Wang Explores Feasibility of CAR T Cells, Personalized Medicine in MCL

Michael Wang, MD

Patients with high-risk mantle cell lymphoma (MCL) are likely to relapse during their treatment course despite the use of BTK inhibitors, chemotherapy, transplant, and radiation, explained Michael Wang, MD. This has prompted investigations into promising alternatives, such as CAR T-cell therapy.

For example, in the phase I TRANSCEND NHL 001 trial, lisocabtagene maraleucel (liso-cel; JCAR017) induced an overall response rate of 71% among a cohort of patients with relapsed/refractory MCL. Notably, the anti-CD19, 4-1BB—containing CAR T-cell product resulted in a low incidence of grade 3/4 cytokine release syndrome and neurotoxicity. As such, the cohort was expanded from 25 patients to 38.

“We live in a very accelerated part of history,” said Wang. “In the past, it would take maybe 10 to 20 years to [make progress]. Now, new advances are made every 6 months or so.”

In addition to liso-cel, the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) is being evaluated in patients with relapsed/refractory MCL in the ongoing phase II ZUMA-2 trial. Although CD19 is the first target that has been validated by the FDA, there are several other targets and dual blockade strategies under investigation that may yield better responses, said Wang.

In an interview with OncLive, Wang, a professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, provided insight on recent advances in MCL as well as research efforts for patients with a high risk of relapse.

OncLive: Could you discuss recent progress made in the field of MCL?

Wang: Where do I start? MCL research is one of the most rapidly progressing fields in hematology, and even oncology. There is fast progress in several areas. The number one area we’ve seen progress in is targeted therapy with agents such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and others. Also, the combinations with these exciting agents are proving to be even more efficacious and safe. We have learned that we cannot put high-risk patients in remission for a prolonged period of time with targeted therapies and chemotherapies. High-risk patients with MCL always relapse. Therefore, cellular therapy is the major advance in the field of MCL.

Could you expand on the challenge of relapse among high-risk patients?

Relapse occurs—especially when patients have high-risk features including high Ki-67, blastoid or pleomorphic karyotype, p53 mutation, or complex chromosomal karyotype. These patients cannot be cured with what we have available with chemotherapy, transplant, radiation, or targeted therapies. Therefore, we have to confront that with cell therapies. CAR T-cell therapy is being explored in many ongoing clinical trials. There are 2 multicenter trials that are focused on CAR T-cell therapy in MCL. There is a trial with liso-cel, which I presented data from at the 2019 ASCO Annual Meeting. The other trial is the ZUMA-2 trial with axi-cel; this is also a multicenter registration study, which will very likely be presented at the 2019 ASH Annual Meeting.

Could you provide background on the TRANSCEND NHL 001 trial and discuss the initial dose findings?

We face patients with relapsed disease in our clinic every day. Therefore, we started to use these cell therapies in the first [dose-escalation] part of the trial. CD19 has been proven to be efficacious with a very good safety profile. Therefore, we have expanded the cohort to 38 patients.

What are some unanswered questions with this approach?

We know that the CD19-targeted CAR T-cell therapy could put a fraction of patients into a long-term remission; however, the majority would still relapse. We need to find ways to overcome CAR T-cell resistance, which could be due to the loss of an antigen, as we learned from other B-cell lymphoma studies. It could also be because CD19 is not lost, but that the parallel pathways are overly activated. If CD19 is lost, we need to find new targets. We could attack 2 targets at the same time. For example, we could attack CD19 and CD22, and in doing so, overcome some of the resistance by loss of 1 target. There are so many new targets we can test.

Right now, we are not totally dependent on CAR T cells. We are quickly approaching the precision medicine era. We could use DNA/RNA epigenetic mutations and wield the discrete mechanism of resistance in each patient and then use what we can to target this pathway and overcome resistance in a personalized fashion. This is what is coming after the cell therapy era.

Are there any ongoing trials looking at evaluating this further?

I'm happy to report that I'm the primary investigator for the B-cell lymphoma Moon Shot program at The University of Texas MD Anderson Cancer Center. We have 3 flagships; the first is testing next-generation precision medicine, the second is testing cell therapies, and the third is looking at a cell adoptive era where we're looking for new targets, such as CD79. We’re also looking at cyclin D/E1. Regarding the next-generation precision medicine trial, we have designed 2 personalized trials: one is the EXPLORE [A Pilot Evaluating Xenografts to Personalize Therapies in Relapsed Mantle Cell Lymphoma to Optimize Response] trial, which uses an in vitro screening from in vivo [patient-derived xenografts] to identify the best combination treatments.

The other trial is called the B-cell lymphoma MATCH trial. In this trial, we're going to use in vitro screening coupled with NanoString RNA information, so that we can identify the pathways that are overly activated in a particular patient. Then, we can target these pathways with personalized therapies. We are in the first [stages] in each category; we're very excited.

Wang M, Gordon LI, Palomba ML, et al. Safety and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving lisocabtagene maraleucel (Liso-cel) in TRANSCEND NHL 001. J Clin Oncol. 2019;37(suppl 15; abstr 7516). doi: 10.1200/JCO.2019.37.15_suppl.7516.