Bruce Feinberg, DO: Ian, the focus isn’t just as a business. A hospital makes that decision or in this case, a private practice. But the volume story is a question of skill and optimizing skill sets. We know from surgical procedures, applying this to chemotherapy takes a certain number of procedures to achieve that excellence. Maybe it’s 20. Whatever that curve, it might be different. Administering chemotherapy as a new drug or a new regimen the first time there’s nuance. After doing it multiple times, you start to figure out the patients who are going to have problems, and it may not always be intuitive. It may not be something you can, in advance, predict. Is there a number that you think a center needs to be doing? Because there’s the 1 thing, which is just the infusion of the CAR [chimeric antigen receptor] T-cell therapy. UPenn [Abrahamson Cancer Center] has been doing it outpatient for a couple of years. That’s not the issue. The issue is, once the patient gets the infusion, how are they going to be managed when the toxicity hits?

Ian W. Flinn, MD, PhD:It’s the downstream issues that you have to be prepared for. I don’t know if there’s a number. If you’re doing 1 a month, then you probably have enough. If it’s the same small group of doctors doing it each time, then your center is probably seeing enough to experience the adverse events and be used to not re-creating the wheel each time it happens. That would be my rough estimate of what it would take. My guess is that those numbers, if you’re doing it, they’ll continue to grow at a center. One thing we didn’t talk about is that these CAR T cells are going to move early in the course, in the natural history, of the disease.

The current wave of clinical trials is comparing CAR T cells with stem cell transplant as first salvage therapy for patients with large cell lymphoma. That’s a bigger group of patients that likely benefit from it. No one knows the results of the trials, but if you’re a betting man I’d bet on the CAR T cell in this situation that it ultimately wins. The buy-in is going to go up and more people are going to need the therapy. If you’re doing 1 a month, you’re probably familiar enough with it to know how to do it.

Bruce Feinberg, DO: That was a question of quality. Then you can throw in things like certain certifications that may or may not apply to this population. They were developed for transplant in leukemia, which was managing patients through protracted dead bone marrow or profound cytopenias, more so than was focused on the CAR T-related toxicities. You have something like that, then you start to think about not just quality but cost and managing the issues that you addressed earlier. If practices are going to do it, it seems to me that whatever we’re calling now, I would say like I used to have the big practice, Georgia Cancer [Specialists], that often was referred to colloquially as the super tanker. It’s different because you have practices like Florida Cancer [Specialists], which is like an armada. Florida Cancer was the super tanker, but around it is this armada of connective practices. RCCA [Regional Care Cancer Associates] is becoming a similar entity. It’s different because they almost had within them the wherewithal to make that determination. We know we’re going to have, based on current referral patterns, a certain volume. Should that be part of that criteria of where are you going to do this? How do you go about? Even when you want to move to the community setting, it can’t be everybody that raises their hand—or maybe it could be. Michael, is it anybody who raises their hand, or should there start to be something more than that? To what extent is it? I’ll know it when I see it vs structure?

Michael Diaz, MD: If I had the answer to that question, well, I’ll tell you what, that would be great. I’d have a lot of issues solved. I don’t think that definitely in the first several years it’s going to be everybody who wants to raise their hands are going to be able to do it. I do not think that. The overall, big picture, as we start to develop the expertise within our practice, as the volume increases, as we see where there are the needs to have this in other locations, we will evolve this responsibly. Who knows. We don’t know which direction all this technology in immunotherapy will continue to evolve in the future. Will CAR T cells be obsolete in 5 to 10 years? Will they be replaced with something else? We don’t know. But you must start somewhere. You have to become and embrace the process, so you’re prepared, and you can take the best care of your patients 1 day at a time.

Bruce Feinberg, DO: Ed, hypothetically, you’ve been hired as a consultant by a CAR T manufacturer that’s got an emerging drug. And they think it should be in the community. What are you telling them? What are the criteria? What should they be looking for if they’re going to start to select sites?

Edward J. Licitra, MD, PhD: Look, to get back to your last question, it can’t be anybody that raises their hands. It’s complex. Physiology, it’s complex medicine. That being said, most of it has to revolve around the downstream effects, as Ian said. It’s the management of the adverse events. These are the things. You have to have proper policies, procedures, and training in place, so you can reproducibly identify the patients from the time they enter into the system, flag them, and then make sure that all the proper consultants and teams are in place to take care of that patient in the most perfect way.

That’s where I would spend a lot of my time. To your point, getting a small vial of 3 cc of CAR T-cells that come out of liquid nitrogen and infusing it over 10 minutes in an outpatient office—that’s the simple part. The hard part is when that patient develops CRS [cytokine release syndrome] 7 days later and winds up in the hospital, and you must make sure you do the right thing. I put all my effort into making sure those teams of appropriate doctors are in place—not only doctors but staff—and formally trained to deal with what will hopefully be a rare event. And take care of it the right way if it occurs.

Bruce Feinberg, DO: Ian, over the 2 years that the products have been in the market, is your understanding that with the use of IL-6, the use of steroids, we are making progress in toxicity? It’s hard to catch up. You can look at the FAERS [FDA adverse-event reporting system database], but it is voluntary data entry. Do you have a sense that we’re managing toxicity better, that we’re having lower mortality, lower grade 4 events? Do you have a sense of that? Where do you think it’s going?

Ian W. Flinn, MD, PhD: Yes, we’re better than we were 2 years ago at managing these adverse events. There was a fear that coming in early with steroids would blunt the effect of the CAR T-cell, the therapeutic effect along with the adverse effects. We learned that, for the most part, that’s not true, you could come in starting with steroids much earlier, decrease the risk of having severe adverse events. There’s definitely a learning curve. We learned when to use tocilizumab and when not. It’s not going to fix your toxicity, in some studies maybe you exacerbate it. That’s much better. Where we’re going is this next generation of CAR T cells is different.

The ones currently in the developmental pathway have a better adverse-effect profile, where they’re expanding in vivo instead of ex vivo in patients. And hopefully getting them into patients quicker, decreasing the risk of cytokine release and the risk of neurotoxicity. We’re getting better at understanding who is likely to have some of these adverse events and realizing that CAR T cells aren’t for everybody. Some people are better off without them, just like transplant. Some people are better off without getting a transplant. Not everyone has to have these therapies. We’re not necessarily doing everyone a favor by giving it to them. The field is developing. It’s having the same natural history that you would see, and we’re going to see more and more outpatient administration of CAR T cell because the incidence and severity of some of these adverse events is going down.