(OA-12) First-in-Human Phase 1 Trial of Trimeric APRIL (TriPRIL) CAR-T Cells in Relapsed or Refractory Multiple Myeloma

Antigen escape is a common resistance mechanism from BCMA-directed CAR-T cells, limiting durable responses as well as the utility of further BCMA-directed therapies. TriPRIL CAR-T cells were designed to target both BCMA and TACI with a trimeric ligand-based CAR using their natural ligand APRIL, offering a novel dual antigen-approach. We report initial results from an ongoing first-in-human phase 1 clinical trial of TriPRIL CAR-T cells for patients with relapsed or refractory multiple myeloma (R/R MM).

Methods:

Eligible patients (pts) with R/R MM had received at least 3 prior lines of therapy or had triple class-refractory disease. The phase 1 trial consists of a 3+3 dose escalation and a subsequent dose expansion cohort. Two dose levels (DLs) have been studied with 1.0 x 10⁸ CAR+ T-cells at DL1 and 3.0 x 10⁸ CAR+ T-cells at DL2 with dose expansion continuing at DL2. Lymphodepletion consisted of cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² on Days -5 to -3. The primary endpoint was incidence of dose-limiting toxicities (DLTs) and adverse events. Secondary endpoints included response, PFS, and OS.

Results:

As of May 1, 2025, 11 pts have undergone leukapheresis and 10 pts have received TriPRIL CAR-T cells. Among the infused pts, 5 pts were treated at DL1 and 5 pts were treated at DL2. The median age was 73 years old (range: 62-78) and 8 pts (80%) were female. Six pts (60%) had high-risk cytogenetics, 4 pts (40%) had R-ISS stage III disease, and 3 pts (30%) had extramedullary disease. The pts had a median of 6 prior lines of therapy (range: 3-10) with 6 pts (60%) having previously received a BCMA-directed CAR-T cell therapy. 

There were no DLTs at either dose level. All pts (100%) had CRS (G1 in 8 pts, G2 in 2 pts) with a median onset of 1 day after infusion (range: 0-11). One pt had G2 ICANS at 10 days after infusion which resolved after one day. Infections occurred in 5 pts (50%; G2 in 4 pts and G3 in 1 pt). There were no instances of non-ICANS neurotoxicities including parkinsonism or cranial nerve palsies.

The ORR was 80% with a CR/sCR rate of 60%. The ORR and CR/sCR rates were consistent across DL1 and DL2. The median follow-up time among patients who remain alive is 5.5 months (range: 0.9-11.3). Among the entire cohort, the median PFS was 10.4 months (95% CI, 0.9-NE) and the median OS has not been reached (95% CI, 4.2-NE). Among the patients who had received a prior BCMA-directed CAR-T cell therapy, the ORR was 66.7% (CR/sCR 66.7%) and the median PFS was 10.4 months (95% CI, 0.9-NE).

Conclusions:

TriPRIL CAR-T cells demonstrated overall safety in patients with R/R MM with no DLT occurrences. Moreover, TriPRIL CAR-T cells showed high response rates with durable responses notably seen even in patients who had progressed after prior BCMA-directed CAR-T cell therapy. This study highlights the potential of this novel dual-antigen CAR-T cell therapy in both CAR-naïve and CAR-exposed R/R MM patients.  

*BRP and CEG contributed equally. MVM and MJF contributed equally.