Earlier-Line CAR T–Cell Therapy Integration: Predictable Delivery Through Clinical and Operational Alignment: Chapter 3

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Sarah Nikiforow: Hi to everyone joining. My name is Sarah Nikiforow. I'm a physician at Dana-Farber Cancer Institute in Boston, and I have roles as a clinician in allogeneic stem cell therapy, as a technical director in our immune effector cell program, which delivers CAR T–cells to patients, and in cell manufacturing as the medical director of our cell processing lab. My colleague Kelly Tomlinson and I will be speaking to you today about some tips we've learned at our treatment centers for operational alignment and system readiness in delivering CAR T–cells, especially as this moves into earlier lines of therapy, making more patients eligible for this potentially lifesaving therapy. Kelly.

Kelly Tomlinson: Hi, I'm Kelly Tomlinson, and I'm the Executive Director of the Immune Effector Cell Therapy Program at City of Hope.

Sarah Nikiforow: So, Kelly, beyond the physician and the coordinator that we've spent a lot of time focusing on, who else needs to be operationally engaged for a CAR T–cell therapy program to work? And as we get more commercially approved products across different disease entities, what key capabilities do you see we need to build at the treatment centers to scale up over the next few years of growth in the field?

Kelly Tomlinson: So, safe CAR T–cell therapy delivery is definitely a team sport. The multidisciplinary infrastructure is very deliberate. We have pharmacists, physicians, infusion nurses, outpatient nurses, advanced practice providers, social workers, case managers, and administrative staff, each with defined, non-interchangeable roles in the delivery of CAR T–cell therapy. Without structured team meetings and clear role assignments, coordination can break down fairly easily. And speaking to outpatient care, that requires even more coordination for safe delivery.

Back to the support of the different departments, the key to the success of an outpatient program, we have found, is with our social workers. Our social workers conduct very in-depth assessments of the patient's ability to truly take outpatient care and be successful with it. There has to be a caregiver available 24/7 for up to 6 weeks. There is back-and-forth between the facility and their home, or potentially a hotel, because they have to stay close. They have cars, have the money to travel, or have the money for food if they have to stay in a hotel. And those are all barriers that could prevent the patient from doing it in the outpatient setting. But for the most part, it seems to be what needs to be done for these patients, because they don't really need to be in the hospital, sitting around just waiting to spike a fever.

So, I really feel like the social worker's support in assessing a patient's readiness for success is key in the outpatient program. There's also outpatient education and training for nurses, APPs, and clinic staff, as well as seeing these patients to identify early CRS or ICANS. So, really, the patient-level suitability for the outpatient management has to be assessed.

And then also the proximity to the treatment center. Caregiver availability is something that continues to be an issue, I feel, across all sites, and we are really trying to look at how we can better support these patients, because it can be a huge disadvantage for them to have someone without a job while they care for them 24/7. Housing, stability, the patient's reliability, and the ability to make daily appointments are very important for health literacy and for knowing when to come in for care, when it's needed, and when it's urgent. That all can influence whether an ambulatory model is appropriate for a given patient, independent of their clinical eligibility. So, looking at some of the toxicities that go along with this, what do you see as needing to be closely monitored from the clinical aspect?

Sarah Nikiforow: Absolutely. And I'll take it back a step, Kelly: before, when we were planning, you said you do 90% of your CARs at the City of Hope outpatient clinic. We are currently doing about 30% of our commercial CARs. So, some of it has to do with patient selection, the caregiver, and all that support. Some of it also has to do with the product itself and the realities of immediate triage in an emergency room versus having a 24/7 sort of urgent care staffed by cell therapists. And then also, frankly, some of the insurance logistics around outpatient infusion and how quickly you get hospitalized. So, I think each center is figuring out how to assess the patients, but also what is your center set up to support? And so, we have specifically targeted CAR T–cells for lymphoma and for myeloma that have a median window to CRS that is five to seven or more days out, and people are not spiking temperatures 12 hours later and ending up in the emergency room, where care may not be as streamlined.

So I think those are all factors that go in, but you are absolutely right. Even if we're waiting several days for CRS, you need to be able to detect it. So, there are multiple grading schemas through ASTCT and others. There's the CARTOX working group and the NCN that have come up with management guidelines, but these are things, as you were talking about, education that gets hard-coded into patient education. You have to make sure the caregiver calls when there's a fever.

And then we did, as you did, tons of infusion nursing education, as well as hiring two more APPs to staff and see these patients once a day, and make phone calls in the afternoon. And we have ICE scores, that mental status checklist being checked every eight hours either by caregivers or us, so all that needs to happen. But then, as I mentioned, if these patients have a toxicity, you need to have the resources inpatient. So right now at our facility, everyone who has a fever, even though we can give tocilizumab for grade one or two CRS in the outpatient setting, everyone gets admitted. Because we do not have the infrastructure to safely monitor a patient, even if they're having grade one CRS on an outpatient basis. So, whether it's grade one CRS and you just monitor them and give them tocilizumab as needed, or if things escalate, you also need to know that you have access when a patient gets really sick.

