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

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. Overall design: This study investigates the therapeutic potential of CRISPR-edited, PD1-deleted T lymphocytes in advanced hepatocellular carcinoma (HCC). The experimental design involved the collection of tumor biopsy samples from 3 patients with advanced HCC before and after treatment. Pre-treatment tumor samples were used to assess the baseline immune microenvironment, while post-treatment samples were analyzed to evaluate the impact of therapy on the tumor microenvironment. All samples were obtained following the local intratumoral injection of engineered T cells.