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Amelia Langston, MD: Hello. I'm Dr Amelia Langston. Welcome to Medscape's InDiscussion series on chimeric antigen receptor (CAR) T-cell therapy. Today we're going to start with an introduction to CAR T-cell therapy from Dr Melody Smith. Dr Smith is an assistant professor in the Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy, at Stanford University School of Medicine. Welcome to InDiscussion.
Melody Smith, MD, MS: Hi, Dr Langston. Thank you for inviting me to join this conversation.
Langston: Thanks for being here, Dr Smith. Let's start with an overview. What is CAR T-cell therapy?
Smith: CAR T-cell therapy is chimeric antigen receptor T-cell therapy, which on its simplest and most basic level involves T cells, which are a subset of the white blood cells in our body. White blood cells play an important role in fighting infection. One of those types of white blood cells are lymphocytes, and of the lymphocytes there is one called T lymphocytes. These T cells in our body and in our immune system are critical to fighting viruses and fighting and killing tumors. We know a lot about the T cell in terms of immunology. CAR T cells are a T cell that we take into the lab, isolate, and cause them to express a receptor that's not native to their T cell. When I talk about a receptor, we know that there are various markers, or what we call antigens, on patients' tumors. We cause these CAR T cells to express a marker, a receptor, that will identify and target those markers on a tumor. We do this so they can kill the tumor in a more specific or antigen-mediated fashion. This therapy has revolutionized the treatment landscape for several cancers, which I'm sure we'll get to talk about.
Langston: You're reprograming those T cells to be tumor killers?
Smith: Correct. And as a fan of Greek mythology in my younger days, I often will remind patients, when I'm explaining to them about CAR T cells, about what "chimera" means. In Greek mythology, I believe it was part lion, part serpent, and also the body of a lion and maybe the head of a goat. It was a creature that had various components of several different creatures in one. The CAR T cell has that complexity in that the CAR receptor is not native to the T cell, but we introduce it into the T cell for the purpose of killing the tumor.
Langston: Can you describe for us what happens to the cells and what happens to the patient in the course of CAR T-cell therapy?
Smith: When a patient is going to receive CAR T-cell therapy, we need to isolate the T cells from their body. I would compare that procedure to a blood transfusion, but the opposite. We're taking cells, the white blood cells — specifically the T cells — from the patient through their vein. It's a procedure that can take just a few hours. We isolate those T cells and then we send them off to the lab. In the lab, those T cells are enhanced or activated, and the CAR T-cell receptor is introduced to them generally through some type of viral vector, either lentivirus or retrovirus. And these cells, once they express the CAR, grow in the lab for days or weeks, until there are enough T cells that we know are sufficient to treat the patient's tumor. Those cells are then brought back to the center, where they're thawed because they are frozen until they're ready to infuse. They're thawed right outside the patient's room and then infused in less than 30 minutes. That time from collecting the T cells and manufacturing them to reinfusing them to the patients is what we call the vein-to-vein time: from their vein back into their vein. That generally takes a few weeks.
Langston: Is that ever a problem, that gap period where the patient has to wait for the T cells to be manufactured?
Smith: That's a really important point because CAR T cells are generally used, and their FDA indications are for patients with relapsed or refractory disease. That means patients whose disease has not responded to standard chemotherapy or has returned. When we think about patients who are in that category, those patients have disease that is often more aggressive than in a patient who is newly diagnosed. A complicating factor of that vein-to-vein time is that if a patient's disease is so aggressive that they can't wait those few weeks without getting a treatment, we may need to give them chemotherapy or radiation. We generally call that bridging treatment. The other thing that can sometimes present is if a patient's disease burden is too significant or they've gotten so much treatment, sometimes we don't get adequate T cells from them, or the T cells when they go to the lab to be manufactured into CAR T cells don't expand appropriately to make a good enough CAR T-cell product to give them. There are some potential complications that can arise during that time, but generally it goes quite smoothly. Bridging treatment is not uncommon.
Langston: Chemotherapy is part of the CAR T-cell process. Is that correct?
Smith: Yes. Chemotherapy is a part of the CAR T-cell process. Chemotherapy, though, that we give for CAR T cells is specifically focused on depleting out their lymphocytes. We call that lymphodepleting chemotherapy. It's a little different from the intensity of the chemotherapy that the patients would receive just to treat their disease. Why do we need to deplete the lymphocytes? Because in order for us to infuse the CAR T cells into the patients and have them expand, we need to deplete the T cells in their own body so that there is a niche or a space for the CAR T cells to expand and do their work. You know, CAR T cells are a living drug. We infuse them at a set dose, but then as they go into the patient, they expand and proliferate as they see their target. We have to create a space for them to be able to do that by giving chemotherapy; it depletes their lymphocytes.
