CAR T-Cell Agents Offer Efficacy in Lymphoma, But Additional Approaches Are Needed to Overcome Resistance

Patients with lymphoma have gained several treatment options with the wave of CAR T-cell therapy approvals by the FDA in recent years. However, additional work is required to find better methods to overcome mechanisms of resistance to these agents, according to Sattva S. Neelapu, MD.

Most recently, on May 15, the FDA granted accelerated approval to the CAR T-cell agent lisocabtagene maraleucel (liso-cel; Breyanzi) for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received 2 or more prior lines of systemic therapy. The regulatory decision was supported by findings from the phase 2 TRANSCEND-FL study (NCT04245839). Findings from the study demonstrated that patients who received liso-cel (n = 94) experienced an overall response rate of 95.7% (95% CI, 89.5%-98.8%). Additionally, the median duration of response was not reached (NR; 95% CI, 18.04-NR) at a median follow-up of 16.8 months (95% CI, 16.3-17.0).

“TRANSCEND FL showed very high efficacy in [the] third-line [setting],” Neelapu said. “[These findings] led to the approval of liso-cel in [the] third line.”

In an interview with OncLive^®, Neelapu, the deputy department chair and a professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, provided an overview of the currently available CAR T-cell therapies in FL, mantle cell lymphoma (MCL), and large B-cell lymphoma (LBCL), as well as the mechanisms of resistance patients can develop to these treatments and how they could potentially be addressed.

OncLive: What are some of the key clinical trial data that support the use of CAR T-cell therapy in standard practice for patients with lymphoma?

Neelapu: There are 4 different CD19-[directed] CAR T products that are currently approved [by the FDA]. With respect to LBCL, initially the approvals were in the third-line setting and that was based on 3 single-arm, [early] phase studies: ZUMA-1 [NCT02348216], JULIET [NCT02445248], and TRANSCEND-NHL-001 [NCT02631044]. Those [studies] showed very high efficacy, with [approximately] 40% of patients achieving durable remissions.

Then, CAR T-cell therapy was evaluated in the second-line setting in randomized phase 3 trials. At least 2 of the trials were positive and led to FDA approvals in the second-line setting, including ZUMA-7 [NCT03391466] testing axicabtagene ciloleucel [axi-cel; Yescarta] and the TRANSFORM study [NCT03575351] testing liso-cel. Both studies showed that CAR T-cell therapy improved event-free survival as well as overall survival in the case of the ZUMA-7 study compared with the existing standard of care, which is salvage chemotherapy followed by stem cell transplantation. This created a paradigm shift in how we treat patients with LBCL in the second-line setting; CD19-[directed] CAR T-cell therapy is the new standard of care.

There is also another trial, the [phase 2] TRANSCEND-PILOT-017006 study [NCT03483103] that evaluated liso-cel in transplant-ineligible patients in the second-line setting. This was a single-arm study that also showed very high efficacy and tolerability, with approximately 40% of patients achieving durable remission. Now both transplant-eligible as well as transplant-ineligible patients with LBCL have CD19-directed CAR T-cell therapy as the new standard of care in second-line setting.

In the FL space, there are 2 trials that have shown high efficacy in the third-line setting; these are single-arm, phase 2 studies. There’s ZUMA-5 [NCT03105336] which is testing axi-cel and the ELARA trial [NCT03568461] which is testing tisagenlecleucel [tisa-cel; Kymriah]. Both studies showed a complete response rate in the 70% to 80% range and showed very high durability. For example, in the ZUMA-5 study, at 4 years of follow-up, more than 50% of patients were still progression free. Both of these trials led to the FDA approvals of axi-cel and tisa-cel in the third-line setting of follicular lymphoma.

In the MCL space, the initial trial that led to an approval was the ZUMA-2 study [NCT02601313] evaluating brexucabtagene autoleucel [brexu-cel; Tecartus]. That was a single-arm study of patients who have had both alkylating therapy, anti-CD20 agents, and BTK inhibitor therapy. That trial showed an approximate 70% complete response rate with ongoing remissions in approximately 35% to 40% of patients at 3 years. There’s also the [MCL cohort of the] TRANSCEND study, which evaluated liso-cel in MCL. That also showed very high efficacy but is not yet FDA approved, although it is also expected to lead to an FDA approval later this month in MCL.

What are some of the mechanisms that lead to patients developing resistance to CAR T-cell therapies and how can they potentially be addressed?

One of the main reasons that patients relapse after CD19-[directed] CAR T-cell therapy is [due to] loss of CD19 in the tumor at progression. That can be addressed by developing CAR T-cell therapy against other targets in B-cell lymphoma, including CD22, CD79, and others. [There was a phase 1/1b clinical trial examining] CD22-directed CAR T that was done at Stanford University [NCT04088890] that is now in phase 2 clinical trials. There are also other trials that are currently in early stages of development.

The second major reason that patients relapse after CAR T-cell therapy is because of T-cell dysfunction. The T cells in these patients are dysfunctional at the time of apheresis, and that yields a poor-quality CAR T product. The T cells become dysfunctional either because of the disease itself, or more commonly because of various therapies that the patients have received.

One way to address that is to move CAR T-cell therapy to earlier lines [of treatment]. Another way to address that is to alter the manufacturing process. Traditionally, CAR T-cell production used to take 7 to 10 days, at least for the currently approved commercial products. But recent data indicate that if we reduce the manufacturing time to 2 to 3 days, it yields a much better-quality CAR T product that has better function in patients and better efficacy without an increase in toxicity. A third way to overcome the T-cell dysfunction issue is to develop allogeneic CAR T-cell therapies. There are a number of different allogeneic CAR T-cell therapy approaches that are currently being evaluated in phase 1 and 2 trials.

Reference

FDA grants accelerated approval to lisocabtagene maraleucel for follicular lymphoma. FDA. May 15, 2024. Accessed May 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-follicular-lymphoma