COMMENTARY

'Real World' CAR T Cells: Comparing and Using Approved Products

Miguel-Angel Perales, MD; Marcelo C. Pasquini, MD, MS

Disclosures

February 02, 2018

Miguel-Angel Perales, MD: Hello. I am Miguel Perales, deputy chief of the Adult Bone Marrow Transplant Center at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City. Welcome to Medscape Oncology Insights, coming to you from the 2017 American Society of Hematology (ASH) annual meeting in Atlanta, Georgia. Today we will be discussing some of the highlights of the CAR T sessions presented at the meeting and, more broadly, where the field is going.

Joining me in this discussion is Marcelo Pasquini, associate professor at the Medical College of Wisconsin and senior scientific director at the Center for International Blood and Marrow Transplant Research (CIBMTR). Welcome, Marcelo.

Marcelo C. Pasquini, MD, MS: Thank you, Miguel.

Dr Perales: We now have two approved indications for CAR T cells. What are your thoughts on how we are going to bring this to the clinic and the real world?

Dr Pasquini: We are in exciting times with the approval of these two potent live drugs for acute lymphocytic leukemia and non-Hodgkin lymphoma. This is a testament to the work conducted in several institutions in the United States and elsewhere, and that brought this over [the line] to make it available to patients. We are living in unprecedented times. These are powerful, living drugs for patients who have very aggressive diseases, and they come with a lot of challenges. These drugs are very expensive, they will be available in a limited number of sites initially, and will require a large amount of scrutiny to follow these patients for the long term.

Dr Perales: At MSKCC, we have spent the better part of this year preparing for this moment. We have had multiple meetings with hospital administration, pharmacy, medicine, and the critical care team just to get the logistics lined up to implement this therapy. [This will] bring a whole new level of patient care, in terms of making sure that we administer this safely to the patients.

Dr Pasquini: Absolutely. As with bone marrow transplant, these patients require complex, multidisciplinary care. As this is rolling out to the community, the centers must be quite prepared, from the baseline of identifying the appropriate patients for therapy, to their day-to-day care, if they have to go to the ICU, the post-care, and so forth. This is really a paradigm shift that we are seeing right now with these patients.

Dr Perales: In the patients with lymphoma, obviously the clinical trials were carried out under very specific circumstances and with very specific criteria. If you look at the label for the first product, manufactured by Kite Pharma, it is basically for relapsed lymphoma after two lines of therapy, which is quite a bit broader than what was studied in the clinical trial. There is no consideration for where the patients have been treated. We know that all of the trial patients were being treated in-house and the label does not address that, and even the usual criteria that you would have in a clinical trial are not included.

We have put together a group of transplant and lymphoma specialists and looked at the label and at the clinical trial, including exclusions. We are going to be okay with the label in this regard, but we are going to make a few additions that we feel are more appropriate in terms of clinical care. I have heard that some insurance companies are saying the label is one thing but [they] are just going to follow the inclusion-exclusion criteria of the clinical trial and not go with the label, which is much broader.

Dr Pasquini: Safety is paramount. The trials were carefully designed to include patients who not only have relapsed-refractory lymphoma, as you know, but they had to keep to an absolute minimum of organ toxicity so that when these patients do get sick, mortality does not increase. That must be translated [to real-life practice]. We are seeing this in the centers that are participating, at least the selected sites that are participating and can prescribe these CAR T cells. They need to select patients carefully—not only the right disease to do this, because there is the potential that the real-world results will be much worse than what we saw in the trials. That is important.

Dr Perales: I believe that should be a concern for the company as well. They are the first ones out and they do not want to have patients not doing well with their product. I do have a concern as they move out from the clinical trial center to larger centers that may never have used CAR T cells. They may just proceed according to the label and not look at other health issues in these patients. That may not give us the same results.

Dr Pasquini: I do like what the company has set up for training physicians at various sites and having a more cautious rollout—not starting with 90 sites at once, but starting with initial sites that had experience from them. The company also requires the centers to have FACT (Foundation for Accreditation of Cellular Therapy) immune effector cell accreditation—that is, not only the physicians who are seeing the patient, but the entire program must be prepared to take care of these patients. Having some sort of accreditation body and guidelines for how to treat these patients is important for safety.

Dr Perales: I think the rollout has been done quite carefully by both pharmaceutical companies, and that is very smart on their part. But we also struggle with the two different grading systems we have been given and the fact that both companies have specific [and different] recommendations for how to manage the cytokine release syndrome and how to manage the neurotoxicity. Their recommendations vary and the grading varies—not so much now, when we are treating two different populations, with pediatricians treating children with acute leukemia and we are treating patients with lymphoma. But imagine in a couple of months when we expect to have the Novartis product approved. You may have, at the same time on the clinical floor, patients getting two different products with potentially slightly different management systems recommended by the companies. Which grading system do you use and how do you put that into practice?

