Unveiling the Cellular and Immunotherapy Service (CITS)

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, Director of International Programs for the Cancer Institute, and Co-Director of the Sarcoma Program here at Cleveland Clinic.

Today I'm happy to be joined by Dr. John Molina, the Inpatient Director of the Cellular and Immunotherapy Service, and today he's here to talk to us about that program. Welcome, John.

John Molina, MD, EdM: Yeah, thank you for having me.

Dale Shepard, MD, PhD: Absolutely. Give us a little bit of an idea in general, what do you do here at Cleveland Clinic?

John Molina, MD, EdM: I am housed in the Leukemia Division, so I'm associate staff. Most of my clinical focus is adolescent young adults, particularly ALL. I trained in both pediatric hematology oncology and adult hematology, and so focus mostly on acute leukemias. Prior to coming into the Cleveland Clinic, I did a lot of work on early-phase CAR-T trials, and it's through that work, I continue that interest here in cellular therapy. And then since then have now taken over as the inpatient director for our recently launched Cellular Therapy Service that is treating any patients with CAR or other immune effector cell therapies are now a single centralized team.

Dale Shepard, MD, PhD: Yeah, so we're going to spend some time talking about what that's all about and kind of what we've put together and where we may go with that. Let's just start from that. A lot of different people might be listening in different familiarity with some of these therapies and toxicities and things, so tell us a little bit about the program that's been in place and why it was developed in the first place.

John Molina, MD, EdM: Yeah. It's been a little over a year since it was first conceptualized. So starting in September of last year, we started looking at, in general, the censuses amongst our main inpatient service lines and also the therapies and what was emerging. And what we saw is that, in general, inpatient services were at very high volumes, and part of that was driven by these types of therapies, which we call immune effector cell therapies. It's any set of treatment that kind of leverages the immune system by activating T cells, either engineering those T cells, which would be the case of a CAR T, where we actually take these T cells from a patient, engineer them to then become leukemia or other cancer-fighting cells and give them back to the patient, or using certain drugs, which we call bispecific antibodies, that essentially grab your existing T cells, bring it close to a cancer cell, tell it that this is bad, and turn it on and attack.

And so when we were looking at the service lines, part of the decision to make this unique service is both the volume of these therapies and their growth, and, really, exponential growth over the last several years, their unique toxicities, and really wanting to move them together so we could create expertise within the Cleveland Clinic in terms of the management of both standard of care and our very large investigational portfolio for these products as well.

Dale Shepard, MD, PhD: You mentioned this is getting bigger, it's becoming more and more of a part of treatment. So on average, how many patients are we talking are being treated with these therapies a year?

John Molina, MD, EdM: It varies between the different products. So we're seeing year-over-year growth as well, and so we look for certain products where we anticipate doing something in the order of 120 CAR Ts, which may be growing up to over 200, close to 300 in the next four or so years. Bispecifics, which are the antibody-based therapies, are actually growing as well. And one of the interesting things about this service is, as we were designing it, most of these therapies were in what we call hematologic malignancies or blood cancers, things like myeloma, leukemia, or lymphoma. What we did not anticipate is, as the service was launching, they had the first approval in a solid tumor, small cell cancers, for one of these bi-specific therapies. So we were actually at much higher volume of patients than we even originally predicted. And we're watching closely the market as these things come out. What is the patient population that'll be utilizing them?

So even, I think, our initial projections were probably under what we had anticipate is going to happen in the coming years because we're really shifting to these types of therapies as much as possible. And with existing therapies, they're moving earlier and earlier in lines of therapy, even into the front line. So what we need to be ready for and manage is this really growth and boom. You take what is typically a rare tumor when we think about hematologic malignancies, so blood cancers, and then you open it up to solid tumors, which is just a much larger population, a much larger number of patients that might be able to access the treatments, and so we're already seeing that in the first several months that we're much higher than our projected volumes because of the growth and new therapies that are already hitting the market.

