Targeting ANKRD11 Reverses HBV-Specific CD8+ T Cell Dysfunction and Tolerance

N/ANot Yet RecruitingNCT07777250

Beijing Municipal Administration of Hospitals40 enrolled

Overview

Achieving a functional cure for chronic hepatitis B (CHB) is largely hindered by the irreversible functional exhaustion and immune tolerance of hepatitis B virus (HBV)-specific CD8 positive T (CD8+ T) cells. In investigators previous studies, an in vivo Clustered Regularly Interspaced Short Palindromic Repeat(CRISPR) screen identified ANKRD11 for the first time as an "epigenetic brake" on CD8+ T-cell effector function. Loss of ANKRD11 markedly enhanced the expansion, effector function, and viral clearance capacity of HBV-specific T cells. Based on these findings, investigators hypothesize that ANKRD11 regulates the epigenetic program of T-cell exhaustion by restricting the activity of AP-1 family transcription factors, and that targeting ANKRD11 can reverse T-cell dysfunction and overcome immune tolerance. This project will: (1) elucidate the epigenetic mechanisms by which ANKRD11 regulates T-cell exhaustion using conditional knockout mouse models and multi-omics approaches; (2) evaluate how ANKRD11 deficiency reshapes the differentiation trajectory and antiviral function of HBV-specific T cells in models of chronic HBV infection; and (3) develop a combinatorial gene-editing strategy integrating "release of the brake" with "stepping on the accelerator" to generate enhanced T Cell Receptor-T cell Therapy(TCR-T) cells and evaluate their efficacy and safety in humanized mouse models. The study is expected to define a novel mechanism by which ANKRD11 regulates T-cell exhaustion, establish an enhanced TCR-T therapeutic strategy, and provide a potential approach toward achieving a functional cure for chronic HBV infection.

The human participant component of this study is limited to prospective collection of peripheral blood samples from patients with chronic hepatitis B and healthy volunteers for preclinical laboratory investigations. No therapeutic intervention is assigned to human participants. The major experimental components of the overall research project are conducted in vitro and in animal models.

Study Type

OBSERVATIONAL

Enrollment

Conditions

Chronic Hepatitis B

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * (1) Inclusion criteria for healthy donors: Age 18-60 years; Voluntary participation in this study and signing a written informed consent form; HLA-A11 positive; Generally in good health condition; No infection with hepatitis B virus, hepatitis C virus, HIV, syphilis, etc.; No severe liver, kidney, heart, lung, or blood system diseases; No recent immunosuppressive agents, cell therapy, or other treatments that may significantly affect immune function. (2) Inclusion criteria for chronic HBV patients: Age 18-65 years; Voluntary participation in this study and signing a written informed consent form; HLA-A11 positive; Meeting the diagnostic criteria for chronic HBV infection or chronic hepatitis B; HBsAg positive for ≥6 months; Able to provide basic clinical data, including HBsAg, HBeAg, HBV DNA, ALT, AST, etc. Exclusion Criteria: (1) Exclusion criteria for healthy donors: HLA-A11 negative; having concurrent infections such as HBV, HCV, HIV, syphilis, etc.; having autoimmune diseases, malignant tumors or severe chronic diseases; having recently used glucocorticoids, immunosuppressants, biological agents or undergone cell therapy; pregnant or lactating women; having obvious anemia, abnormal coagulation function or conditions unsuitable for blood collection; researchers consider them unsuitable to participate in this study. (2) Exclusion criteria for chronic HBV patients: HLA-A11 negative; having concurrent infections such as HCV, HDV, HIV or syphilis; having other clear liver diseases such as autoimmune liver disease, alcoholic liver disease, drug-induced liver injury, genetic metabolic liver disease, etc.; having liver cell carcinoma or other malignant tumors; having decompensated liver cirrhosis or severe liver failure; having severe heart, lung, kidney or blood system diseases; pregnant or lactating women; having recently received systemic immunosuppressants, biological agents or cell therapy; having severe anemia, abnormal coagulation function or other conditions unsuitable for blood collection; researchers consider them unsuitable to participate in this study.

Outcomes

Primary Outcomes

Antigen-Specific Cytotoxic Activity of HBV-Specific TCR-T Cells

Antigen-specific cytotoxic activity of HBV-specific TCR-T cells will be assessed using HBc141-151 peptide-loaded T2-A11 target cells at effector-to-target ratios of 1:1, 2.5:1, 5:1, and 10:1 by LDH release assay and flow cytometry-based cytotoxicity assay.

Time frame: After 4 hours of co-culture