Updated clinical results of first-in-human study of CD19/BCMA dual-targeting fast CAR-T GC012F for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma

Background: CD19-directed CAR-T cell therapy has been demonstrated to be a valuable treatment option for relapsed/refractory B-cell non-Hodgkin’s lymphoma (r/r B-NHL). It has been shown that 39% to 97% of clinical B-NHL samples also express B cell maturation antigen (BCMA). To further improve safety and efficacy, we have been exploring utility of a CD19 and BCMA dual-targeting CAR-T, GC012F, manufactured through a novel next-day FasTCAR-T process, for treatment of r/r B-NHL. Aims: The initial 3-patient data of an investigator-initiated trial (ChiCTR2100047061) was reported at EHA 2022 (#2938). Here, we present updated results of this ongoing IIT trial with more patients and longer follow-up. Methods: From October 2021 to January 2023, nine eligible r/r DLBCL patients were enrolled and treated with a single infusion of GC012F in escalating dosing cohorts after a standard lymphodepletion regimen over 3 days (20 - 30 mg/m2/day Flu, 250 - 300 mg/m2/day Cy). The primary objectives of this study were safety and tolerability; the secondary were pharmacokinetics and efficacy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by ASBMT 2019, and adverse effects were evaluated according to CTCAE 5.0. Efficacy assessment of GC012F was referred to the Lugano criteria. Expansion of CAR-T cells and CAR copy numbers were analyzed by flow cytometry and qPCR, respectively. Results: As of data cut-off of January 16th, 2023, with a median of 207 days (range 94 - 460) of follow-up, all nine patients received single GC012F infusions at dose levels from 3.7×104 to 3×105 CAR-T/kg, and completed follow-up of 3 months or longer time. The median age was 52 years (range 18 - 60). Eight patients enrolled with Ann Arbor stage III/IV disease, and one patient with a double hit, and four patients with IPI score of 3. All patient lymphoma samples expressed CD19, and 6 out of 7 expressed BCMA. The median SPD was 2690.81 mm2 (408.3 - 13325.96 mm2). Patients received a median of 2 prior lines (range 2 - 3) of therapy including rituximab and anthracyclines. Two patients received prior auto-HSCT. The ORR in nine patients was 100% (9/9) at month 3, CR rate was 77.8% (7/9) at month 3 and 71.4% (5/7) at month 6, respectively. To date, the longest duration of remission was 14.4 months. No dose-limiting toxicities were observed. Five patients experienced grade 1 CRS, and one patient in the maximum dose group (3×105 CAR-T/kg) had grade 3 CRS over 2 days. No ICANS were observed. Of the nine treated patients, ≥ grade 3 TEAEs were neutropenia (7/9), leukopenia (5/9), thrombocytopenia (3/9), lymphocytopenia (1/9) and anemia (1/9). All TEAEs were resolved after treatment with standard of care and supportive care. The median peak copy number of CAR-T cells in peripheral blood was 71,000 copies/μg DNA (range 9263 - 185,039), and the median peak time was 14 days (range 9 - 21d). CAR-T geometric mean AUC0-28 for patients was 658,538 copies/μg DNA × day (319,104 - 1,359,031; 95% CI). CAR-T cells were also detected in tumor biopsies from all five patients tested. Summary/Conclusion: This first-in-human trial of GC012F, a CD19-BCMA dual targeting CAR-T product, for the treatment of r/r B-NHL showed a manageable safety profile and promising clinical responses. The ORR was 100% at month 3 with 77.8% (7/9) achieving CR. GC012F CAR-T cells were detectable in the tumor biopsies, indicating the infiltration of CAR-T cells into the tumor lesions. Study with larger cohort and longer follow-up is ongoing.Keywords: CAR-T