A novel bispecific CAR T-cell therapy targeting both CD19 and CD20 B-cell antigens has demonstrated remarkable efficacy in patients with mantle cell lymphoma (MCL), according to data presented at the 2023 Transplantation and Cellular Therapy Meetings.
The lentiviral bispecific CAR T-cell therapy, known as LV20.19 CAR or zamtocabtagene autoleucel, achieved a 100% overall response rate (ORR) in patients with relapsed/refractory MCL, with complete response (CR) rates increasing from 71% at day 28 to 92% at day 90.
"Just thinking about disease biology, dual-targeting CD20 and CD19 may be beneficial in patients with relapsed/refractory MCL," said Dr. Nirav N. Shah, associate professor at the Medical College of Wisconsin in Milwaukee, who led the research. "The data here are very encouraging, but obviously need to be validated in a multicenter setting."
Study Design and Patient Population
The single-center, prospective, phase 1/2 study (NCT04186520) evaluated the safety and efficacy of LV20.19 CAR in adult patients with B-cell malignancies who had progressed on prior therapies. The trial used a 14-patient, single-stage design, with calculations based on the 3-month CR rate in the pivotal trial of ibrutinib for relapsed/refractory MCL.
The researchers targeted a 50% 3-month CR rate and considered the study positive if six or more patients achieved a CR by day 90. The trial established the target dose of LV20.19 CAR at 2.5 × 10^6 cells/kg based on a previous phase 1 dose-escalation and expansion study.
Impressive Efficacy Results
The efficacy data from the trial were striking. At day 28, all 14 patients (100%) showed a response to treatment, with 71% achieving a complete response and 29% showing a partial response. By day 90, while the ORR remained at 100%, the CR rate increased to 92% as some patients converted from partial to complete responses.
"In the phase 2 cohort, we now have 8 patients with a CR at day 90. We do consider this to be a positive clinical trial," Dr. Shah explained. "We also have reasonable follow-up on these patients. At a median follow-up of 22 months, there's been only one relapse among 14 patients."
The median overall survival (OS) and progression-free survival (PFS) were not reached after 22 months of follow-up, suggesting durable responses to the therapy.
Favorable Safety Profile
The safety profile of LV20.19 CAR also appears promising compared to existing CAR T-cell therapies. While cytokine release syndrome (CRS) occurred in 93% of patients, no instances of grade 3/4 CRS were observed. Only 21% of patients experienced neurotoxicity, with two patients developing grade 3/4 immune effector cell-associated neurotoxicity syndrome (ICANS) and one patient experiencing grade 1/2 ICANS.
"No patients required intensive care unit-level care in the first 28 days," Dr. Shah noted, highlighting the manageable toxicity profile.
The study did report one non-relapse mortality in a high-risk patient who had relapsed after prior allogeneic transplant for MCL. This patient passed away from gram-negative sepsis at day 46, which was outside the dose-limiting toxicity period. All other patients remain alive.
Rationale for Dual-Targeting Approach
The researchers specifically chose to evaluate LV20.19 CAR in MCL due to the unique characteristics of this non-Hodgkin lymphoma subtype, which is known to have high levels of CD20 expression.
"In a disease with high levels of CD20, drugs like rituximab have been shown to elicit survival benefit by targeting CD20," Dr. Shah explained. "We thought that this CAR T-cell construct would be optimally primed for MCL because it targets both CD19, which we know is effective in MCL based on prior CAR T-cell approvals, and CD20."
This dual-targeting approach may help overcome some of the limitations of single-target CAR T-cell therapies, potentially reducing the risk of antigen escape and improving long-term outcomes.
Future Directions
Based on these encouraging results, the research team has already launched a phase 2 trial of LV20.19 CAR in diffuse large B-cell lymphoma. Dr. Shah is also working with partners to develop a multicenter trial with the CD20/CD19 CAR T-cell product in MCL.
"We're really excited by these outcomes. The safety profile and efficacy profile of this CAR T-cell product are favorable compared with what's currently available," Dr. Shah said. The planned multicenter trial aims to confirm these single-center results in a broader patient population.
The researchers are also exploring the potential of this dual-targeting approach in other B-cell malignancies, with ongoing efforts to demonstrate feasibility, efficacy, and safety across different patient populations and clinical settings.
Implications for MCL Treatment
Mantle cell lymphoma represents approximately 6% of all non-Hodgkin lymphomas and is characterized by its aggressive clinical course and frequent relapses. While several treatment options exist, including BTK inhibitors and single-target CAR T-cell therapies, patients with relapsed/refractory disease continue to face poor outcomes.
The impressive response rates and durability observed with LV20.19 CAR suggest that this bispecific approach could potentially transform the treatment landscape for MCL. By simultaneously targeting two B-cell antigens, this therapy may address some of the resistance mechanisms that limit the efficacy of current treatments.
As Dr. Shah and colleagues move forward with multicenter trials, the medical community will be watching closely to see if these promising results can be replicated in larger, more diverse patient populations. If successful, bispecific CD20/CD19-targeted CAR T-cell therapy could become an important new option for patients with this challenging malignancy.
