Paper Details

ABSTRACT

Introduction

Primary central nervous system lymphoma (PCNSL) is an aggressive B-cell lymphoma associated with poor clinical outcomes and a high unmet medical need. Although CD19-directed chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory (r/r) B-cell lymphomas, patients (pts) with PCNSL have been historically excluded from prospective registration trials because of concerns regarding neurotoxicity, resulting in limited clinical data with CAR-T therapy in this population. Zamtocabtagene autoleucel (zamto-cel; MB-CART2019.1) is a tandem CD20/CD19- directed fresh CAR T-cell therapy being developed for the treatment of B-cell lymphoma. A dedicated cohort of pts with r/r PCNSL was evaluated as part of the DALY II USA clinical trial (NCT04792489), an ongoing prospective Phase 2 study of zamto-cel. Here, we report efficacy and safety outcomes for pts from this cohort.

Methods

Adult pts with r/r PCNSL after ≥1 prior line of therapy were eligible. Enrolled pts received a single dose of zamto-cel at 2.5×106 CAR T cells/kg manufactured using the CliniMACS Prodigy® (Miltenyi Biotec) closed, automated platform with a 14-day vein-to-vein time and infused as a fresh product. Lymphodepletion was initiated during manufacturing to facilitate fresh infusion. The primary endpoint was objective response rate (ORR), defined as a best overall response of complete response (CR) or partial response (PR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Responses were assessed by an independent review committee (IRC) according to the International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) response criteria.

Results

As of the 15 January 2026 data cutoff, 21 pts with r/r PCNSL have been enrolled, with 17 pts who received the target fresh dose of zamto-cel and had at least 6 months of follow-up after CAR T-cell infusion; these pts had a median follow-up of 15.2 months. The median within this population age was 64.0 years (range, 33-80), and 7 pts (41%) were female. The cohort represented a high-risk population, with 14 pts (82%) refractory to their last line of therapy. Excluding prior autologous stem cell transplant (ASCT), pts received a median of 2 prior lines of therapy: 1 line in 6 pts (35%), 2 lines in 5 pts (29%), and 3 lines in 6 pts (35%). All pts had previously received methotrexate, either as monotherapy or in combination, and 7 pts (41.2%) had undergone prior ASCT. Manufacturing of a fresh zamto-cel product was successful in 100% of production runs; 2 pts received cryopreserved product to accommodate comorbidity management.

The ORR by IRC was 70.6% (12/17; 95% CI, 44-90), including a CR rate of 41% (7/17; 95% CI, 18-67). A best response of PR was achieved in 5 pts (29%), while 3 pts (18%) had progressive disease. The median DOR was 8.4 months (95% CI, 2.8-not estimable); median PFS was 5.8 months (95% CI, 2.9-12.4), and median OS was 14.3 months, with an estimated 12-month OS rate of 71%.

Treatment with zamto-cel was well tolerated in the PCNSL cohort. Overall, 12/17 pts (71%) experienced a serious adverse event (SAE), including 8 pts (47%) with treatment-related SAEs. There were no treatment-related deaths or T-cell malignancies. No Grade ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. Grade 1-2 CRS occurred in 11 pts (65%), and Grade 1-2 ICANS occurred in 4 pts (24%). Grade ≥3 infections occurred in 1 pt (6%). Hemophagocytic lymphohistiocytosis/immune effector cell-associated hemophagocytic syndrome was not observed.

Conclusions

In this prospective Phase 2 study, zamto-cel demonstrated encouraging clinical activity and a favorable safety profile in pts with r/r PCNSL, a population historically underrepresented in CAR T-cell studies because of concerns regarding neurotoxicity. Within this high-risk population, treatment resulted in durable responses and encouraging survival outcomes, with no Grade ≥3 CRS or ICANS observed. Together with successful fresh manufacturing and a14-day vein-to-vein time, these findings demonstrate the potential of tandem CD20/CD19-directed CAR T-cell therapy for pts with r/r PCNSL, a population with high unmet need.