoing research is exploring off-the-shelf CAR-T cell products made from stem cells, potentially **reducing costs and increasing accessibility**.
* 🤒 Safety concerns include **cytokine release syndrome (CRS** and **T cell exhaustion**, which researchers are actively working to address through **new CAR designs** and **treatment strategies**.
* 💰 Cost is a significant barrier, as current CAR-T cell therapies are **expensive and complex to manufacture for each individual patient**.
* 🎯 Identifying suitable targets for CAR-T cell therapy in solid tumors is a key challenge, as there is no **single universal marker like CD19 in blood cancers**.
* 🔬 Dr. Sadelain highlights the need for further research to **overcome these challenges** and extend the benefits of CAR-T cell therapy to a **wider range of cancer types**.

hello welcome to the Cancer Research Institute. Cancer immunotherapy, a new 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 select Asst. I'm Dr. Arthur Brodsky, senior science writer at the Cancer Research Institute, and today's expert speaker is a pioneer of CAR-T cell immunity, Dr. Michele Saddling Abom Oriole Sloan-Kettering Cancer Center. Thank you for joining us today, Doctor Satellite. 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, there are 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 a coordinated fashion lead to powerful immune responses. For example, those that protect us against 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 target 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.

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, 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, and to the right here, the T-cell receptor recognizes a potential target. 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 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 had 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 cell. 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 ancient mythology. You know, animals are part lion or part goat or 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 antibodies or activating receptors or other molecules, and assemble them together into a single receptor, an artificial receptor, which, as we will see in the next slides, serves multiple purposes. As the slide implies, it is necessary to introduce the car into a t-cell, such that, as shown here on 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 a, 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 a critical, 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 co-stimulatory 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 ignite ignition switch. But that alone, as critical as it is, is not enough to produce a durable and therefore protective or therapeutic immune response. 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 coast and military 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 custom Ettore receptor, depicted here in purple, into the CAR itself. So, the CAR is a fairly complex machine. You can see one end recognizes the 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 costimulatory 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 amplifying. 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 activating or ignition switch and custom Ettore 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-cells, T-cell, I'm sorry, that is collected from the patient, they are modified. 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 US 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. So, the CAR therapies that are approved target the types of cancers in which CD19 can be found, and those are essentially leukemias.

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. You know, 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, 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's a certain novel mechanics of how to produce a drug such as this one, and with it comes a certain cost. We agree that at least for the early days these costs seem to be too elevated. 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, you know, 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. Thank you, Dr. Stein, 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 cells 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 they where do those natural t-cells come from that are used to make them? Okay, thank you. That's a great question. As I did due to the production or manufacturing, if you like, of these drugs is unlike anything any other medicine 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 patient. So, these cells have to be collectively now. One of the very facile er are favourable attributes of this is that it's easy to get T cells from any human being because we have plenty of T cells and blood. So, it starts with collecting blood. The amount of blood that is needed requires is more than what you would collect for, say, a transfusion, for example, and so the patients have to sit onto a chair and an apparatus to go through a procedure that is called an a

phoresis. These T cells, this blood, and then the T cells contained in that blood are then processed in a facility in academia. In those centers that have spearheaded car therapy, there are facilities that process these T cells in the Cancer Center, and then in an 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, this process, 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, the process often takes 9 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, this overall, this process could take, therefore, from, you know, a week or so to several weeks. That a way that the gene encoding the car is introduced into the t-cell is 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 use gene editing technologies, such as CRISPR cast nine. But the bottom line is that there are multiple ways to safely and efficiently introduce the gene into T cells. Great. So you mentioned the safety just now and during your presentation. And it's great that these, you know, cells are helping patients in the clinic. But sometimes, you know, they're they're too powerful. And they can cause that excessive inflammation through a process called cytokine release syndrome or cytokine storm. Do 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 T-cell safer for patients? 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, you know, 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 a 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 and 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, 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 macrophage 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. I'm sorry, 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 last 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, pre-existing a cardiac condition, high fever and hypotension 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, meaning that they can be infused, but

