Paper Details

ABSTRACT

Introduction:

Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma characterized by bright CD20 and t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression. For relapsed/refractory (r/r) MCL, targeted therapies, including CD19-directed chimeric antigen receptor (CAR T)-cell therapy have improved clinical outcomes. However, patients (pts) with high-risk disease, including TP53 mutations, complex karyotype, blastoid or pleomorphic morphology, or early relapse (≤24 months; POD24) after frontline treatment continue to have inferior response rates and shorter progression-free survival (PFS) and overall survival (OS). Relapse due to CD19 antigen loss and manufacturing delays remain ongoing limitations of currently approved CAR products. Zamtocabtagene autoleucel (zamto-cel; MB-CART2019.1) is a tandem CD20/CD19-targeted, fresh CAR T-cell therapy with a 14-day vein-to-vein time. Zamto-cel is being evaluated in DALY II USA (NCT04792489), a multicenter, open-label, single-arm, Phase 2 study with a dedicated r/r MCL cohort. Here, we report results from the prespecified interim analysis.

Methods:

Adult pts with r/r MCL after ≥1 prior systemic therapy, including rituximab-containing chemotherapy and a Bruton tyrosine kinase inhibitor (BTKi), were eligible. Enrolled pts received 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 infusion as a fresh product. Lymphodepletion was initiated during manufacturing to facilitate fresh infusion. The primary objective was objective response rate (ORR); secondary objectives included complete response rate (CRR), duration of response (DOR), PFS, and OS. Responses were assessed by study investigators per Lugano 2014 criteria. Safety included adverse events, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) graded per ASTCT criteria, and treatment-related mortality. This interim analysis was performed after 20 evaluable pts completed ≥3 months of follow-up after zamto-cel infusion.

Results:

Fresh zamto-cel manufacturing was successful in 100% of production runs. Among the 20 evaluable pts, the median age 70.5 years (range, 47-79), and 5 pts (25%) were female. Pts were heavily pretreated with a median of 3 prior lines of treatment. The cohort included multiple adverse prognostic features, including TP53 mutation (6/16 tested; 37.5%), complex karyotype (1/8 tested; 12.5%), blastoid/pleomorphic morphology (3/20; 15%), and early relapse after frontline treatment (POD24) (12/20; 60%).  Bridging therapy was administered to 8/20 pts (40%) prior to lymphodepletion: 6/20 pts (30%) received a BTKi and 2/20 pts (10%) received corticosteroids.

ORR by investigator assessment was 100% (20/20; 95% CI, 83-100), including a CRR of 75% (15/20; 95% CI, 51- 91) and a partial response (PR) rate of 25% (5/20; 95% CI, 9-49). At data cutoff, 15 pts remained in response, including 2 of the 5 pts with PR who have maintained an ongoing response for >12 months. With a median follow-up of 7.5 months, the median DOR was not reached.

Fifteen/20 pts (75%) experienced at least 1 treatment-emergent serious adverse event (TESAE) and 8 pts (40%) had a TESAE assessed as related to zamto-cel. Grade 1-2 CRS occurred in 16 pts (80%) and Grade 1-2 ICANS in 5 pts (25%); no Grade ≥3 CRS or ICANS were observed. Grade ≥3 infections were reported in 3 pts (15%). One pt (5%) experienced Grade 3 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. No treatment-related deaths were observed among the 20 evaluable pts.

Conclusions:

This study represents the first multi-center trial of dual targeted anti-CD20/anti-CD19 CAR T cells in r/r MCL. In this prespecified interim analysis, zamto-cel demonstrated robust early clinical activity, including a 100% ORR, and a favorable early safety profile in r/r MCL. Successful fresh manufacturing with a 14-day vein-to-vein time and the addition of CD20 targeting support the continued development of zamto-cel for pts with r/r MCL.