Earlier-Line CAR T–Cell Therapy Integration: Predictable Delivery Through Clinical and Operational Alignment: Chapter 1

Watch Chapter 2 here.

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 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 today we'll be talking about the expanding role of CAR T–cell therapy across many diseases, especially in lymphoma and multiple myeloma, where it's moving into earlier lines of therapy. All FDA-approved products in the lymphoma and myeloma space have been compared in a randomized fashion to some form of standard of care therapy, and the labels either have been or will soon be expanded to reflect that. And even in lymphoma, we're seeing first-line therapy trials. So, more patients are potentially eligible for these therapies, and we have been seeing different types of patients in the past. And we'll think specifically today about cilta-cel, ide-cel, axi-cel, and liso-cel as therapy products; have those in the back of your minds. 

And Kelly and I will be framing the challenge of translating some of these efficacy, and also safety data that are coming out of the earlier phase studies into how do we have reproducible, scalable infrastructure at the treatment center site, recognizing that treatment centers are part of the equation in this cell therapy field in a way that we never have been before as active collaborators, with commercial sponsors and industry manufacturers. So, we will continue discussing various topics within this and break it down, with the first focusing on vein-to-vein time and getting patients into this process. So, Kelly, I'll ask the first question. From your vantage point, coordinating these CAR T–cell patients in this program day-to-day, where do you see the greatest operational vulnerabilities arising in getting CAR T–cells into patients in a timely fashion?

Kelly Tomlinson: Thanks. That is really a difficult question, because the vein-to-vein interval involves not only clinical vulnerability but also logistical inconveniences arising from a multi-step process involving different internal and external departments. And so, the autologous manufacturing process includes apheresis, shipment, manufacturing, release, and infusion, and that timeframe can be extended for various reasons. Within that process, there is also the need for authorization, workup, and patient care, creating a window of time when treatment failure can occur and requiring bridging therapy. And unfortunately, sometimes when the patients are having to wait during this extended period, they do end up not being able to move forward with therapy. 10 to 20% of patients who complete apheresis don’t receive infusion because of disease progression during that interval. So, it's not merely a background statistic; it's operational problems that the center is uniquely positioned to address.

Sarah Nikiforow: And what we've seen on our side is, one, there is data that shows, for the most part, in the studies, support that increased overall survival correlates with shorter vein-to-vein time. The question, in my mind, is always a chicken-and-egg one: whether the sicker patients who have trouble receiving the therapy on time, or the truly manufacturing quicker, can help it get to the patients and improve outcomes. But regardless, everyone recognizes that moving through this expeditiously is critical. But apheresis slots are not unlimited. We make assumptions about the patient’s status when we start this process, and it may change even before they get on the apheresis machine; they may suddenly have circulated disease. Then you will also have the patients having to be bridged. That's the period during which manufacturers have control, but we also assume that bridging therapy will keep them stable. Sometimes it does not, and they fall off, leaving you with your washout periods. So, you must closely monitor all of that. And then also, if there is an out-of-specification or a manufacturing failure, that puts us back to square one.

So, I think this emphasizes the need to move quickly, but also that all of this is written in pencil and that you need an incredibly carefully attuned coordinating staff who can pivot when you might have changes at any of these time points. Unfortunately, patient readiness at the beginning and the plan we lay out are not always what transpires. And I think that each center needs to find its sweet spot between what we anchor in and what we have flexibility in. So, Kelly, before we move on to insurance authorization, could you comment on how you built in some flexibility in your program, knowing that you may need to change apheresis states, outpatient appointments, and even inpatient admission reservations?

Kelly Tomlinson: Yeah. Thanks. So, I think it's important to have that standardized process laid out, because you start to veer into other areas and other things you need to look at, and being able to go back and track where you're supposed to be is very important. And then having nurse coordinators who are overseeing all of this, and being able to make sure that the patient is following as quickly as possible all of the different avenues that they could be going down during that manufacturing time slot, to make sure they're being seen by the physician, that any of their issues are being addressed, and that they are hopefully moving through as quickly as possible. Because every transition, every internal workflow with a handoff, can be time-consuming, it can result in the patient not achieving the outcome we would like.

Mapping these in advance and assigning clear ownership for each step allows the program to intervene before delays become clinical problems, rather than after they occur. So having that oversight, having a really good process in place, and having nurse coordinators who understand that they... Or any coordinator, that they are the ones that are really moving the ball forward, and that it's critically important that that be monitored closely, and on a daily basis, and sometimes on an hourly basis. So, the practical implications, including early slot reservations with manufacturers, confirmation of cryopreservation, adherence to chain-of-custody protocols, and proactive communication with your apheresis team, help reduce some of the most common sources of downstream delays.

Sarah Nikiforow: And then I just saw, as I was getting ready for this, the phrase brain-to-vein time, which I thought was a great one. So, by vein-to-vein, we refer to apheresis to the time the patient gets infused, but brain-to-vein time, which is the time at which someone decides this patient would benefit from CAR T–Cell therapy, is key. And so, insurance authorization is a major part of this, which can lead to delays in therapy. So, our institution has tried to reach general agreements, but we are still stuck negotiating single-case agreements with some insurance companies. And so that is something that, with the clinical data we have showing improved patient outcomes from shortening this time, would be critical to address. So, one of the things we're doing as a field is looking at contracting both for sites with commercial sponsors and for insurance companies to expedite. Do you have any experience with that?

Kelly Tomlinson: So, we have tried to change things around multiple times to move much more quickly. Obviously, going to a case rate where we don't have to get letters of agreement or single-case agreements has been what we've been trying to do, and we’ve been successful. Also, when working with the HMOs, we can have difficulty completing the workups because they must be done at very specific centers. And so, we have closely monitored and tweaked many workflows to be a little bit quicker and move things through. Luckily, this is becoming more standard of care. So, having the case agreements and all of those in hand before the patient comes in is very helpful. But we do have a process we can institute if it’s a high-risk case, especially in our pediatric patient population, where we assess the risk and may take additional steps to ensure patients are cared for.

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

Kelly Tomlinson: Thank you.