Phase I Study of a CD19-Directed CAR-T Cell Therapy for Relapsed/Refractory Mantle Cell Lymphomas(MCL)

Background:

IM19 is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product, which is manufactured in China using a commercial process. We aimed to evaluate the efficacy and safety of IM19 in patients with relapsed or refractory mantle cell lymphomas in a Phase I clinical study.

Methods:

A phase 1 clinical trial has been launched to evaluate the safety and efficacy of IM19 for the treatment of relapsed/refractory MCL. We enrolled adult patients (aged ≥18 years) with relapsed or refractory MCL who had received at least 2 prior treatment regimens (including BTK inhibitor). Patients were assigned to one of two target dose levels of IM19 as they were sequentially tested in the trial (100×10⁶ CAR+ T cells [one or two doses], 200×10⁶ CAR+ T cells [one or two doses]). Leukapheresed patients could receive bridging chemotherapy based on investigator assessment of disease burden and tumor progression risk. Lymphodepleting (LD) chemotherapy was administered over 3 days, including fludarabine (30 mg/m² i.v. daily) and cyclophosphamide (300 mg/m² i.v. daily), followed 2 days later by intravenous infusion of IM19 at the assigned dose. The first three subjects in each dose group will receive the second LD chemotherapy and infusion of IM19 CAR-T cells for consolidation treatment (with the same dosage as the first treatment) if the efficacy evaluation after the first infusion shows no progression and no DLT occurs. The investigators can determine the start time of consolidation treatment based on the patient's tolerance, but no later than 60 days after the first infusion. Efficacy was assessed at 1, 3, 6, 9, 12, 18, and 24 months post first infusion. Safety events were monitored from beginning of LD through 2 years follow-up. The primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate.

Results:

Between Mar 3, 2022, and May 7, 2024, 11 patients underwent leukapheresis for manufacture of CAR+ T cells (IM19) and ten patients received bridging chemotherapy during the production of IM19. ALL eleven patients received LD and first infusion of IM19 at a dose of 100*10^6 or 200*10^6 CAR+ cells and no DLTs were observed. Five patients (5/11)experienced cytokine release syndrome (CRS), with only one of five patients in the first-dose group experiencing grade 1 CRS, and four of six patients in the second-dose group experiencing CRS, including one with grade 2 and 3 with grade 1. Five patients in the first dose group did not experience ICANS, and one patient in the second-dose group developed grade 2 ICANS. Ten patients (10/11) achieved complete remission by D28 and the best CRR is 91% . The mean maximum CAR-T cells expansion (Cmax) was 156×10⁶ in 100*10^6 CAR+ dose group and 301×10⁶ CAR+ cells/L n 100*10^6 CAR+ dose group, and median area under the curve from 0-28 days post-first infusion (AUC0-28d) was 860 and 1344 day×CAR+ cells/L in each groups.

In the first dose group , 2 patients received the second LD chemotherapy and infusion of IM19 CAR-T cells for consolidation treatment (with the same dosage as the first treatment) at 44th days post first infusion. No DLTs，CRS or ICANS were observed after second infusion. Meanwhile, CAR-T cells expansion was not detected by Flow cytometry after second infusion. In 2 patients who received consolidation treatment, One patient maintained complete remission after 24 months of follow-up and another patient experience PD at 7th month after first infusion. For three patients who received single infusion of IM19, one maintained complete remission after 12 months of follow-up，one progressed at 3th month after infusion and one progressed at 12th month after infusion.

In the second-dose group, all six patients received single infusion. one patient died of pulmonary embolism due to tumor progression, while the remaining five patients are currently under follow-up and have not shown disease progression.

Conclusions:

Initial data from this Phase I study demonstrate that use of IM19 resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory MCL. We observed that CAR-T cells cannot expand in vivo after secondary infusion. Therefore, secondary infusion may not be necessary.

No relevant conflicts of interest to declare.