Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC).

person Qi Zhang Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China info_outline Qi Zhang, Qihan Fu, Wanyue Cao, Hongkan Wang, Xingyuan Xu, Jiaqi Huang, Andy Zou, Judy Zhu, Hui Wan, Yihong Yao, Eric Tu, John Stone, Attilio Bondanza, Benedetto Farsaci, Tingbo Liang

Authors person Qi Zhang Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China info_outline Qi Zhang, Qihan Fu, Wanyue Cao, Hongkan Wang, Xingyuan Xu, Jiaqi Huang, Andy Zou, Judy Zhu, Hui Wan, Yihong Yao, Eric Tu, John Stone, Attilio Bondanza, Benedetto Farsaci, Tingbo Liang Organizations Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China, AbelZeta Pharma, Inc., Shanghai, China, AstraZeneca, Gaithersburg, MD, AstraZeneca, Cambridge, United Kingdom Abstract Disclosures Research Funding AbelZeta Pharma, Inc and AstraZeneca Background: GPC3 is a surface antigen overexpressed in HCC and virtually absent on healthy tissues. Chimeric antigen receptor (CAR) T cells targeting GPC3 offer a promising option for advanced unresectable HCC treatment. C-CAR031 is an autologous GPC3-directed CAR-T armored with dominant negative TGF-b receptor II. Here we report the safety and preliminary efficacy of C-CAR031 in advanced HCC patients (pts). Methods: The first-in-human, open-label dose-escalation trial employs an accelerated titration plus i3+3 design. GPC3+ advanced HCC pts who failed ≥ 1 line systemic treatments received a single i.v. infusion of C-CAR031 post standard lymphodepletion. Primary endpoints are safety and tolerability, others include pharmacokinetics and preliminary efficacy. Adverse events (AEs) were graded by CTCAE 5.0, and cytokine release syndrome (CRS) / immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed per ASTCT 2019 criteria. Objective response was assessed by investigator per RECIST 1.1. Results: As of Jan 5 th , 2024, a total of 24 pts received C-CAR031 infusion at 4 dose levels (DLs). All pts had BCLC stage C HCC, 83.3% (20/24) had extrahepatic metastasis. The median number of prior lines of therapy was 3.5 (range 1-6), 23 (95.8%) pts received ICIs (immune checkpoint inhibitors) and TKIs (tyrosine kinase inhibitors). All pts were evaluable for safety. No dose-limiting toxicity and ICANS was observed. CRS was observed in 22 (91.7%) pts with only 1 (4.2%) grade (G) 3 CRS. The most common ≥G3 AEs were lymphocytopenia (100%), neutropenia (70.8%), thrombocytopenia (37.5%) and transaminase elevation (16.7%). One pt (4.2%) had G4 myelosuppression and 1 pt (4.2%) had G3 interstitial pneumonitis at DL4 caused by G3 CRS. All AEs were reversible. 22 pts were evaluable for efficacy. Tumor reductions were observed in 90.9% pts, not only in intrahepatic lesions but also extrahepatic ones with a median reduction of 44.0% (range, 3.4%-94.4%). The disease control rate was 90.9% and the objective response rate (ORR) was 50.0% for pts of all DLs. In DL4, the ORR was 57.1%. Conclusions: The study showed a manageable safety profile and encouraging anti-tumor activity of C-CAR031 in heavily treated advanced HCC patients. Clinical trial information: NCT05155189. Clinical Response DL1 DL2 DL3 DL4 Overall n (%) N = 1 N = 6 N = 8 N = 7 N = 22 PR 0 3 (50.0%) 4 (50.0%) 4 (57.1%) 11 (50.0%) uPR 0 0 0 1 (14.3%) 1 (4.5%) SD 1 (100%) 2 (33.3%) 4 (50.0%) 1 (14.3%) 8 (36.4%) PD 0 1 (16.7%) 0 1 (14.3%) 2 (9.1%) With 5.82-month median follow-up, Kaplan-Meier estimation of median progression-free survival was 4.27 months (95% CI, 2.86-8.90). Median overall survival has not been reached. C-CAR031 showed a robust cellular kinetic profile with a median T max , C max and AUC 0–28Day of 10 days, 367,711.5 copies/μg gDNA and 4,105,036 days*copies/μg gDNA respectively.

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