CAR T-cell Therapy Management

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest, innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Betty Hamilton. Dr. Hamilton is the associate director of the Cleveland Clinic, blood and marrow transplant program. She is here today to talk to us about managing CAR T-cell therapy and other cellular therapies across our cancer center programs. So welcome, Betty.

Betty Hamilton, MD: Thank you and thanks so much for having me.

Dale Shepard, MD, PhD: Absolutely. So to start, maybe you can tell us a little bit about your role here at Cleveland Clinic.

Betty Hamilton, MD: Sure. So as you said, I am the Associate Director of the blood and marrow transplant program here. In this role, I oversee the research and clinical operations of the program. And this also includes the other expanding field of cell therapy and research trials within cell therapy. Clinically, I'm an adult transplant physician, and I specifically specialize in complications after transplant, such as graft versus host disease.

Dale Shepard, MD, PhD: One of the things I guess we're going to focus on here is something called CAR T-cell therapy. So a lot of people may be listening in that don't really know for sure. They may have seen it, don't know what it is. Can you tell us a little bit about what that is?

Betty Hamilton, MD: Yeah, absolutely. So CAR T-cell, it stands for chimeric antigen receptor, T-cell therapy. It is a new type of treatment in which a patient's T-cells, which are a specific type of immune cell are actually taken from the patients. And they're actually engineered in the lab to better recognize and target specific cancer cells, typically with a marker that's on the cancer cell.

As these T-cells are taken from a patient's blood they're taken to the lab and basically a special program or gene is inserted that then creates this special receptor that can bind to a patient's cancer cell. And so these T-cells now can specifically target a patient's cancer cells. And this receptor is called chimeric antigen receptor or CAR, and these T-cells or immune cells are expanded in large numbers in the lab, and then are basically given back to the patient. These CAR T-cell therapies are now FDA approved for several different types of cancers, more specifically blood cancers at this point.

Dale Shepard, MD, PhD: So what types of cancers would those be? Tell us a little bit about who might be a candidate for these.

Betty Hamilton, MD: These CAR T-cell therapies are now FDA approved for several different type of lymphoma, such as diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma. It is also approved in younger patients for acute lymphoblastic leukemia. And most recently, it's been approved for a blood cancer called multiple myeloma.

There are many, many actually clinical trials ongoing that are studying either car T-cells or CAR T-cell like therapies using sort of the same concept, in other types of blood cancers, other types of acute leukemias, as well as solid tumor cancer. So cancer such as lung cancer, gynecologic cancer, skin cancers. So it's a rapidly expanding field and new treatment.

Dale Shepard, MD, PhD: These have been approved exclusively in blood cancers. Why is the focus been blood cancers, not solid tumors, maybe help us understand that?

Betty Hamilton, MD: A lot of these blood cancer cells do have specific markers that are present on the cells. And those markers can basically provide a nice target to allow for that immune cell to recognize. Although this is where the initial research has been and thus led to the FDA approval, it is also expanding in solid tumors. So in those types of cancers, it's not necessarily called CAR T-cell.

There are now these therapies that we call TIL therapy, which tumor infiltrating lymphocytes. So in which we actually can take a piece of the tumor and identify specific proteins or markers in that tumor to then allow for the production of immune cells to target those specific cancer cells. So same type of approach, but a little bit different for those solid tumors. And there can be a lot of different markers, but all of this is going on the concept of a more targeted and personalized approach to treating cancer.

Dale Shepard, MD, PhD: So this truly is personalized because you're taking part of the patient's tumor to come up with a therapy. So unlike chemotherapy, everyone gets the same sort of drugs. Is there some thought that this could move away from that and become more generalized, off the shelf, I guess, is the expression sometimes used therapy? Tell us a little bit about that.

Betty Hamilton, MD: Yeah, absolutely. That's a great question. While CAR T-cell therapy has been very effective and obviously again, it's uses is expanding. It does require, which sometimes leads to some logistical challenges for us to collect the patient's cancer cells or tumor cells. And there is a process in creating these CAR T-cells or new therapy, so that process can take some weeks.

And as you had mentioned, these off the shelf therapies, a lot of these cancer cells share similar targets. And so if there is treatment and trials ongoing that are studying basically taking immune cells that are targeted to specific targets that are shared among many cancer cells, and those types of cells are much easily readily available.

Dale Shepard, MD, PhD: So we're talking about using immune cells and oftentimes patients will come in and when they see me, I'm a solid tumor oncologist, they're looking for immunotherapy. So how does the therapies you're offering to your patients in terms of car T-cells and cellular therapies, how does that differ than what I'm being asked about in terms of immunotherapies, like checkpoint inhibitors and things like that?