only at certain centers, under the oversight of an experienced 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 develops that's too strong. Now, luckily today, patients are well, and I'm sorry, the physicians are well informed of this, and while in the beginning this had been a surprising and unexpected toxicity, today, everywhere, 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 evade 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 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-cell sees the tumor through the CAR, and it's 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 to 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. I think that that's certainly welcome news. So now I want to turn to the second challenge that you mentioned earlier during a presentation, dealing with the long-term persistence of these cells. So it's great that in that a lot of leukemia and lymphoma patients, and I guess it's still in clinical trials, but multiple myeloma patients, is these party cells have worked pretty well a good amount of the time, but unfortunately, sometimes they can become what we call exhausted, and then that kind of allows they stop doing their job, and then that allows the cancer to come back. I understand like you've mentioned in your talk that being the type of ignition switches or co-stimulatory domains can affect this long-term persistence and whether or not the teeth 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? Yes, yet another very important question for the future of the field. As he just said, the incorporation of these so-called co-signaling 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 cell. 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 a long time here could be, for example, referring to several months. What good is it if the

t-cell is not does not remain functional, and this is a biological issue that goes way beyond car t-cells. You know in what is called checkpoint blockade therapy that is also one of the big challenges that is being tackled by trying to, you know, 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 the 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 as the this is the term used by immunologist to describe the poor functionality of a t-cell sometimes it settles in progressively over time and sometimes it settles and rather fast and an exhaustive 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 key. So, you know, while you're engineering the t-cell, why not engineer two genes, or three genes? A few years back, that seemed to be not in the realm of the feasible. But today, introducing two genes or three genes is not technically, no law 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, 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 one xx, that we will be bringing to several trials at Sloan-Kettering 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. Excellent and I think it's very promising. The conceptual foundation has kind of been established and now as you mentioned with these newer gene editing technologies, that 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 - FDA-approved CAR-T cell therapies. Each one has to be made from that patient. 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 can 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? 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 the

car because they are in your own t-cells. These t-cells will not, you know, attack you when you infuse 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 and a living drug in the Otago 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 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 to that. If we take yourselves and introduce the car into

your cells and infuse them into me to treat my lymphoma. For example, will your T-cells with armed with a CAR attack my lymphoma? Yes, they will. They will because the CAR is telling those T-cells, Go and attack that lymphocyte 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's 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, 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 a 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 yourselves? Well, there are a few approaches that different groups are pursuing. The first part of 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 put them in AD the CAR T cell. The CAR T cell should do this job. The other way is to say is to not keep a T-cell receptor.

even a virus-specific T cell is just remove it get rid of it so it is generate ejected generate a T cell that has lost its essential attribute which is this 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 of 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 in to 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 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 sir, the main solutions of the transplantation field do not apply here because we want to keep those teeth. 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, and which is an even more radical idea. The idea of going of using donors. The scientific term is allogenic 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 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 Carty cell. So this car T

cell is not made by collecting the blood of an individual and introducing the change. 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 showed 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 and 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 that would open up the possibilities of engineering, once again, the stem cells in ways that scientists see deemed to be most efficacious and safest for therapeutic purposes and have in the laboratory 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 it were this to materialize the effect of the safe and be cost effective that this would contribute to lowering the cost of cell-based medicines. 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 a lot of the time you know 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 this that almost all of the cells expressed to cd19 marker so car t-cells that target cd19 are fairly effective against these cancers and like not quite as advanced multiple myeloma a lot of these blood cancers also Express some of the same expressed that.

marker called ECMA, which is being targeted, and that target can kind of help the car t-cells detect and eliminate all of the cancer cells. But with solid tumors, there's not as many. 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? It might be that haven't really worked thus far. What targets are being explored that you think might help these help make car t-cells more effective for patients with brain cancer, breast cancer, or lung cancer? Yeah, 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, can this, can car, 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, no antibodies, the target molecules such as CTLA-4 or PD-1 or 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 that uses tumor-infiltrating lymphocytes, which are collected from cancer patients, expanded and cultured, 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, you know, 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 a 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 neill antigens, 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, and also the limitation is that not all 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 a sugar, as 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's a work to be done. So this is one of the big challenges, challenges I mean just things that need to be done early 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 are 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 tissues 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 that form 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's 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 the car T cell therapies for solid tumors of tomorrow excellent yeah certainly as you mentioned the 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 we that these are challenges that can be overcome and hopefully extend this promising immunotherapy for more patients thank you so that is all the time that we have for today thank you so much dr. saddling for your extremely informative and inspirational webinar for more of our webinars and additional resources we have for patients and caregivers as part of CR eyes answer to cancer educational programs we encourage you to check out our website at cancer research org slash 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 patient 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 Selectis. 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. Thank you. It's been a pleasure to be

with you today. Thank you. Have a good one.

