A Clinical Study of Multi-target Hi-TCR-T Cells in the Treatment of Advanced Hepatocellular Carcinoma

NCT06902389 | Recruiting Phase 1 DMC

• 1 other identifier: EHBHKY2025-H010-P001
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a prospective, single-arm, open, single-center clinical trial initiated by the investigator. The principal investigators are professors Shen Feng and Zhang Xiaofeng from The Third Affiliated Hospital of Navy Military Medical University (Shanghai Eastern Hepatobiliary Surgery Hospital). Primary Objectives:

1. 1.To evaluate the safety and tolerability of super Hi-TCR-T cells targeting Nectin4/NKG2DL/TROP2/B7H3/GPC3/FAP in the treatment of refractory/recurrent advanced hepatocellular carcinoma (HCC) and other solid tumors.
2. 2.To assess the efficacy of super Hi-TCR-T cells targeting Nectin4/NKG2DL/TROP2/B7H3/GPC3/FAP in the treatment of refractory/recurrent advanced HCC and other solid tumors, focusing on progression-free survival (PFS).
3. 3.To evaluate the efficacy of super Hi-TCR-T cells targeting Nectin4/NKG2DL/TROP2/B7H3/GPC3/FAP in the treatment of refractory/recurrent advanced HCC and other solid tumors at 1, 3, 6, and 12 months, assessing disease control rate (DCR: CR+PR+SD), time to progression (TTP), and overall survival (OS).
4. 4.To observe and assess the quality of life (QOL score) of patients receiving super Hi-TCR-T cell therapy targeting Nectin4/NKG2DL/TROP2/B7H3/GPC3/FAP for refractory/recurrent advanced HCC and other solid tumors.
5. 5.To evaluate the relationship between the in vivo expansion and persistence of super Hi-TCR-T cells targeting Nectin4/NKG2DL/TROP2/B7H3/GPC3/FAP and disease progression.
6. 6.To explore potential predictive biomarkers. Thirty patients are planned to be recruited for this study. The subjects were advanced HCC patients who had failed second-line therapy or could not tolerate therapy. The expression levels of Nectin4, NKG2DL, TROP2, B7H3, GPC3 and FAP were detected by immunohistochemistry in the pathologic tissues of the primary and metastatic sites. Meanwhile, 20ml peripheral blood was extracted to evaluate the quality of T cells (in vitro proliferation activity and lentiviral transduction efficiency). Patients with positive expression rates of at least 2 targets (excluding FAP) \>10% and qualified T cell quality could be considered for inclusion.
7. 7.Safety assessment: at baseline, 4, 7, 10, 2, 3, 4, 8, 12, 16, 20, 6, 9 and 12 months after cell therapy;
8. 8.Effectiveness evaluation: at baseline, 4, 12, 6, 9, 12, 24, and 36 months after cell therapy. Safety assessment: At baseline, 4, 7, 10, 2, 3, 4, 8, 12, 16, 20, 6, 9, and 12 months after cell therapy;
9. 9.Exploratory study: 20ml peripheral blood was collected from patients at baseline, 7 days, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 6 months, 9 months, 12 months after cell therapy, to explore the relationship between the proliferation and survival time of Hi-TCR-T cells in vivo and the changes of disease and peripheral blood cytokines.

Conditions

Advanced Hepatocellular Carcinoma (HCC)

Keywords

Hi-TCR-T; Advanced hepatocellular carcinoma

Outcome Measures

Primary Outcomes (2)

• progression-free survival

  In treated subjects, the time from first recording to tumor progression (based on RECIST 1.1 and mRECIST) or death from any cause.

  From the date of enrollment of each patient, the end point was 12 months after the end of the patient's medication, or the patient died (whichever occurred first).

• Adverse event

  Adverse medical events that occur after a clinical trial subject is accepted into the trial, but are not necessarily causally related to the treatment. All adverse events that occur during the trial must be faithfully recorded on the Adverse Event sheet.

  From the date of enrollment of each patient, the end point was 12 months after the end of the patient's medication, or the patient died, or the patient was lost to follow-up or withdrew consent (whichever occurred first).

Secondary Outcomes (4)

• Overall survival

  From the date of enrollment of each patient, the end point was 12 months after the end of the patient's medication, or the patient died (whichever occurred first).

• duration of disease control

  From the date of enrollment of each patient, the end point was 12 months after the end of the patient's medication, or the patient died (whichever occurred first).

• time to progress

  From the date of enrollment of each patient, the end point was 12 months after the end of the patient's medication.

• Disease Control Rate

  From the date of enrollment of each patient, the end point was 12 months after the end of the patient's medication, or the patient died (whichever occurred first).

Study Arms (1)

Hi-TCR-T Cell Therapy Group

EXPERIMENTAL

Biological: Super Hi-TCR-T cells

Interventions

Super Hi-TCR-T cells BIOLOGICAL

Intravenous infusion of 3.0×10⁶ cells/kg of Super Hi-TCR-T cells targeting Nectin4, NKG2DL, TROP2, B7H3, GPC3, and FAP. The expression levels of Nectin4, NKG2DL, TROP2, B7H3, GPC3 and FAP were detected by immunohistochemistry. Meanwhile, 20ml peripheral blood was extracted to evaluate the quality of T cells. Patients with positive expression rates of at least 2 targets (excluding FAP) \>10% and qualified T cell quality could be considered for inclusion. Peripheral blood lymphocytes were collected and Hi-TCR-T cells targeting three targets (including FAP) were prepared. After pretreatment with fludarabine + cyclophosphamide chemotherapy (FC regimen), the prepared Hi-TCR-T cells were transfused back, in which the dose of Hi-TCR-T cells at each target was 3.0x106 cells/kg body weight (the dose was the extended therapeutic dose obtained in the previous clinical trial), and the drug was administered by peripheral intravenous infusion.

Hi-TCR-T Cell Therapy Group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with advanced HCC who are inoperable and unsuitable for local therapy, and whose disease has progressed or cannot tolerate therapy after first - or second-line therapy, and who meet one of the following requirements: 1) have a histological or cytological diagnosis of HCC; 2) According to the National Health Commission's Guidelines for Primary Liver Cancer Diagnosis and Treatment (2024 edition), the clinical diagnosis was HCC;
• At least one measurable lesion was present according to RECIST1.1 and mRECIST criteria;
• The expressions of Nectin4, NKG2DL, TROP2, B7H3 and GPC3 in tumor tissues were detected by immunohistochemistry in primary and metastatic specimens or in white paraffin sections of previous pathological pathology (the expression of tumor cells with a target \>10% is considered positive, and at least 2 targets are required to be positive), as well as the expression of FAP in tumor tissues;
• The patient's T cell quality (pre-experimental) assessment met the criteria: at least 5 times T cell proliferation within 3 days, and at least 10% lentivirus transduction efficiency;
• ECOG performance status score of 0-2;
• Child-Pugh score ≤6;
• Expected survival time of at least 3 months;
• No contraindications to peripheral blood mononuclear cell (PBMC) collection;
• Seven days prior to the first treatment with the study drug, organ function levels must meet the following requirements: Hematology: Hemoglobin (Hb) ≥90 g/L; Absolute neutrophil count (ANC) ≥1.5×10⁹/L; Platelet count ≥75×10⁹/L. Blood Biochemistry: Serum albumin ