Armored CAR T Therapy Shows Activity in Refractory Hepatocellular Carcinoma

An armored glypican-3-directed chimeric antigen receptor (CAR) T-cell therapy incorporating a dominant-negative transforming growth factor (TGF)-β receptor II demonstrated a manageable safety profile and clinically meaningful antitumor activity in heavily pretreated advanced hepatocellular carcinoma (HCC), according to a first-in-human trial (NCT05155189) published in Nature.

The trial enrolled 36 patients with advanced, treatment-refractory HCC who received C-CAR031 across 4 dose levels ranging from 0.75 × 10^6 to 4.0 × 10^6 cells/kg following lymphodepletion. The cohort was heavily pretreated, with a median of 4 prior lines of therapy and 69.4% of participants having received at least 3. Most had Barcelona Clinic Liver Cancer stage C disease (94.4%), extrahepatic spread (83.3%), and hepatitis B virus infection (97.2%).

Treatment exposure was feasible, with a 100% manufacturing success rate and preserved cell viability. Cytokine release syndrome (CRS) occurred in 94.4% of patients, predominantly grade 1 to 2, with grade 3 events in 5.6%. Grade 3 or higher nonhematologic toxicities were reported in 9 patients, and serious adverse events occurred in 8.3%. No immune effector cell-associated neurotoxicity syndrome or dose-limiting toxicities were observed.

Efficacy outcomes showed objective responses in 44.4% of patients, all partial responses, with a disease control rate of 91.7%. Tumor reduction was observed in 32 of 36 patients, with a median maximal decrease of 41.6% (range, 3.4%-94.4%). Median time to response was 1.43 months, and median duration of response was 4.4 months (95% CI, 2.9-7.4). Median progression-free survival was 4.2 months (95% CI, 2.9-4.8), and overall survival reached 14.2 months (95% CI, 10.1 to not evaluable), with 12-month survival of 60.7%.

Pharmacokinetic analyses demonstrated rapid expansion and sustained persistence of CAR T cells, detectable up to 361 days. Higher peak cellular levels correlated with more severe cytokine release syndrome (P =.031). Cytokine profiling showed marked increases in interleukin-6, interleukin-8, and interferon γ following treatment, with higher interferon γ (P =.025) and interleukin-2 (P =.045) levels associated with higher-grade cytokine release syndrome.

Correlative and spatial analyses identified biologic determinants of response and resistance. Downregulation of GPC3 in tumor cells and increased TGFβ signaling characterized nonresponders, alongside greater T-cell exhaustion and reduced effector infiltration. In contrast, responders demonstrated enhanced antigen presentation signatures and chemokine-mediated immune recruitment, particularly involving the CCL3/CCL5-CCR5 axis.

These findings suggest that although TGFβ-resistant armouring preserves CAR T-cell function, persistent immunosuppressive signaling and antigen escape continue to limit durability in patients with advanced hepatocellular carcinoma. The authors noted that studies using combinations with other therapies such as antiangiogenesis tyrosine kinase inhibitors and/or immune checkpoint inhibitors are planned, and customized probes to identify CAR T cells in the tumor microenvironment may deepen understanding of resistance mechanisms.