Betty Hamilton, MD: Sure. So, great question. They do overlap a little bit because what they share is that it is a immune based therapy. With some of the drugs that you had mentioned, like checkpoint inhibitors, those are drugs that basically go in and try to, I guess, enhance the immune effect in a patient's body. In cellular therapy or immuno cellular therapy, we're actually taking the patient's specific immune cells that they already have in them, and engineering those immune cells to then target the cancer cells. So we are actually taking their immune cells, manipulating them to better zone in or target cancer cells.

Dale Shepard, MD, PhD: These CAR T therapies, are the advantages primarily with better responses or with improved durability of response? Is there an element of both? What are the advantages to some of the more traditional therapies?

Betty Hamilton, MD: Cancer therapy historically, has been based on traditional chemotherapy, which unfortunately is not very specifically targeted towards cancer cells. It can kill healthy cells, as well as the cancer cells. CAR T-cells, of course, as we just discussed, they can target these cancer cells with a bit more precision. And these CAR T-cell therapies, which have been approved and are being studied currently, they're in both blood cancers and solid tumors that unfortunately have been quite refractory to other historic agents.

So these other chemotherapy agents have really failed to treat the tumor or cancer cell. And so this is a really refractory patient population, that otherwise doesn't have a lot of treatment options. And it's been actually quite revolutionary because the CAR T-cell therapies really have demonstrated success and efficacy in patients with long lasting duration. Now, of course, it's not a perfect therapy, so it's not effective for everyone. But that is also an ongoing area of research in determining, who are the patients who don't respond and why do they not respond?

Dale Shepard, MD, PhD: What does this look like for a patient? So you obviously do a lot of transplants and transplants patients come in and they get really intense therapy and really long recoveries. And you mentioned some of the complications you treat as well. How does this differ? How's it similar? How's it differ? What does it look like for a patient to get something like this?

Betty Hamilton, MD: Yeah, sure. So, yeah. There's definitely a little bit of overlap, but it is also different. So as part of CAR T-cell therapy, what happens first is that we do collect the immune cells or the T-cells from a patient first. And as I had briefly mentioned before, it can take about three to four weeks to manufacture these T-cells, so that they have the CAR or the receptor engineered into them.

Once that process is complete and those cells are made and expanded, they come back to us at our center. The patient does undergo a little bit of chemotherapy. It is not very intensive chemotherapy, but the point of that chemotherapy is basically to suppress the patient's immune system a little bit to make sure that they're not going to reject or have any sort of reaction to the engineered T-cells coming back in.

And after that chemotherapy, we infuse those CAR T-cells into it just by an IV. And we monitor for about a week, sometimes a little bit less, sometimes a little bit more, for any side effects that might happen. In particular, there are two main side effects that we monitor for. One is called cytokine release syndrome and the other one is a neurologic type of syndrome.

So in the beginning, when we first started these CAR T-cell therapies, we did admit most of our patients, these lymphoma patients in particular. And again, the admission could be anywhere from a week to a couple of weeks, depending on some of the side effects. But more and more of these CAR T-cell therapies are becoming actually safer and capable of doing them outpatient. So many of these therapies are now being offered outpatient as well.

Dale Shepard, MD, PhD: So remember, as these were being developed, certainly there was concern about the neurologic effects, for instance. Is that less of a concern, more because of changes in the therapy or ability to support the patients?

Betty Hamilton, MD: I think a little bit of both. We are now much, much more aware of what those symptoms look like and how to treat them, which is typically steroids. And those symptoms typically resolve with high dose steroids. But also a number of these therapies are becoming basically safer in terms of side effect profile. There's less side effects. We can basically monitor as an outpatient and perform these therapies as an outpatient.

Dale Shepard, MD, PhD: You mentioned things like graft versus host disease that certainly could be a really debilitating problem after transplants. Any long-term impact from CAR T therapies that we're aware of?

Betty Hamilton, MD: We're still learning a little bit about that in terms of what the long-term side effects are in patients who either develop that cytokine release or neurologic symptoms. We aren't aware of any late sequela of that or long-term side effects of that. Once it resolves, it tends to resolve. There are things that we're learning more about that how the immune system recovers. So sometimes patients do have some low blood counts that can last for a little while, and there's parts of their immune cells that take a while to fully recover. So again, determining the differences between patient to patient and how their immune system recovers is something we're still learning about.

Dale Shepard, MD, PhD: Certainly from a transplant standpoint, that's a much more intense therapy and there's certainly patients that aren't, they're not candidates for transplant. Any similar concerns with CAR T therapies? Are there patients that may have the right type of cancer, but just aren't good candidates and what are some of those characteristics?