Dale Shepard, MD, PhD: I'm happy to say that a CAR T is now approved for a sarcoma.

John Molina, MD, EdM: It is, and we are anxiously awaiting to start being able to provide that to patients here. And so that's one of the spaces that historically has not been successful, has been solid tumors. We have several on the clinical trial side. We're kind of trying to crack that nut. It had not been able to translate, the successes in blood cancers like leukemia and myeloma and lymphoma to date, but now we're finding better targets and better ways to direct these cells so that we can open the door in the solid tumor space. Again, this will be our first FDA approved that we'll provide here. And so also looking in terms of trials, there's a lot of excitement in and around certain kind of brain cancers as well, so we're hopeful that we can utilize this kind of technology and this type of treatment for a broader population in the future.

Dale Shepard, MD, PhD: When we think about the patients that are being served with this service, is it mostly our own patients that have sort of gone on to those therapies or are we seeing maybe a little bit more than expected of people being referred in for these treatments?

John Molina, MD, EdM: Yeah, it's a little bit of both. So we have our patients that are here and then have moved through lines of therapy with us. There's also, we have the ability to provide therapies here at the Cleveland Clinic that a community provider may not be able to. So for the example, the tarlatamab, which is for small cell cancers, we have to give the first two doses here admitted in the hospital to monitor them for toxicity. And so a lot of local providers can then send and refer their patients, start the therapy here, get them through the most dangerous component of it getting going, and then send them back.

There's other therapies that really require it. For example, we've now done several what we call TILs, so tumor-infiltrating lymphocytes, which is a unique therapy for melanoma patients. And there's only few centers in the country that can do that, that have the capacity to do it. It's a pretty lengthy process between collecting tumor cells, sending them out, processing cells, and then bringing them back. So it's a really well-orchestrated kind of procedure between us and our melanoma team, our surgical oncologists, and then our cellular therapy team moving these patients from patient selection to being able to deliver the therapy. And it's the first FDA approved therapy of this kind.

So there are that combination of people that kind of have to come here to receive these and then our own patients that are receiving them. And then the other thing that draws a wider patient population is some of our clinical trials, so some of the things that are first in human, some of the things that aren't available outside or very few centers that can offer these therapies.

Dale Shepard, MD, PhD: Most people of course are familiar with this sort of toxicities we see with traditional chemotherapies, small molecule-targeting receptors, things like that, and those patients frequently would show up with complications, or even the checkpoint inhibitors might end up on our regular solid tumor services. When we think about this particular class, these types of drugs in this service, what are the toxicities that we're commonly seeing and what are we trying to manage with this service?

John Molina, MD, EdM: And so that's one of the reasons this service was built was because it is a unique set of toxicities and we really wanted to create a kind of specialized training both in our physician, our APP, our nursing, and really expertise in how to manage these which are unique toxicities. And so when you leverage the immune system, one of the benefits is you're not giving what we call cytotoxic chemotherapy that's hurting lots of different cells. We have a very targeted approach.

But when you are activating T cells, either creating something like a CAR T or giving a therapy that activates your own T cells, there is a process in which you release things called cytokines. So inflammatory molecules that are there that are released at a much higher level than normal, and that leads to a process that we call cytokine release syndrome or CRS. And so this is a unique toxicity that can present with fevers, problems breathing, shortness of breath, needing oxygen requirements, and low blood pressure. And so it's something you have to watch and mitigate and use specific therapies to correct.

There's additional toxicity. That's the unique one that goes in line with the CRS, is a neurotoxicity that we can also see as part of the activation of your immune system, your innate immune system, all those other cells that are kind of going around, you kind of recruit what we call these macrophages. They release different chemicals that can eventually lead to what we call a neurotoxicity. It can go from headaches to just confusion to not being able to answer questions appropriately to truly seizures. So part of the service is designed to know the time course in which these are going to potentially happen. And every product can be different, and so every product, these might show up at different times and every patient can be different as well. The more tumor burden you have, the more disease, there's more likelihood that you may get these sorts of toxicities, and so we might have to watch that patient a little bit differently than somebody who could even start as an outpatient and come inpatient.