Langston: Why is it that this therapy is only done in specialized centers?
Smith: The therapy is only done in specialized centers primarily because of the potential toxicities that may arise following the therapy. As I mentioned, the CAR T cells are a living drug. They go into the patient, and they expand as they see their target. They start killing tumor. T cells, though, by their nature, when they start to mediate cytotoxic or killing effects, release something called cytokines. And these cytokines are essentially a byproduct of their functionality. We want them to release cytokines because they're working. At the same time, those cytokines can have adverse side effects for the patients — what we call their on-target, off-tumor effects. The reason why CAR T cells should be done in a specialized center is that if the side effects are not treated promptly, there could be bad outcomes for the patient. We watch out for cytokine release syndrome. It's where those cytokines are being secreted at such a level that the patients may have fever. We may need to monitor low blood pressure or provide more intensive therapy in an intensive care unit. Again, we watch out for this while the patients are in the hospital and promptly treat it so that we can avoid escalation of care. The other side effect we watch out for is a neurologic side effect. We call it immune effector cell–associated neurotoxicity syndrome, or ICANS for short. This is a neurologic side effect where patients can have altered mental status. They can have confusion because of the activity of the CAR T cells. For these two reasons, it's important that CAR T cells are administered at specialized centers.
Langston: I remember in the early days of CAR T-cell therapy, when we were not so familiar with how to manage these things and not so familiar with the phenomenology, patients would die, on occasion, from some of these complications. It certainly is a very big deal and something that we at our center take very, very seriously. In fact, we require patients to be in our immediate vicinity even after they get out of the hospital for the first 30 days after infusion of cells. It's really no joke.
Smith: Additionally, patients aren't able to drive for those first 30 days because of the potential for side effects. One thing I didn't mention, which you are reminding me of, is that the toxicity window for CAR T-cell therapy tends to be the first 30 days. We know that the median time to onset of cytokine release syndrome and ICANS can vary by products, but generally those first 30 days, patients are required to be in an area that's most often within an hour of the treating center, so that if there is an issue, they can come back promptly. I do also want to say that, as you mentioned, comparing the early days vs now, we have a really good understanding of the pathophysiology and how these toxicities develop, and we have various treatments that work well to tamp down the excessive cytokine secretion that causes these side effects. We can observe, and we can also treat and avoid further complication.
Langston: What sorts of diseases are currently treated with commercial CAR T cells, and what kind of results have we seen so far?
Smith: The diseases that are treated with commercial CAR T cells include B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. That includes diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. Those are all B-cell malignancies that have expressed CD19, and the CAR T cells that target them are CD19 CAR T cells. There are also CAR T-cell products from multiple myeloma. There are two CAR T-cell products in that setting. The target for the multiple myeloma CAR T cells is BCMA, or B-cell maturation antigen. In total, there are about six FDA-approved CAR T-cell products.
Langston: What do the results look like to date in terms of efficacy?
Smith: The results are really promising across these various disease indications. CAR T-cell therapy for these patients, as I mentioned, with relapsed/refractory disease, can lead to long-term disease remission, and it varies by product. Really high response rates that we have seen, both overall response rates and increased survival, is in these patients who received the CAR T-cell product for both acute lymphoblastic leukemia and non-Hodgkin's lymphoma. There's a growing body of data on the efficacy of CAR T cells for patients with multiple myeloma.
Langston: The diseases that we treat with CAR T cells right now are blood cancers. Why has it been a little bit harder to develop these therapies for solid cancers?
Smith: There's some different immunology that we need to keep in mind when we're developing T-cell products and CAR T-cell products for solid tumors. The nice thing about these hematologic malignancies is that they're in the blood or they're in the lymph nodes, they're in the bone marrow. Those are all places that the T cells can easily go to and target. We are realizing, as we treat more patients with CAR T cells, that there are some patients whose disease may come back after CAR T cells. We're learning how to develop safer or even more efficacious CAR T cells by understanding how a tumor can outsmart the CAR T cells. Now, in the solid tumor space, not all solid tumors have as much immune-cell infiltration, or specifically infiltration of T cells. Getting a CAR T-cell product that can go into a solid tumor is not going to be the same for all solid tumors. We know that there are some solid tumors — for example, melanoma — that are very what we call "hot"; they have a lot of immune-cell infiltration. Various immune therapies, like immune checkpoint blockade, have worked well in that setting. However, there are other solid tumors that we sometimes refer to, on the converse, as "cold," meaning they don't have a lot of the immune-cell infiltration. Right now, a lot of labs and scientist clinical researchers are looking at developing a CAR T-cell product that can get into those tumors.