Betty Hamilton, MD: Yeah. So I think one of the biggest differences for our group and we were starting to use a lot of these CAR T-cell therapies. In transplant, as you said, a lot of our patients, they have to be in remission from their disease and they have to be in very good shape and have a good functional status. With CAR T-cell therapy, the actual therapy is, is fairly well tolerated. And actually, you have to actually have active disease at the time.

So coming in for treatment, patients can actually be quite sick. That's a big difference for our group, taking care of these patients, knowing that, and getting used to that. But there are certainly different qualifications because we recognize that with all these blood cancers, patients can get quite sick. But the reason why we're doing the CAR T-cell therapy is because they still have active refractory disease.

Dale Shepard, MD, PhD: Either within CAR T-cells or within other cellular therapies, you mentioned TILs, what do you find most interesting as you look forward in terms of new therapies?

Betty Hamilton, MD: Really just the expansion of all of these cell therapies into all of the different diseases and making them personalized and targeted. And as you had mentioned, the off the shelf therapy, so making it easier, basically more accessible also. One of the challenges of CAR T-cell therapy, as I alluded to, is that these patients come in with active refractory disease. And we have to be able to control the disease just enough for all that time to make the CAR T-cell therapy.

So having a product that is still targeted, is still personalized, but is readily available is something that is really promising. And it's just from transplant to CAR T-cell for lymphoma, to all of these other indications. It's really not just stem cells, it's not just lymphocytes. It's all different types of immune cells that people are studying and manipulating to basically make it more effective and more safe.

Dale Shepard, MD, PhD: So as you talk about expansion, maybe we'll talk for a couple of minutes here. I think one of the big successes that we sometimes have here at the clinic is our ability to collaborate well together. And I think one of the things you've done really well is help with organizing this cellular therapy assist team. So as we expand into other indications in solid tumors, tell me a little bit about that and let us know what you're doing from that standpoint.

Betty Hamilton, MD: Yeah, sure. As you mentioned, we have this, what we call CAT team or cellular therapy assist team. I always like to say, or joke that in blood and marrow transplant, we are the original cellular therapy or immunotherapy. Unfortunately, we are not as targeted or personalized, which is what is so exciting about cell therapy. But we have a lot of expertise in not only the logistics of collecting, infusing, side effects, complications of cell therapy products, but also collaborating, like you said, with other groups.

So we have a big umbrella where we work with and oversee things like our apheresis unit or our cell processing unit, the blood bank, all of these groups that are important to making sure the success and safety of cell therapy products. And as the cell therapy field expands and immune cellular therapy expands, there are a lot of different diseases involved and they may not be as familiar as the logistics of the cell therapy and some of the potential challenges, as well as the clinical care and complications that we might expect from cell therapy.

So we basically created this group to help assist and support other disease groups in performing these clinical trials. So we have our BMT team. We do have a dedicated CAT nurse, research nurse and a dedicated CAT research coordinator and all of the resources that BMT does have, like I mentioned, apheresis and cell processing and we basically help different disease research groups review the protocol, identify challenges, questions, and basically help move the protocol along and help care for the patients and identify potential complications and things like that. We're hoping to streamline this process to allow for good collaboration between groups.

Dale Shepard, MD, PhD: I know that being on the solid tumor side and we get these protocols that look interesting, but we may not know the pitfalls or feasibilities, and so it's been very helpful to be able to work with you guys. Any other gaps, what's going to make the difference? Anything else that you see as a real need to move the field forward?

Betty Hamilton, MD: Yeah. I mean, I think learning how one, accessibility, making the treatment available in a timely fashion. I think that's one of the issues. Determining, who are the responders and not-responders, expanding it to all the different diseases, actually. For example, in acute myeloid leukemia, a lot of these treatments are focused on lymphoid diseases and blood cancers. And when you start targeting other cells, have potential complications, but finding ways to work around that and finding the right personalized target and precise target. And then again, accessibility. These treatments are expensive. They come with quite a cost and I think those are things that we're all working on and trying to figure out.

Dale Shepard, MD, PhD: And I guess when you say accessibility, there's not only costs and things like that, but I'm guessing most of this is being done at larger centers, just because all of the support that's required.

Betty Hamilton, MD: Yes, absolutely. So it does require a multi-disciplinary team. So these CAR T-cell therapies are primarily available at large, called tertiary care centers or large referral centers, because it does take a lot of organization and resources to do.

Dale Shepard, MD, PhD: Very good. Well, thank you for your insight today on CAR T-cell therapies and cellular therapies and appreciate all you're doing to help with expanding that into other areas. Thanks for being with us today.

Betty Hamilton, MD: Absolutely, thanks so much for having me.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget you can access real-time updates from Cleveland Clinics Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.