1054P - A phase Ia study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of a modular CLDN18.2-targeting PG CAR-T therapy (IBI345) in patients with CLDN18.2+ solid tumors

Background

Chimeric antigen receptor (CAR) T-cell therapy holds great promise for the treatment of solid tumors; however, how to avoid or minimize the “on-target off-tumor” effect of CAR-T therapy remains a major issue, we developed a P329G (PG) modular and switchable CAR technology, in which CAR-T cells bind tumor antigens indirectly via an Fc-silent tumor-targeting human antibody(Ab) containing the PG mutation as an adapter molecule, whose activity is controllable by the PG Ab. Here, we report the first-in-human clinical results of a CLDN18.2-targeting PG CAR-T product (IBI345) for the treatment of CLDN18.2+ solid tumors.

Methods

In this phase 1a study, patients (pts) with CLDN18.2+ advanced solid tumor received an infusion of IBI345 consisting of one dose of PG CAR-T cells at escalating doses of 50, 250×10⁶ cells plus ≥ 1 dose of CLDN18.2-targeting PG Ab at a fixed dose of 1mg/kg Q3W after lymphodepletion preconditioning. The objectives include safety and tolerability, pharmacokinetics and preliminary efficacy (per RECIST 1.1) of IBI345.

Results

As of Apr 7, 2023, 5 pts were treated with IBI345. All 5 pts experienced TRAEs, and grade ≥ 3 TRAE were neutrophil count decreased (n=2) and decreased appetite (n=1). No CRS, ICANS or treatment-related deaths occurred. For 4 efficacy-evaluable pts (Table), 1 EGJC pt achieved PR and 2 pts (1 GC, 1 PC) achieved SD. CAR-T expansion and persistence were detected in all pts, with a median peak of 1,840 copies/μg gDNA (1,500-4,020), a median time to peak of 16 days (9-20), and a median persistence of 45 days (35-127). Table: 1054P

Overview of clinical and biomarker results for each individual patient

Conclusions

IBI345 demonstrated a manageable safety profile and preliminary efficacy in patients with CLDN18.2+ advanced solid tumors. To realize the full potential of this modular CAR-T cell product, the dose and regimen of the P329G Ab and CAR-T cells requires further exploration.

Clinical trial identification

NCT05199519.

Editorial acknowledgement

Weichang Chen is the corresponding author.

Legal entity responsible for the study

Innovent Cells Pharmaceuticals.

Funding

Innovent Cells Pharmaceuticals.

Disclosure

M. Li: Other, Personal, Affiliate, EMPLOYMENT: Innovent Cells Pharmaceuticals. H. Wei: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. L. Sun: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. Q. Xie: Other, Personal, Other, EMPLOYMENT: Innovent Biologics, Inc.. E. Lin: Other, Personal, Other, EMPLOYMENT: Innovent Biologics, Inc.. D. Xu: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. J. Tian: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. J. Chen: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. W. Lu: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. N. Gao: Other, Personal, Other, EMPLOYMENT: Innovent Biologics, Inc.. L. Chen: Other, Personal, Other, EMPLOYMENT: Innovent Biologics, Inc.. J. Duo: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. L. Ye: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. T. Cheng: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. Y. Sui: Other, Personal, Other, EMPLOYMENT: Innovent Cells Pharmaceuticals. C. Klein: Other, Personal, Other, EMPLOYMENT: Roche Innovation Center Zurich. All other authors have declared no conflicts of interest.