Co-founder and CSO Oricell Therapeutics Co.,Ltd, United States
Introduction/Rationale: Reported GPC3-targeted CAR-T therapies in HCC showed clinical activity with acceptable toxicity, yet efficacy remains to be improved.
Methods: To obtain GPC3-targeting sequences, we humanized GPC3-specific mAbs derived from hybridoma immunization, performed phage display and chain pairing optimization. CAR001 pre-clinical efficacy was evaluated in vitro and in vivo. A clinical trial in 10 GPC3⁺ patients was conducted via HAI or IV, with doses from 9E7 to 6E8 CAR-T cells.
Results: We identified high cell-surface-GPC3 binding sequence (EC₅₀ ratio vs GC33 = 0.023:0.203). CAR-T produced with optimized process showed high CAR⁺(median 65.6%), high early-memory T (median 72.7%), and elevated IFNγ secretion (median 14.37 ng/mL). CAR001 showed potent and durable responses in mice even after rechallenge. In the clinical trial of CAR001, we observed a high ORR ( 83.3% for HAI and 60% for HAI & IV overall) with a median OS of 9.4 months. No neurotoxicity was observed and CRS was dose-dependent. Preliminary analyses indicated a positive correlation between post-treatment CAR copy number (VCN) and DCP reduction, whereas no significant association was observed with AFP. There was a trend toward higher post-treatment VCN with higher Tcm proportion of drug product (DP) and IV. A significantly correlation was observed between PFS and DCP reduction. DP IFNg secretion exhibited an inverse correlation trend with AFP and DCP reduction.
Conclusion: CAR001 represents a promising advance in the treatment of advanced HCC with manageable safety. Patients with greater expansion tended to have deeper drops in DCP but not observed for AFP. Higher DP IFNg secretion inversely correlated with AFP reduction and DCP reduction. These findings suggest that AFP and DCP may independently reflect treatment response and highlight the complexity of cellular therapy responses in HCC.
