IL-6 Knockdown Anti-CD19 CAR-T Cells (ssCART-19) for Patients with Relapsed or Refractory Acute Lymphoblastic Leukaemia: Phase 1 Trial

Abstract

Background: Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has shown great efficacy in relapsed or refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL). However, CAR-T related cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are widespread and severe. We aim to evaluate the safety profile and efficacy of CAR-T targeting CD19 with short hairpin RNA (shRNA) IL-6 gene silencing technology (ssCART-19) in patients with r/r B-ALL.

Methods: This single-centre, single-arm, phase 1 trial was conducted at the First Affiliated Hospital of Soochow University (Suzhou, China). The trial enrolled patients aged 18–65 years with CD19-positive r/r B-ALL and an Eastern Cooperative Oncology Group performance status of 0–1. Patients were consecutively assigned to receive infusion of ssCART-19 at 1×106 CAR-T cells per kg (low-dose group), 5×106 CAR-T cells per kg (low-dose group), or 10×106 CAR-T cells per kg (high-dose group) in the dose-escalation phase. Subsequently, patients received infusion of ssCART-19 at 1×106 CAR-T cells per kg as the expansion dose. The primary endpoints were safety, which was based on the rate of dose-limiting toxicity in patients who received ssCART-19 infusion. Secondary endpoints were the efficacy and survival. This trial is registered with ClinicalTrials.gov (NCT04825496) and has been completed.

Findings: Between 9 April, 2021 and 31 October, 2023, 31 patients were screened. Ten patients failed screen (four met with the exclusion criteria and six did not meet with the inclusion criteria). Four patients were excluded after apheresis (two with active lung infection, one with complicated intracerebral hemorrhage and one with progressive disease). A total of 17 patients received infusion of ssCART-19 ultimately. Ten patients were assigned to the dose escalation phase (three at 1×106 CAR-T cells per kg, six at 5×106 CAR-T cells per kg, and one at 10×106 CAR-T cells per kg). Seven patients received infusion of 1×106 CAR-T cells per kg at the dose-expansion phase. The median age was 39 years (IQR, 20–51). Nine (53%) patients were male, and eight (47%) were female. All patients were Chinese. The most common grade 3 or worse adverse events were haematological, including lymphocytopenia (16 [94%] of 17 patients), neutropenia (15 [88%]), leukopenia (15 [88%]), anaemia (12 [71%]), and thrombocytopenia (10 [59%]). CRS occurred in 76% of patients, with 10% of patients in low-dose group, 33% of patients in medium-dose group, and no patient in the high-dose group experienced grade 3 CRS. No grade of ICANS was observed, including one patient had CNS leukaemia. The objective response rate (ORR) at 3 months post-infusion was 73%. In particular, all responders achieved minimal residual disease negativity. Of the ten patients who received 1×106 CAR-T cells per kg, the ORR was 88% (7/8). Two patients died due to septic shock at 12 and 42 days post-infusion, respectively, which deemed unrelated to ssCART-19 treatment. At a median follow-up of 20·1 months (IQR, 4·0–36·4) post-infusion, the median duration of response for all treated patients was 25·8 months (95% CI, 4·8–46·9). The median progression-free survival and overall survival for all treated patients (n=17) was 22·2 months (95% CI, 0·0–47·0) and not reached, respectively.

Interpretation: ssCART-19 shows potent efficacy in patients with r/r B-ALL, with a low incidence of grade 3 CRS. Notably, no grade of ICANS was observed.

Keywords: B-cell acute lymphoblastic leukaemia, Chimeric antigen receptor T-cell, IL-6, Cytokine release syndrome, Immune effector cell-associated neurotoxicity syndrome