Dr Pasquini: This is a testament to how novel this field is. We now have a third version of these grading systems coming out. I believe the approach should be similar to what we developed with graft-versus-host disease in the transplant field. We had several iterations of revised criteria, so we can evolve. One very important point is that we must speak the same language to provide appropriate supportive care for these patients. If we are treating grade 3 in one way and grade 2 in the other and grade 4 in another, that is going to be problematic.

Dr Perales: And it's not even the same grade 1, 2, 3, or 4. I worry about the typical situation where the physician covering at night, who has many other patients, gets called to the floor and wonders, Is it this product or that product? Which grading system am I using? When do I use the tocilizumab? That is the scenario we do not want. We want it to be very streamlined and to have specific guidelines.

Dr Pasquini: The publication from the MD Anderson group[1] related to the CARTOX guidance, published early in 2018, will be important in this effort. That paper describes a comprehensive, multidisciplinary approach to treat these patients. This is going to be very different from the clinical trial patients. Out in the community, patients will be under less scrutiny compared with the clinical trials, in terms of monitoring and auditing these patients. These guidelines provide centers with a way to begin, at least, and then follow up.

Dr Perales: This is a critical paper. And I think you know also that the American Society for Blood and Marrow Transplantation (ASBMT) and the European Society for Blood and Marrow Transplantation (EBMT) are working together to develop some guidance as well, and are thinking in very practical clinical terms about how they can issue some guidance in terms of what is the best management. It is going to change over time, obviously, but at least they will provide some very practical recommendations. The other area that is still a big question mark is long-term follow-up. We know that because it involves genetically modified T cells, we have a long-term follow-up requirement from the US Food and Drug Administration (FDA). The CIBMTR has been very active in that field.

Dr Pasquini: The word "unprecedented" is about this point exactly. This is the first time that we are seeing such scrutiny of a commercial product that you have to follow these patients for 15 years. This requirement comes from the concern of having second cancers develop, even though, with this class of genetic manipulation, we have not seen this so far. Still, the follow-up is cautionary, not only because of the potential for second cancers, but if you have robust cells that persist and now you have a young woman who becomes pregnant and these cells persist and carry to the baby...

These are all very important points that increase the importance of following these patients. The CIBMTR is a research organization that follows patients after a hematopoietic stem cell transplant. We have been doing this for more than 30 years. We helped advance the field of transplantation by collecting the data, sharing the data, and allowing multiple investigators to use the data for research.

With that, we created a system that can follow these patients for a long time. We have been working with the different commercial companies that FDA mandated should monitor patients and collect data on second cancers. We do have experience with that. About 2 years ago, as we saw the field changing, we initiated a project to create an outcomes registry for cellular therapy, thinking that this would be coming.

Early in 2017, we launched this cellular therapy registry. It is fully operational to collect data. The objective is quite large, in a way that we want to create a standardized outcomes database that everyone can use. We do not want to be in a situation where each company has its own registry and the centers that are using multiples of these products have to rely on each one. You cannot have that. Having a standardized way of collecting cellular therapy data would be very good for the field in a way that we can eventually compare these products and see what is the best for the patients.

Through this cellular therapy registry, we can get input from the community, from experts in the field, and also from our European and Japanese colleagues. If it is a global product, we can use the same language whether this is used in America, Europe, or in Asia, and if we want to collapse the data or consolidate the data, that will be doable. This system mirrors the large experience we have with transplant. We follow these patients yearly. There is a mechanism that is similar to transplant, again, because centers are familiar with collecting the data.

We are not trying to take over the world of cell therapy, but it is a way of having a continuum. We envision that these patients will probably have a transplant before or after cell therapy, or cell therapy can be compared to transplant. This situation would be ideal, so we can really decide which treatment is the best for the patient.

Dr Perales: To me, what is unique about transplant is that we are so data-driven. You can ask any transplant center, "What is your 1-year survival for acute leukemia, what is your 1-year survival for lymphoma?" and they can give you that data. You go to the leukemia chief or the lymphoma chief and say, "What is your 1-year survival for leukemia induction?" and he or she will get back to you 2 weeks later. If, as we imagine, a year from now, we have three different products in the lymphoma space, being data-driven and being able to collect this in one location will be critical.

Dr Pasquini: The other point, with this follow-up, which will be critical, is: What happens to the patient who goes to Memorial, is treated with one type of CAR T cell for lymphoma that does not work, then goes to University of Pennsylvania and gets a second type that does not work, then goes to a third center and gets the third product, and then eventually gets a transplant? Who has the responsibility to follow these patients for 15 years? Is it the first center or the last center? Having a system that is standardized will help track these patients. That will be ideal. And it will probably be a benefit to the field.

