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Locoregional delivery of autologous PD-1 knockout T cell in patients with failed first-line therapy in advanced hepatocellular carcinoma

ABSTRACT: The study aims to evaluate the efficacy and safety of a novel cell-based therapy for advanced hepatocellular carcinoma (HCC). Current guidelines for advanced HCC recommend systemic therapies, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); however, their combined efficacy as first-line treatments remains suboptimal. This study reports findings from a first-in-human phase I clinical trial involving 3 patients with advanced HCC who had previously demonstrated poor responses to first-line therapies. The treatment involved local intratumoral injection of CRISPR-edited, PD1-deleted T lymphocytes, engineered to enhance antitumor immunity (ClinicalTrials.gov NCT04417764). Key outcomes include a treatment response rate of 90% among assessable patients, with a median survival after enrolment of 17.2 months and an overall median survival after HCC diagnosis of 46.9 months. As of December 31, 2023, the three-year survival rate was 20%, and one patient exhibited an exceptional survival duration of 43.6 months. Secondary outcomes revealed that patients receiving the engineered T-cell therapy reported a significantly improved quality of life compared to the observation group. The tumor immune microenvironment was analyzed pre- and post-therapy using single-cell RNA sequencing, which demonstrated that tumor-infiltrating lymphocytes (TILs) developed an effector-like phenotype following therapy. In conclusion, this study provides strong evidence supporting the viability of CRISPR-edited, PD1-deleted T lymphocytes as a therapeutic option for advanced HCC, addressing an urgent need for more effective treatment strategies in this patient population.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287386 | GEO | 2026/01/18

REPOSITORIES: GEO

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Project description:Background and purpose: Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. Basic procedures: We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. Main findings: Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. Principal conclusions: Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

Project description:Background: Hepatocellular carcinoma (HCC) develops on background chronic liver disease where exposure to uncontrolled inflammation drives hepatocarcinogenesis. Current first-line therapies have limited response, and most patients will eventually progress. There are no agents that specifically target the underlying liver inflammation. We investigated the safety and efficacy of itacitinib, a highly selective JAK1 inhibitor, as a potential second- or third-line therapy in patients with advanced HCC. Biomarkers of response were investigated. Methods: Participants with advanced stage HCC, Child Pugh <B7 who had progressed through at least one previous line of therapy received 400mg of itacitinib QID every 28 days. Treatment-related adverse events (trAEs) were assessed weekly during cycle 1 then every 28 days (CTC-AE version 4.03). Response was assessed 8-weekly using RECIST 1.1. Progression-free (PFS) and overall survival (OS) were reported as secondary endpoints. Tumour samples were analysed for targeted transcriptomics. Sequential serum samples were assessed for metabonomic determinants of toxicity and response. Results: Nineteen patients were enrolled. The most common trAEs were thrombocytopenia (31%), fatigue (26%) and palmar-plantar erythrodysesthesia syndrome (26%); four episodes of dose-limiting thrombocytopaenia were observed. Over a median follow-up of 3.5 months, the best overall response was stable disease (47%). Median PFS and OS were 3.5 (95% CI: 2.6 - 4.5 months) and 7.4 months (95% CI: 4.3-10.5 months), respectively. Subgroup analysis illustrated a significantly increased risk of progression for patients that had received combination immunotherapy prior to itacitinib (HR 4.7, 95%CI 1.3-16.6, p=0.016). Untargeted tumour and serum transcriptomics identified a signature predictive of response. Discussion: Itacitinib either as second- or third-line therapy showed promising activity. We identified a transcriptomic signature predictive of response.

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Locoregional delivery of autologous PD-1 knockout T cell in patients with failed first-line therapy in advanced hepatocellular carcinoma

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