Considerations for CAR T-Cell Therapy in NHL

Babis Andreadis, MD

Chimeric antigen receptor (CAR) T-cell therapy exploded onto the scene in 2017 with the approval of tisagenlecleucel (Kymriah) in acute lymphoblastic leukemia (ALL) and axicabtagene ciloleucel (axi-cel; Yescarta) in non-Hodgkin lymphoma (NHL).

Tisagenlecleucel was the first FDA-approved CAR T-cell therapy, and one that is indicated for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. The approval came following the advice of the FDA’s Oncologic Drugs Advisory Committee, which voted 10-0 in July 2017 to recommend approval.

OncLive: Please provide an overview of your presentation on CAR T-cell therapy in NHL.

Axi-cel was approved in October of 2017 for the treatment of adults with relapsed or refractory NHL. This approval was based on the single-arm ZUMA-1 study, in which axi-cel demonstrated an objective response rate of 82% and a complete response rate of 54%. In an interview during the 2017 OncLive^® State of the Science SummitTM on Hematologic Malignancies, Babis Andreadis, MD, associate professor of clinical medicine, Department of Medicine, director, Clinical Research Support Office, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, reflected on the successes seen with CAR T-cell development in the past year and the use of CAR T-cell therapy in patients with NHL.Andreadis: We are living in an exciting era in lymphoma therapy because of the recent developments in immunotherapy, specially CAR T-cell therapies. In 2017, we saw the approval of 2 novel therapies in patients with ALL and diffuse large B-cell lymphoma. My talk focused on how these therapies work and what are the expected management complications and toxicities associated with them. In the lymphoma sphere, we know that both therapies can produce 30% to 40% long-term responders, meaning people who are out 6 months or more with a complete response. The goal is to determine whether those patients can be seen as longer-term responders and eventually be cured. We think CAR T-cell therapy has the ability to do that.

Currently, it is only available in specialized centers because of the ramifications and toxicities involved with the treatment. We are seeing a big increase in our referral patterns to accommodate those patients, and all major centers across the country are doing that.

The main toxicities with the treatment have to do with 2 broad spheres, one being cytokine release syndrome (CRS), which usually presents with fever, low blood pressure, low oxygen levels, and organ toxicity; it usually happens in the first week. The other short-term toxicities are anything from confusion to inability to speak, to disorientation, to tremors, and even a coma. These usually happen in the first week and can last a little longer than CRS. Therefore, the physicians in centers who are doing this therapy need to be educated and trained in order to safely administer the therapy. Once this acute phase is over—about 1 month—most patients can return back to their local physicians. The long-term side effects are manageable. Those can be low blood count—and may need transfusion support—as well as needing to have hypervigilance about infections.

How have you noticed the approvals of axicabtagene and tisagenlecleucel impacting the treatment landscape?

This great era that we have been waiting for is here, and we now have a therapy that works for patients who don't have any other options.We have seen a big uptake in referrals. People with large cell lymphoma have a great chance at cure. Frontline treatment cures 60% to 70% of patients, and if they relapse, second-line treatment cures about 25% of patients. Historically, patients who don't respond to the second-line treatment have no options, and their 1-year survival rates are somewhere around 10%.

Will we ever reach a point where this therapy could be implemented widely across the country?

Therefore, these patients would not have been referred to major centers, historically; they would have been managed locally and in a palliative manner. However, now we are seeing all of these patients being referred because they believe there is finally an option that can work. Everyone has a good chance.There are some parts to it that we are being careful about. The structure of the treatment is much like a stem cell transplant in that you need a stem cell collection, the manufacturer, the intravenous administration, and toxicity monitoring. Therefore, the structure of the treatment requires a lot of resources that the average community practice does not employ.

Reflecting on the data seen at the 2017 ASH Annual Meeting, what studies have garnered excitement in the CAR T-cell space?

Having said that, stem cell transplantation, which started out at transplant centers, has transitioned out to the community and there are large community practices that do them. They do need certification and a lot of different processes in place. Therefore, I do foresee those centers being able to administer CAR T-cell therapy in the future. It is exciting to see long-term follow-up. All of these studies are very new, and we don't have the 10- and 20-year experience that we have with autologous stem cell transplantation. It’s exciting to see the longer follow-up with these studies and how patients that are in remission have maintained that remission at 1-year follow-up.

The other interesting thing is that we are beginning to understand who this therapy does not work for. We are seeing what those who relapse look like. It does not appear that patients who relapse lose CD19, which is the main antigen that is employed in this product. Unlike ALL, where there is a big component of CD19 loss, we don’t see that here.

Will that include combinations of CAR T-cell therapies?

What are some lymphoma subsets that are likely to see an approval for CAR T-cell therapy?

Also, we don’t see the T cells going away. Lack of persistence is not a marker of relapse. Most likely, the reason that patients are failing is that the T cells get exhausted. We are working on ways to increase T-cell function to be the next wave of improvements in this therapy.Absolutely. That would be a good way to do it. Combining clonal T cells, or even receptor T cells would be something to look forward to in the future. The other thing would be making CAR T cells a kind of off-the-shelf product. This would involve avoiding the different collection and production that is required on an individual basis, and being able to use it as a universal treatment for patients. There is a lot of research going on right now in follicular lymphoma. Dr Stephen Schuster and researchers from the University of Pennsylvania have presented their data on those patents, and they seem to do remarkably well. Historically, follicular lymphoma is very sensitive to immunotherapy; vaccine studies have shown that there may be benefit with vaccinations. That is going to be a very active area of disease.

Mantle cell lymphoma is being included in some studies, and we don't have a lot of data there, but it’s also a lymphoma that is immunologically sensitive. I hope we see improvements. There is a lot of activity in chronic lymphocytic leukemia, which is technically a lymphoma, and there are some studies going on right now. All of those areas, which all express CD19, will be hot topics for research.

Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). In: Proceedings from the 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.