Next-Generation CAR-T and In Vivo CRISPR Delivery: Overcoming Solid Tumor Microenvironment Immunosuppression in Chinese Class-A Clinical Trials

• Claudin18.2-targeted armored CAR-T achieved 48.7% ORR and 22.4% complete remission (CR) in a Phase I trial at Ruijin Hospital (n=98), with median progression-free survival (PFS) of 7.2 months. • GPC3-targeted CAR-T with IL-7/CCL19 secretion showed 56.3% ORR and 31.2% CR in hepatocellular carcinoma at PUMCH (n=64), but 12-month relapse rate reached 38.5% due to antigen escape and T-cell exhaustion. • In vivo CRISPR via LNP targeting PD-1 in T-cells achieved 68% editing efficiency in non-human primates, but translation to human trials is pending; ex vivo PD-1 knockout CAR-T shows 41% ORR in refractory B-ALL with 6.5% Grade ≥3 CRS. • Armored CAR-T with dominant-negative TGF-beta receptor (DNR) reduced TGF-beta-induced SMAD signaling by 85% in vitro, but increased on-target/off-tumor toxicity in Claudin18.2-positive normal gastric mucosa, requiring dose de-escalation. • Prophylactic tocilizumab (8 mg/kg) and dexamethasone (10 mg/m²) reduced Grade ≥3 CRS from 28% to 12.4% and ICANS from 15% to 8.1% across 212 patients treated at Class-A centers.