Gaining Knowledge of CAR T-Cell Therapy, and CRS, Over Time

As clinicians gain knowledge of the nuances of chimeric antigen receptor (CAR) T-cell therapy, the opportunities arise for treatment to occur beyond the walls of the academic medical center. But the academic medical center is still an important partner in this treatment evolution, said Amit Kumar Mehta, MD, who has several roles at the University of Alabama at Birmingham. Mehta is associate professor and director of the Lymphoma Program director of the Immune Effector Cell/CAR T-cell Program at the O’Neal Comprehensive Cancer Center.

Mehta discussed the evolution of CAR T-cell therapy with The American Journal of Managed Care® (AJMC®) this week. (This interview has been edited lightly for clarity.)

AJMC®: Can you discuss how the knowledge base for determining which patients would most benefit from CAR T cell therapy has evolved over the last several years?

Mehta: Primary antigen T-cell receptor therapy has been in practice now for a period of 5 years, and it was a fantasy 5 years back. There are 2 products, which are approved in lymphoma space and a specific indication. The clinical trial told us that is a process for preparation of CAR T, and that process involves collection of T cells and preparation of those T cells; then, you infuse those T cells in patients.

Why it is important? Because there is a time period in between when the CAR T cells are selected or prepared, and that time period is critical, because these patients are relapsed lymphoma patients. If you don't select the patient, then during this preparation time, the disease might progress, and ultimately, they will not be able to receive the CAR T product. So, selection of the patient is the key in the setting.

After learning from various clinical trial, and now [with] this therapy being in practice for a period of 2 years, we realize that selecting the patient is the key—as these patients are having active disease, and they've already failed couple of lines of therapy. If the patient has high risk disease, bulky disease, very high lactate dehydrogenase (LDH), these are the patients that you would be very skeptical to go through the process because they don't have time to wait. …

So [this knowledge] has evolved from clinical trial findings as well as real world experience. And that was presented at cancer congresses and meetings, that the intent-to-treat population in this patient group is very key, not those patients who could receive the cells, but how many of those patients could not receive the cells? And what were the reasons for most of the patients? The reason was progression of disease. That is why it is very key that we don't select a patient who has very aggressive, raging disease who cannot wait for the therapy.

AJMC®: How has the management of cytokine release syndrome evolved over time in in your practice? Are patients as likely to have extended hospital stays as they were 3-5 years ago?

Mehta: When the clinical trials related to CAR T came into existence, we did not have formal guidelines for cytokine release syndrome (CRS). You know, everybody remembers the case of Miss [Emily] Whitehead, who was a young patient who first underwent a CAR T-cell therapy who got very sick, and responded very well to tocilizumab, and that created a foundation for treating cytokine release syndrome.

Over a period of years, we have learned a lot about CRS. The criteria that we were using before was Lee criteria; now, we have consensus guidelines on grading of CRS. We [now] know a lot about CRS—when it starts and how to handle it, what the signs and symptoms are, and how to treat it. All the [CAR T] products that FDA approved have a mandated REMS program, [which require] 2 doses or tocilizumab per patient available before even you decide to treat. That is key—management is not only identifying symptoms and signs of CRS, but management has also evolved over a period of time, and it has become better and better. From initial fears of CRS, we are at a point that we know how to have a patient prepared for CRS.

We are learning from the products we have there are two costimulatory domain(s); in the CAR T products that we have approved, one is called 4-1BB and the other one CD-28. And each has a different timeline for CRS as well as neurotoxicity. Now, if you look at the data, the 4-1BB product has a little bit delayed onset of CRS, and not as intense as with CD-28. So, in those patients who are 4-1BB, technically, you can still handle this patient as an outpatient, or they may not need that longer hospital admission compared to CD-28 products. Again, those patients who have bulky disease, hybris disease, very active disease, and those who end up with multiple complications—they may end up in the hospital for a longer period of time.

