Paper Details

ABSTRACT

Background: Vispacabtagene regedleucel (vispa-cel, formerly CB-010) is an allogeneic anti-CD19 CAR-T cell therapy manufactured from healthy donor T cells. The Cas9 chRDNA genome-editing technology is used for three genome edits: (1) knockout (KO) of the TRAC gene to reduce the risk of graft-versus-host disease (GvHD), (2) insertion of a CD19-specific CAR (FMC63 scFv, 4-1BB), and (3) KO of PD-1 to prevent premature CAR-T cell exhaustion and potentially enhance antitumor activity. We have previously reported that vispa-cel manufactured from young donors (< 30 years of age) with HLA matching of two or more alleles (between product and patient) leads to durable outcomes and this will be the vispa-cel dosing strategy moving forward. Here we report the long-term clinical outcomes for patients (pts) who are progression free at ≥12 months after a single infusion of vispa-cel with no subsequent therapy.

Aims: ANTLER is a Phase 1 trial (NCT04637763) with 3+3 dose escalation and dose expansion to evaluate the safety and efficacy of vispa-cel in pts with r/r B-NHL.

Methods: All pts received lymphodepletion of cyclophosphamide (60 mg/kg/day x 2 days) and fludarabine (25 mg/m²/day x 5 days) followed by a single infusion of vispa-cel. Three vispa-cel dose levels (40 million [M], 80M, and 120M cells) were evaluated in dose escalation and dose expansion, and 80M cells was selected as the RP2D.

Results: As of March 06, 2026, 85 pts have been treated with vispa-cel, and 80% (68/85) responded (47 CRs, 21 PRs). Among the responders, 22 pts had at least 12 months of follow-up and were progression free at 12 months (median follow-up of 21.4 mo; range: 11.6-48.8 mo). The NHL subtypes for these 22 pts were DLBCL (N=15), tFL (N=4), HGBL (N=1), MCL (N=1), and FL (N=1). The median age was 66 (range 20-86), 68% (15/22) were ≥ 65 years old, 91% (20/22) had an HLA match of 2 or more alleles, 77% (17/22) received vispa-cel product from a young donor (< 30 years), and 68% (15/22) received optimized vispa-cel (young donor and HLA matched at 2 or more alleles). The median number of prior lines of therapy was 1 (range 1-8). The majority of pts (82%; 18/22) were treated with vispa-cel in the 2L setting, and most (86%; 19/22) were refractory to frontline therapy. The median time from eligibility confirmation to start of lymphodepletion was 3 days (range 0-7), and 73% (16/22) of pts were treated with the RP2D of vispa-cel (80M cells). Complete responses were observed in 95% (21/22), and a partial response was ongoing in one pt at 24 months who was ctDNA-negative from day 28 onward. The longest ongoing progression-free durations were 48 months (N=2), 36 months (N=2), and 24 months (N=5), including the first patient ever treated with vispa-cel who is approaching 5 years progression-free after 8 prior lines of therapy.  Vispa-cel was generally well tolerated in these long-term responders, with no GvHD, ICANS, or IEC-HS observed. The most common adverse events were cytopenias with a 14-day median time to cytopenia recovery to ≤ grade 2 (anemia recovery range 2-27 days, neutropenia recovery range 6-49 days, and thrombocytopenia recovery range 4-27 days). No grade 3+ CRS occurred (46% had grade 1 or 2 CRS), grade 3+ infections occurred in 36% (8/22) of pts and had a median duration of 9.5 days. One grade 5 event of progressive multifocal leukoencephalopathy (PML) occurred on day 520. IVIG was administered in 27% (6/22) of pts, tocilizumab was administered in 27% (6/22) of pts, and corticosteroids for systemic use were administered in 36% (8/22) of pts. Vispa-cel expansion peaked at ~7-10 days and CAR-T cells were undetectable by 28 days in all 22 patients. Updated safety, efficacy, and translational data will be presented.

Summary/Conclusion: Vispa-cel is an off-the-shelf CAR-T cell therapy that has demonstrated multi-year complete remissions after a single-dose. The generally well-tolerated safety profile supports outpatient administration and use in the community setting. Due to the favorable benefit-risk profile and long-term durability established with vispa-cel in the ANTLER trial, vispa-cel is moving forward into a pivotal trial as a potential treatment for 2L LBCL patients.