So the rates of grade three or four CRS and ICANS are definitely lower as we go. We are sometimes seeing different toxicities and timing in patients on earlier lines. So, I think that is going to be a new education for us from the clinical trials and from the people we're working with. But then you can also have patients who develop odd Parkinsonian symptoms. So, all of this needs to be looked at, and on the inpatient side, you need to make sure, even with the low incidence of severe toxicities, that you have neurologists on board. In the initial studies, we had brain herniation from ICANS. You need to detect and act quickly.

Nephrologists, especially if you think outside the CAR T–cell box into the TIL, the tumor-infiltrating lymphocyte space, we have cardiologists, we have hematologists for people who have odd coagulation history who are going to get thrombocytopenic, and what do you do? So all those things need to play in. And when we talk about outpatient, or maybe even in the future, more community-based CAR T–cell administration, people are going to need access to the expertise, even if they're not physically in the building. So those are things that I think about when it comes to scaling.

So we'll end up, Kelly, in this section, I'm going to throw the question back to you and say, as the field grows, as our programs are going to need to grow, what do you see as the biggest challenges for scalability across the field, and then also at your center?

Kelly Tomlinson: So, I think that's a great question, and it's wonderful that we're having it now, because one of the most important things is that we need to be proactive in scaling rather than reactive. As referral volumes increase, driven by earlier line indications, broader awareness, and more patients surviving CAR T–cell therapy, programs need to evaluate line placement, apheresis, infusion chair availability, monitoring bed capacity, and nurse-to-patient ratios.

These patients do get sicker and can be a lot more complex than your average med-surg patient. So, ensuring that the pharmacy can handle compounding throughput and the on-call clinical coverage for physicians needs to be well thought out and put in place. So proactive workforce development, including standing CAR T–cell therapy competency training for nursing and advanced practice providers. We also need to prevent capacity constraints from becoming patient safety risks, and doing so can help reduce those gaps and significantly increase safety.

Sarah Nikiforow: So, Kelly, I'll also mention that. Agree with you 100%. Those are all challenges at our site as well. And even if this were a community site, it would still be the same thing, but we are seeing tumor-infiltrating lymphocytes. We're seeing engineered TCRs approved in sarcoma. We're seeing CARs in clinical trials for solid tumors and autoimmune diseases. So, one of the aspects I see is broadening the base of people who understand cell therapy and ensuring that we have a cell therapy program that is not just a siloed cell therapy program but also has disease-specific expertise from the colon cancer doc, the neuro-oncologist, and the rheumatologist. And I think that being able to standardize while recognizing the profusion of different types of therapies, indications, and patients who may have complications related to the reason they need CAR T–cells, not just their CAR T–cells, is key.

So, it's an incredibly exciting time in the field, but it really does challenge each given treatment center to say, what do we want to do, and "Do we want to try to do it all, or be devoted to our hemalignancy commercial CARs?” So that's an overarching question. So, I will try to conclude this whirlwind tour by saying, I hope you appreciate that, obviously, a predictable and safe CAR T–cell therapy delivery requires many aspects of coordination, whether it be the patient being referred at the right time, which the data now justifies as most effective. Whether it's evaluating the patient's and caregiver’s social situation to figure out where they are best served. Whether it's getting insurance authorization most proactively, scheduling, and streamlining apheresis manufacturing and delivery of care. All of these require coordination within the treatment center and active collaboration with the manufacturers.

I think we are no longer passive observers here. We must actively engage and advocate for our patients, but the operational expertise and skills at the treatment center are foundational for delivering this to patients and for clinical decision-making. I'm more on the MD level and an actual operational coordinator in nursing, which Kelly has spoken to quite eloquently. All of those need to proceed in tandem. So Kelly, I'll leave you to close up with some calls to action for us. What do you think those might be?

Kelly Tomlinson: So I think making sure that you're mapping your program's current vein to vein, or actually even the brain to vein, as you mentioned, workflow is going to be key to that, as well as identifying the high-risk handoff areas where we have to make sure that we're overseeing the care very closely with referring physicians. Creating safe oversight and practices for our outpatient program, also being very proactive in that space, making sure you have clearly identified those workflows and that it's safe for the patient from a psychosocial perspective and all others. Establishing standardized referral and communication protocols with referring centers before patients are identified so that they can easily move through the system, and you can communicate with those referring physicians closely, so the patient doesn't get lost. As well as conducting a prospective capacity assessment against projected earlier-line patient volumes, I think all of these can be key actions you can take to ensure you're ready for the boom of patients who will need cellular therapy in the very near future.

Sarah Nikiforow: So, both Kelly and I would like to thank you, the audience, for listening and encourage you to explore more resources on the Oncology Learning Network about CAR T–cells or anything else that tickles your fancy. Thank you.

Kelly Tomlinson: Thank you.