At our center, we were near the point of doing it as an outpatient in a select group of patients with a select product. But with this COVID-19 pandemic, things have changed. And we've decided not to experiment that as an outpatient at this point. Because if the patients get sick, they must come in [to the hospital]. And if COVID-19 patients have occupied the beds, then the CAR T patients may not be able to come in when needed. So that's why we have moved forward with all inpatient hospital admission. But on an average, we see about 7 to 10 days of inpatient hospitalization for a wide variety of reasons; the CRS could [lead to] neurotoxicity, or tumor lysis syndrome.

AJMC®: The American Society of Clinical Oncology has published guidelines about improving the diversity of patients in clinical trials. How has this issue applied to your work in CAR T-cell therapy?

Mehta: This is a burning national question right now—the inclusion of minority patients or underserved patients—and I'm proud to say that we have a good program here. We have a Patient Navigator program and we are nationally recognized [in this area], so that we can address the issues for the minority patient as well as the underserved patient. And that applies not only for people across the clinical trials, and it is a priority to make sure that we have a true representation of the community among those we treat in the academic center. We have community engagement programs, and we have a lot of education program for the patient themselves.

In Alabama, as we all know, there is a long [and difficult] history involving minority patients and the underserved population being involved in clinical trials. So that's why we are very sensitive in that issue and [provide] support to our patients. … We also have shown that patient enrollment has increased not only in clinical trials, but also in the commercial program of CAR T. We engage patient navigators in the community with patients as well as their physicians, we also get engaged with the community doctors. This has helped a lot in engaging these stakeholders in patient management, and it shows in the results.

AJMC®: What improvements in the next generation of CARs or you feel are going to make the biggest impact.

Mehta: CAR T is still in its early phase. But we now know, based on the products that are available, that on average at a year to a year and a half, about half the patients will be in remission and half the patients will progress. So, why do they progress? What happens? Do they have immune checkpoint pathways, which get upregulated or delusory 19? Or [do] they exhaust the T cells that were prepared? There are a wide variety of reasons [for progression], and nobody at this point is pinpointing at one cause that why these patients progress.

Second, we also know that this process of preparation of CAR T varies from 2 weeks to 4 weeks, depending on the commercial product. So that's the second challenge, as we addressed before, that [affects which patients] I want to treat with CAR T, whether I have enough amount of time to wait.

Among the improvements we have seen, one is dual antigen CAR T, with CD-19 and CD-20, which has shown promising results. And that could be because tumor cells [are] losing CD-19 expression; so, we feel comfortable, and there are early data to suggest that dual-antigen CAR T has higher responses and sustained responses. Second, is whether we can avoid the whole process of preparation, when we harvest a patient's own T cells and prepare them, rather we have those cells available on the shelf. This would allow us to bypass the wait time of 2-4 weeks. And that's the next generation that we are seeing, the off-the-shelf or allogenic CAR T. We are also seeing CAR NK [natural killer] cells, which are off the shelf or they're getting from donors or we are getting it from cord blood. So, I think this are the excitement for the next-generation CAR piece.

Also, [when it comes to] identifying CRS and neurotoxicity early in the course and treating it effectively, we still don't have good prognostic markers for which patients will develop CRS. If we can do that, there are 2 benefits. Number 1, there’s the [ability] to improve safety of the patient. Number 2, we can [decide] whether to handle the case as outpatient or not, which is a critical question, especially for such a costly therapy. And there is a wide difference in reimbursement for inpatient versus outpatient.

AJMC®: Speaking of reimbursement, you have published papers discussing the reimbursement challenges with CAR T. How has reimbursement changed since treatment reached the market?

Mehta: I will say that the reimbursement has improved compared with [prior years]. There were many challenges before; there was palpable resistance from the academic centers, especially for financial health of the institution, if we decided to do multiple patients. Also, CMS has now kept up with the third-party payers, and they're also increasing their reimbursement. So that improved at this point, compared to a couple of years back.