The other critical factor that has to be discussed in this context is that in order for the CAR T cell to kill the tumor, there has to be a target antigen. And you want a target antigen on the tumor that is predominantly on the tumor and not on a lot of healthy cells. In the comparison for CD19, we know that CD19 is on tumors as well as on normal B cells. And even though patients who get CD19 CAR T cells lose their B cells, we know how to manage that because there are other therapies, such as rituximab, that have caused that. We have really good experience bridging patients with low B cells and mitigating infection in that context. On the other hand, if you have a patient with a solid tumor that has a marker on their tumor, but then this same marker is on other important tissues or organs in their body, giving a CAR T cell could cause undue toxicity. That's really not something that we would be able to easily manage. We don't want to put a patient at that risk. The other critical issue in the solid tumor space is finding antigens that are on the tumor and not on other healthy organs that would cause effective toxicity to the patient. Those are the critical issues that need to be addressed, and various individuals are investigating that to help to develop CAR T cells for solid tumor patients.
Langston: CAR T-cell therapy and improving CAR T-cell therapy is really your main area of research. What do you think the future looks like, and what are you most excited about?
Smith: I talked a little bit about that vein-to-vein time. I think there are some really exciting studies coming out, both in the preclinical and clinical setting, where investigators are looking at how to shorten that vein-to-vein time to sometimes days, definitely less than weeks; but I've even heard just a few days. So essentially what that would look like is cells being isolated, activated, introducing the CAR T cell into the cells, and infusing them at a much earlier time point, and letting them expand in the patient. I've even heard about injecting the CAR T-cell vector into the patient and letting the CAR T cell be manufactured in the patient. We are thinking about ways we can do it in a shorter fashion and make the window of time, when a patient's disease might progress while waiting for the therapy, much lower, and decreasing that risk there. That's one exciting avenue where I'm looking forward to seeing the data come forth in that space. The other area, which dovetails with my research interest, is understanding how we can develop CAR T cells from a donor or from off-the-shelf sources, or even nonconventional T-cell sources, so that we can have a readily available bank of CAR T cells. That will help with the vein-to-vein time. That will potentially drive down the cost of the therapy. Allogeneic, or off-the-shelf, therapies are an exciting avenue that we'll see more in terms of the next generation of CAR T-cell therapies. In my lab, one of my research interests is looking at other endogenous factors that may impact how CAR T-cell patients respond, because we know that some patients respond to the therapy, their disease relapses, and we have some understanding as to exhaustion and other factors that may minimize the long-term efficacy of the CAR T cells. One of my interests is understanding endogenous factors like the microbiome and how the bacteria within our gut and the metabolites they produce may impact CAR T-cell therapy. Delving into that from a mechanistic perspective is another thing that I'm interested in — understanding how we can make the therapy more efficacious, more safe, and understanding how we can mitigate some of the factors that we see are driving a lack of response or a lack of a durable response.
Langston: One of the areas of interest at our center is in rejuvenating a patient's T cells after they've been through so much chemotherapy and disease. Certainly, there's a lot of research in that area as well. Dr Smith, are there particular challenges in the hematologic malignancies space that you'd like to talk about?
Smith: I spoke a little bit about the potential for finding an antigen in the solid tumor space, that it's not on healthy tissues. I think there are still several hematologic malignancies, various blood cancers, that are challenged by that limitation as well. I would note acute myeloid leukemia as well as T-cell lymphoma, as in T-cell leukemias. In both of those spaces there are challenges as to finding a target antigen that is not on healthy tissue and being able to develop a CAR to target that. That's another area where I look forward to seeing innovation so that we can provide better or more options for patients in the cell therapy space who have either of those malignancies.
Langston: I couldn't agree more. Today we've had Dr Melody Smith here, discussing CAR T-cell therapy. Thank you so much for joining us. This is Dr Amelia Langston for InDiscussion.
Resources
Non-viral, Specifically Targeted CAR-T Cells Achieve High Safety and Efficacy in B-NHL
Cytokine Release Syndrome With Chimeric Antigen Receptor T Cell Therapy
A Review of Clinical Outcomes of CAR T-Cell Therapies for B-Acute Lymphoblastic Leukemia
CAR T-cell Therapy for B-Cell Lymphoma
Current State and Next-Generation CAR-T Cells in Multiple Myeloma
Rapid Manufacturing of Non-activated Potent CAR T Cells
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Cite this: When Is CAR T-Cell Therapy the Answer? - Medscape - May 11, 2023.
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