MCL Researcher Highlights Future of CAR T-Cell Therapy, Other Approaches

Michael Wang, MD,

In the ongoing phase II ZUMA-2 trial, investigators hope that the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) can lead to a breakthrough in patients with mantle cell lymphoma (MCL) who no longer respond to treatment (NCT02601313).

“In ZUMA-2, we are aiming to overcome resistance cost in mantle cell lymphoma,” said lead author Michael Wang, MD. “[To overcome] cost by targeted therapies and immunotherapies and to overcome resistance with cell therapies.”

Adult patients with pathologically confirmed relapsed/refractory MCL and an ECOG performance score ≤1, and who have received no more than 5 prior therapies, are eligible. Prior therapy must include anthracycline- or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, and ibrutinib (Imbruvica) or acalabrutinib (Calquence).

Patients who have undergone allogenic stem cell transplantation, received prior CD19-directed therapy, have clinically significant infection, or a history of CNS lymphoma or CNS disorders are not eligible.

The primary endpoint of ZUMA-2 is overall response rate (ORR). Secondary endpoints include duration of response, overall survival, progression-free survival, and safety.

In 2017, the FDA approved axi-cel for use in patients with large B-cell lymphoma, including diffuse large B-cell lymphoma, following 2 prior therapies, based on ORR results from the phase II portion of the ZUMA-1 trial. Axi-cel induced an ORR of 82% and a complete response (CR) rate of 54% in ZUMA-1. Thirty-nine percent of patients remained in CR after 8.7 months of follow-up.

OncLive: How did this trial come about?

In an interview with OncLive during the 2018 ASCO Annual Meeting, Wang, professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, discussed what he hopes to find in the ZUMA-2 trial and his belief that MCL can be cured in his lifetime.Wang: I am the principal investigator of the B-cell Lymphoma Moon ShotTM at The University of Texas MD Anderson Cancer Center. The overall goal of the program is to double the cure rate of B-cell lymphoma from 30% to 60%. In order to achieve this, we have to find out where the problem is. The natural course of B-cell lymphoma is a repeated process of remission/relapse and remission/relapse. During this process, drug resistance progressively increases. Eventually, the resistance becomes too much, the patient stops responding to any therapies, and they will die from lymphoma.

To overcome drug resistance, we have 3 major technological achievements over the past few years. In the past, we always used chemotherapy, but the 3 areas of breakthrough are the targeted therapies—for example, the BTK inhibitors ibrutinib and acalabrutinib—and they are both approved for MCL. Targeted therapies are usually targeting a small molecule. The second option is immunotherapies. There are checkpoint inhibitors such as nivolumab (Opdivo), which is approved for Hodgkin lymphoma.

How many patients are you looking to enroll in ZUMA-2?

If CAR T-cell therapy eventually gains approval in MCL, could that affect the sequencing of treatment? Could CAR T-cell therapy be moved into the first-line setting?

The third therapy, which in my opinion is very promising, is the cell therapies, what some people call cellular therapies. The major breakthrough in cell therapy is the CAR T cells. ZUMA-2 utilizes the cell therapy by taking an amount of the CD19 antigen, from the top of the tumor cells, and then manipulating the T cells and infusing them back; those T cells will kill the lymphoma cells. That's what ZUMA-2 does. Cell therapy is a big category; there are so many targets. CD19 is the first target that has been validated by FDA approval.We are looking at about 80 patients. They must have relapsed MCL and they have to have progressed on either ibrutinib or acalabrutinib. We are discussing whether we would present some data at the 2018 ASH Annual Meeting, but it is not finalized.In B-cell lymphoma, we almost always move the best therapy to the frontline setting. For example, I led the international trial that paved the way for FDA approval for ibrutinib in November 2013. Then, I led another clinical trial that led to the approval for acalabrutinib in relapsed MCL in October 2017. For both of those therapies, we quickly moved from the relapsed setting to the frontline setting.

Where are we at with some of the toxicity concerns with CAR T-cell therapy?

Could CAR T-cell therapy make stem cell transplant obsolete in MCL?

Where do you see treatment for MCL going in the future?

There is a 550-patient trial that's already fully enrolled with bendamustine/rituximab (Rituxan) plus or minus ibrutinib (NCT01776840). This is an effort to move a regimen approved in the relapsed setting into the frontline setting. On the same line, acalabrutinib was approved in the relapsed setting and is now being studied in an international trial called ECHO (NCT02972840). I'm sure that if the CAR T-cell therapy is approved in the relapsed setting, it will be moved to the frontline setting with caution and with hope.Cytokine release syndrome, and the newer toxicities like CAR-T-cell-related encephalopathy syndrome…can affect the heart, leading to arrhythmias. It can affect the liver, leading to hepatitis. It can affect the colon, which leads to colitis. Therefore, we're still battling with toxicities. [However], we have become very successful with managing toxicities.That's a good question. CAR T-cell therapy [will] challenge old paradigms, but I don't think we will ever get to the point where we don't need autologous stem cell transplant. We shall always need autologous and allogenic stem cell transplant as a modality, but we'll just have more tools in our bag.Overall, MCL is enjoying a very rapid progression in its therapeutics, which has resulted in much improved patient outcomes. We are making progress in targeted therapies, immunotherapies, and cell therapies. It used to be that patients only survived 3 to 5 years, and now it's 7 to 10 years. With time, we could even cure [MCL] within my lifetime or my career. I hope we can contribute to the cure of a big fraction of patients.

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.