But this is very costly treatment, there is no doubt about that. And we don't have a single payer system, so everybody has different reimbursement. Especially with Medicare and Medicaid, as we discussed about patients who are below the poverty line or if they have a financial challenge, they absolutely cannot get this CAR T-cell therapy. So, those challenges are still there. We don't have a compassionate use program as we do with many other cancer drugs, because of the cost.

AJMC®: There’s been discussion about using CAR T-cell therapy earlier in the life cycle of the disease when perhaps the patient is healthier. At this stage, the therapy might work better before the patient's system is so depleted. What are your thoughts on this strategy?

Mehta: I will address this question 2 ways. One is you're exactly right. You know, we don't want the patient to be so sick that they cannot get the Carty and there are a bunch of clinical trials already going on the way the cancer drug approvals happen in the United States is you know, they enter at a lower relapsed refractory stage of the disease and they slowly climb back up. So, there are trials ongoing, which will help us know whether that is beneficial or not. But what in my viewpoint, what is important is those patients who are high risk, you know, there are certain characteristic in every cancer, if you look at diffuse large B cell lymphoma, we know that double hit double expressor, those who are activated diesel subtypes, they are high risk patients. So those are the patients who should get this therapy earlier in the course. And why do we have to wait till their relapse? I think it's depends on the label and the clinical trials that were done. But I would be extremely interested down the line for those high-risk patients, that they get CAR T [treatment] earlier, when they have first remission as a consolidation, so that that disease does not come back down the line. I think there are a lot of interest in that setting. There are many clinical trials are ongoing at this point. And hopefully it will climb back as we go. And especially with the cost, we are looking at the cost effectiveness in every everything. So those specifically for high risk patient, we should address it earlier.

AJMC®: It’s been pointed out that if you give the therapy earlier and it works, then you've also avoided the cost of whatever other therapy you would have given that would have failed.

Mehta: Absolutely. So why do we have to wait till the relapse? And then we struggle to find a good treatment for that patient.

AJMC®: Finally, let’s talk about the process of bringing CAR T-cell therapy into the community. You mentioned this in your previous answer, but can you discuss the role of the academic center in collaborating with the community practice? It sounds like you have long-range plans about this therapy working in the outpatient or the community practice setting.

Mehta: This is the issue dear to my heart. I feel that if the therapy is [too] expensive, that is this is not an option for treatment. And secondly, if it is not widely available, then it will not be successful. So, when we say “community,” we want to make it make sure that it is safely administered in the community. There are multiple ways that we can do this; either we can engage the academic center in the catchment area with their hospital so that they are up and ready. They are factor created, they are supervised and making sure that everything happens as per the REMS requirement. And the second entity that can get involved is the pharmaceutical company themselves. They have a team of physicians, nurses, pharmacists, who are available in the community setting so that if [the physicians] have any question they can always ask.

I envision down the line that we will have a mechanism where there will be a community program for administering CAR T under strict supervision of an academic center in the catchment area, and with a team of pharmaceutical companies, a specialist in that setting, which could be physician, and of course nurses and pharmacists available 24 /7 for help if the patient gets sick. …

If you have that mechanism, only then can you safely administer [CAR T in the community]. Those physicians must repeatedly go undergo training to handle this patient. As we all know with CRS, if you don't identify it early, and if it gets out of control, it is extremely risky for patients—it’s life-threatening.

AJMC®: Any final thoughts?

Mehta: I would say that the treatment is extremely exciting. I personally have multiple patients who would not be with me without this treatment, because this was a life-saving treatment for them. And I've also lost a few patients who had out of control side effects. So, this is a two-edged sword, and you must handle it extremely carefully. The second part, which I'll bring up is cost-effectiveness; it's expensive treatment. And we are lucky that we are in United States can offer this treatment for our patients; at many centers throughout the world, they have even not seen or heard or read about this treatment. I think there is a long way to get this to the patients who really need it, and I get a lot of international referrals [for patients] who need this treatment. So, that tells us that it’s very effective, but at the same time it is not available to everyone. … I'm more excited for off-the-shelf CAR T so that we don't have to wait.