What’s Next in CAR T Cell Therapy with Dr. Michel Sadelain

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Cancer Research Institute

The Promise of CAR-T Cell Therapy in Cancer Treatment

CAR-T cell therapy harnesses the power of T-cells to target and kill cancer cells.

The therapy involves genetically engineering T-cells to express chimeric antigen receptors (CARs), which enable the T-cells to recognize and attack cancer cells.

This approach is a promising new frontier in cancer treatment, with the potential to revolutionize the way we combat the disease.

The Evolution of CAR T-Cell Therapy for Cancer

CAR T-cells are designed to recognize cancer cells without the need for MHC molecules, and their incorporation of a co-stimulatory receptor helps to produce a durable immune response.

The therapy has been approved for CD19-positive leukemias and lymphomas, but still faces challenges in terms of safety and cost.

The novel manufacturing process and the need to extend the therapy to more cancer types are also key areas of focus for the future.

The Use of CAR T-Cells in Cancer Treatment

CAR T-cells are being explored for use in various cancers beyond lymphoma and leukemia.

The process of making CAR T-cells involves collecting T cells from the patient's blood, genetically modifying them, and then expanding and testing the cells, which can take several weeks.

Different genetic tools, such as viral vectors and gene editing technologies, are used to introduce the CAR gene into T cells.

The variability in T-cell quality and the patient's tumor burden can lead to excessive activation of CAR T-cells, causing cytokine release syndrome.

Researchers are working on strategies to address this issue and make CAR T-cell therapy safer for patients, taking into account the variability in T-cell response.

CAR T-cell therapy can lead to a cytokine release syndrome (CRS), causing high fevers and hypotension, but it is now well-managed and controlled with drugs.

The therapy's long-term effectiveness relies on preventing T-cells from becoming exhausted, which is being addressed through T-cell engineering to ensure they remain functional in fighting cancer.

New agents are being tested to control CRS, offering hope for reduced impact in the future.

New gene editing technologies may allow for the introduction of multiple genes into CAR-T cells, as well as the removal of genes to prevent rapid exhaustion.

Researchers are exploring the development of next-generation CAR-T cell designs to improve therapy effectiveness and persistence.

Efforts are being made to create off-the-shelf CAR-T cell products using stem cells, but biological obstacles such as graft-versus-host disease and T-cell rejection need to be overcome for this approach to be successful.

Managing T Cell Attacks and Rejection in Cell Therapy

Trials are being conducted to prevent T cells from attacking the recipient, either by using virus-specific T cells or by removing the T cell receptor altogether.

The challenge of the recipient rejecting the T cells is being addressed through innovative approaches, including using severely immunocompromised patients and exploring the use of allogeneic donors.

Another radical idea involves generating CAR T cells from pluripotent stem cells in a laboratory, offering the potential for off-the-shelf therapy.

The Potential of CAR T-Cell Therapy for Solid Tumors

CAR T-cell therapy has shown great effectiveness in blood cancers targeting CD19, but solid tumors present a challenge as they lack a single identifiable marker.

The therapy's success in solid tumors requires the identification of suitable targets and addressing the heterogeneity of the cancer cells.

Research is ongoing to find additional targets, but the limited presence of surface proteins on tumor cells poses a challenge in identifying suitable targets for CAR T-cell therapy.

Challenges in Developing CAR T-Cell Therapy for Solid Tumors

Research on CAR T-cell therapy for solid tumors is still in early stages and faces significant challenges in adapting the approach to these tumors.

The complex nature of the tumor microenvironment, including its ability to suppress immune responses, requires further engineering of CAR T-cells to overcome these barriers.

Despite the formidable challenges, the field has made significant progress in the last decade, offering hope for overcoming these obstacles in the future.