And so what we have in the system is we really work to build standard treatment protocols to identify these early, to intervene early so that we can limit them to progressing to more serious complications that may be even needing ICU stays. Within this first three months, we've had I think only one patient of all the patients we treated has required the need to go down to the ICU for management of one of these toxicities. And so that's what we're hoping for, is to really get some expertise in sort of these unique complications.

I would say in addition to what we see the CRS or ICANS, which are throughout the class of these, what we call, immune effector cell therapies, we also have to be mindful of phenomenon called on-target, off-tumor. Oftentimes we're targeting antigens, so proteins on the outside of these tumor cells, those are often found places that are not on tumor, and those can lead to other complications and other unique toxicities. And so part of it is being able to identify and manage those, and there can be such a wide variety amongst these various products that it's useful to have a singular service that's kind of developed the expertise to identify and manage them appropriately.

Dale Shepard, MD, PhD: On average, how long are patients hospitalized for observation when they're getting these treatments?

John Molina, MD, EdM: It can vary greatly. We have some products that they're in and out in 20 hours. So they get an outpatient infusion, they're admitted to the service, they're watched overnight, and if everything goes well, there's no complications, no toxicities, they get discharged and then they come back the following week for a second dose and the same process of being monitored in the hospital.

On the other side you have therapies like a CAR. There are certain of these chimeric antigen receptor or CAR-T cells that are engineered. Some of those patients need to be watched for a minimum of 10 days in the hospital. They get therapy, a type of chemotherapy, before they receive the CAR as an outpatient, they get admitted for their infusion, and then they remain with us. Sometimes on the product it's seven days, sometimes it's upwards to 10 days, because that's where the window might be where these certain kinds of ICANS or CRS may emerge, and so it can really vary from product-to-product in terms of the length of stay. And one of the things we're trying to monitor is are patients staying any longer than we would've expected? Are we able to get patients in and out based on the length of stay that we would assume would happen with each product?

Dale Shepard, MD, PhD: On the outpatient side, looking at more traditional checkpoint inhibitor-type of toxicities, we have this pharmacovigilance clinic that we've established and it's kind of a multidisciplinary approach. Who's involved with this particular program on the inpatient side to take care of the patients?

John Molina, MD, EdM: So of the stakeholders, when started building it, it really started with a lot of the disease leads and the main diseases that were managing these patients already. So between leukemia providers, myeloma and lymphoma who are doing probably the bulk of these types of treatments, and then our transplants where the CAR-Ts were existing at that time. We also have a good group of the melanoma doctors who are interested and some of the solid tumor doctors that are interested in this type of therapy. And so we have a core group of doctors that manage it and they're on the service managing it as an inpatient side.

Initially, it was mostly our BMT and LMS pharmacists, and now we have a CIT-specific pharmacist, and we're building the cellular therapy service-specific kind of needs. So we have now our own nurse practitioner service, again, that are providers that are only managing patients on the service and getting a lot more accustomed.

Currently, the service lives geographically between different floors. Some are currently on the floor that primarily takes care of patients with lymphoma and myeloma, and those are the patients that are receiving what we call the bispecifics. Those antibodies. Other patients live on a different floor, which is our bone marrow transplant floor, and that has a lot to do with what the requirements providing a cellular product. So if you're giving something like a TIL or a CAR T, because of what's called a FACT accreditation, they have to be provided on a certain floor, and so they actually have the expertise as well. So geographically, we've kind of also leveraged the expertise of both of those nursing units and their experience to date with the management of these patients as well.

Dale Shepard, MD, PhD: If we think about someone who's in the hospital, how have you reached out to hospitalists and ICU docs and things that might be taking care of these patients overnight or if things get a little more serious?