Dr Perales: My record is three CAR T's for one patient at three different sites. I do not believe that will be common, but we are certainly going to see some of it, especially as they develop CAR T -cells for other targets. Crystal Mackall presented some data[2] at this meeting looking at the CD22 targeting in patients who failed CD19. She and Terry Fry have some very nice data showing that they can rescue patients with CD22 CAR T cells.[3]

Dr Pasquini: It was fascinating. [Data] at ASH this year demonstrated some other mechanisms of resistance. In acute leukemia, we have seen that the patients lose the CD19 antigen expression, but it has not been seen very much in lymphoma. But we now see some elements of this; that loss of antigen expression for CD19 also happens with lymphoma.[3]

Dr Perales: It will be challenging financially to imagine patients getting two different CAR T-cell treatments. What are your thoughts on combining CAR T's? I know that there has been some discussion of dual targeting and whether you mix cells against two targets or whether the same cell expresses the two targets.

Dr Pasquini: That is interesting. Oncologists or hematologist/oncologists [tend to believe] that more is better. If one agent does not work, increase the dose or add another agent. There are a few studies that combine CD19 plus CD20 or CD22 CARs. In her talk, Dr Mackall mentioned that this is going to be really problematic financially. She suggested using these bi-specifics or even tri- or quad-specifics—that you look at a variety of different antigens in a single CAR within the same construct that can basically potentiate its effect. I believe that is probably the way we will go. The other important element is combination therapy, by trying to add immune checkpoint inhibitors to the CARs or modifying the CARs so that the CARs have a slightly more regulated approach and you will see less toxicity.

Dr Perales: I thought that was a nice part of her talk as well, where she talked of the exhaustion of the T cells and mechanisms to try to overcome that, and thinking about new delivery methods. That is fascinating.

Dr Pasquini: We are still quite early. She mentioned that, right now, it is still only on and off; you view it as a 60-mile-per-hour car or you see a car that is not moving. You want to have that throttle so you can actually go up to speed when you need it and control it.

Dr Perales: You talked a bit about being able to compare CAR T's. It is conceivable that we will have three approved products in lymphoma by ASH 2018. The Kite product is approved now; the Novartis product will probably be approved within the next couple of months, based on their data; and Juno Therapeutics, with very promising data being presented at the meeting,[3,4,5,6] will probably get approval for its agent later in 2018. I can certainly picture that next year we will have three approved indications.

I struggle with who will make that decision. Do I get to decide with the patient that we want to give this CAR or that CAR? Or is it just going to be that the insurance company has a better deal with one of the CARs, so they decide? Do we think there are really data right now that could say, well, this one may be better or not, or safer or not? Obviously, the companies all say that theirs is better and safer, but what is your sense, knowing that we cannot really compare side-by-side trials?

Dr Pasquini: I believe there will be a bit of everything. As they roll out, at some centers there will be overlap, but some centers may select one product versus another, so they will have more experience with that one agent and you do not have the predicament of choosing one versus the other.

The constructs, as we know, are different. It seems that there is a difference in how they proliferate or expand initially and how they stay with the patient, depending on whether it is a 4-1BB or C28 type of construct; they differ in that. We do not have a way of comparing one way or the other.

Even the pivotal trials that are being used for approval are very early. The ZUMA trial[7] has been presented with 8 months of median follow-up, which is rather early. When you look at ZUMA versus the SCHOLAR patients that they presented at the meeting,[8] of course there is a fourfold or so better response in the ZUMA trial. The question will be the duration of response and how we are going to choose. You bring up very important questions: What is going to be the selection process and which agent will you choose? Quite possibly, the insurance company will dictate at different sites, "This is the first-, second-, and third-line." You can imagine the third-line CAR in terms of cost. This is also a consideration.

Dr Perales: Looking at the different vectors, as you pointed out, the co-stimulation is different, the rate of expansion is different; so that may be relevant in terms of the onset of toxicity. Certainly, if you are trying to do this as an outpatient versus inpatient, if the delayed onset of toxicity may allow you to treat the patient as an outpatient and only admit them a few days later, as opposed to having to admit them almost immediately, that will certainly have an impact.

I was struck by the early data from the Juno product, that the safety signal seems to be slightly better, but it is obviously very early data and they are still in the dose-escalation phase, so we have not really seen full data at the higher dose. But the preliminary data seemed interesting in that regard. They are using the 4-1BB antibody, which is the same as the Novartis product, but they do have the defined composition of cells, and that may be playing into it or it may have nothing to do with it and it is just different manufacturing. I think there are so many questions.

Dr Pasquini: The issue was that the cells expanded rather quickly when you separated CD4 and CD8 and transduced them separately and then infused them. It is a different package. It is a slightly different product. I think it will be important to be able to compare the activities in similar patient populations. With the registry, or the outcomes database, I believe that will be doable. We hope that the pharmaceutical companies understand that this is important, that we could use the same mechanism for all of these products.

Dr Perales: This has been a fascinating discussion. We need to make a date for the next ASH because we will have so much more to talk about. We predicted this, and now we will see if we were right or wrong, or if we were halfway there. Marcelo, thank you for joining me today. It has really been a great discussion. This is Miguel Perales at ASH 2017 in Atlanta.

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