John Molina, MD, EdM: And that's a lot of the lead-up. First, some of these patients are in the outpatients. So how do we work closely with our emergency room colleagues to identify quickly that a patient has received this type of therapy and that their needs might be slightly different in terms of responding to a fever where we typically are thinking fevers may be more infection, but in this circumstance we might be having to think of this CRS type process? And so there's been a lot of education, a lot of work with them. And then part of what's come out of that was that hopefully, to launch soon, is an actual kind of signaling that if a patient has received one of these therapies and they land in our emergency room, that actually sends an automatic kind of flagging of the patient saying, "this patient has received this therapy. These are the types of things you need to consider in terms of their management."

Within the hospital, again, it's outside of the day-to-day, rounding of the CIT service with the attendings and APPs, it's working closely with our nocturnists and so that they're comfortable with the management of these patients, with the management of these unique toxicities, and particularly having more of these patients on the service at one time. So having more patients with toxicity than previously might be one a night or two a night. If there's more patients, there's just more risks that we see these toxicities. And then with our ICU, particularly our oncology ICU unit, again, close conversation in terms of that management and how do we effectively communicate as patients are moving to and from, potentially, the floors overnight. And then having strict criteria in which when are the attendings involved, when are they being called In terms of the management and decision-making around the delivery of some of these Reversible agents that kind of reverse some of the toxicities that we see.

Dale Shepard, MD, PhD: You mentioned previously about accreditation. What was required in order to set this up from an accreditation standpoint?

John Molina, MD, EdM: The wonderful thing is that we have such a strong Transplant and Cellular Therapy Program that had existed, and so we go through a process called FACT accreditation. So the Foundation for the Accreditation of Cellular Therapy. It's what allows us to do Transplants. And with the emergence of CARs, that actually got kind of folded in years ago is a part of that accreditation process. Because you're taking a cellular product, you're sometimes thawing it, you have quality metrics for release of that product and delivery. And we actually went through our most recent FACT accreditation to then get that again and did very well in terms of the level of care that we can provide. It allows us to say how many of these infusions we can do per day. Are they on the right floor? The right type of monitoring? Are the right safety checks in place for these patients?

And so it's a metric in which we held ourselves accountable for in terms to be able to provide this therapy, and that's what allows us to provide certain things like CAR T and TILs that community hospitals might not be able to. The challenge and the time and effort and infrastructure that requires to be FACT accredited is quite a bit. And so we've invested heavily in that to make sure that we can provide high quality care and maintain this FACT accreditation.

Dale Shepard, MD, PhD: We think about a lot of things start off as being done in the hospital, shift to outpatient setting. What's anticipated in terms of outpatient management of these toxicities?

John Molina, MD, EdM: That's the main goal. Everything starts in the hospital, most often, but then you start identifying patients, and we've learned over years of using these CAR and bispecific products that there are populations that are going to be safe to be in the outpatient. And so one of the questions we're asking is who would those patients be, what would those products be, and how do we increase our outpatient infrastructure to transition as many of these patients safely outpatient as we can? It allows them to be in their own home, it allows them to come back and forth from the hospital for potentially daily checks, but then have time away from a hospital.

And so some ways we do it currently, the first major step was actually the pre-treatment for CAR T. So patients get a series of what we call lymphodepleting chemotherapy. They basically wipe out, to some level, the existing immune system to allow those CAR-T cells that are infused kind of take hold and expand. Historically, we did that all inpatient. So their stay was not only the 7 to 10 days of monitoring, it was actual an additional several days, up to a week, prior to that. We've been able to move that all to the outpatient setting, and so that provides patients more time away from the hospital.

We now have several CAR products where we will actually infuse in the outpatient and then admit them later on when they get closer to that range in which we're concerned about potential toxicity. And the hope is to get to some percentage of patients that will fully be able to have outpatient. And that's the ultimate goal. A lot of institutions across the country are asking that same question for two reasons. One, it's safe and we've proven which patients it's safe to do that, and two, the capacity. So to be able to provide this to more patients, we need the capacity to do it both as an inpatient and outpatient.

And so I think as we've now established the CITs program, I think that's one of the main things that leadership is asking in terms of the next step is who can we keep inpatient and who can we move outpatient? I think that's the important part of having the CITs as well, is that the patients who will then be inpatient primarily will be the ones at highest risk, the patients who may have the most toxicities because you're going to shift some of those other patients to the outpatient in the future.

Dale Shepard, MD, PhD: So if somebody's listening in and says, "Wow, that's a really cool idea, maybe we should do this kind of service," what was the biggest challenge? Was there something that surprised you as you started to set this up that was a little more challenging than you thought it might be?

John Molina, MD, EdM: A lot of challenges. Anything. It's having good stakeholder involvement. And what we're doing is we essentially had several different service lines that we had to work with. They had different processes of getting patients on and off services, they had different ways in which they managed. It was kind of getting everybody at the same table and having being in agreement so that we can really have a focus way that we do it.

And so when I think of the challenges, you kind of have the outpatient challenge of multiple disease groups with different ways of practicing that need to bring patients onto a service, we then have to manage these toxicities in the hospital, and then transition them back to their team. So there's a lot of risk of transition and transition of care. And so we spent a lot of time thinking about what do those transitions look like? Who needs to know about these patients? How are we scheduling things appropriately? And I think scheduling became one of the hardest challenges, truly, because the scheduling systems didn't talk to each other. So if 10 providers wanted their patients to get therapy on the same day, we don't have the capacity to do that. And we're very clear in terms of from a cellular therapy side, we only want to do so many infusions a day. We try to limit IT so that we can kind of not overwhelm the system. And so it's been a lot of that process of streamlining expected, but then always the unexpected challenges.

I think the biggest unexpected was a good one. We had a whole new patient population open up. So initially the solid tumor group, the lung group, hadn't been heavily involved in CITs because we didn't have a product that we were thinking about and was in mind. That FDA approval came right as the service was ready to launch and we really had to think things and make sure that we had a system in place that was adequate for getting these patients that historically, unlike lymphoma, myeloma, or even leukemia who had some experience coming on and off and using these therapies, it was a whole new thing that was being opened up and also opened up to community providers that could refer to our main campus lung doctors, get this therapy started and go back.

So I think every month, and this past Tuesday was our quarterly check-in, we planned for quarterly meetings that we sit back and we look at all levels of the service from patient outcomes, patient safety, patient metrics, staffing. Are we staffing inappropriately? Are the nocturnists feeling comfortable? Are we doing well in the ICU, in the ED? Looking at all these various metrics and then putting in our action plans, and then we'll readdress it in three months. I guarantee there'll be more challenges.

We have four new products that are likely eminently coming. That will be another kind of patient burden on the surface, and so we have to be prepared for that. And so one of the first feedbacks is we have already grown bigger than we thought we would be in the first six months, so we're already adding our nurse practitioner capacity, our APP capacity. So that was something that, a day after the meeting, we're already hiring up to make sure that we're prepared to manage these patient volumes as it continues to grow.

Dale Shepard, MD, PhD: It's certainly an exciting category of drugs and looks like you got a great way to get them to patients safely. So appreciate your insights today.

John Molina, MD, EdM: No, thank you so much. It's been a really eye-opening process, a really exciting process, and we want to have the capacity built to really grow this and build it not only in standard of care, but our investigational agents. Getting therapies to patients they might not be able to get anywhere else in the country. And so that's one of the hopes, is that if we do this well, we build our capacity and we're able to provide, again, what we feel is best quality care and the highest level of care to these patients and get these therapies to them when it should be inappropriate.

Dale Shepard, MD, PhD: Fantastic. Thank you.

John Molina, MD, EdM: Thank you.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Thank you for listening. Please join us again soon.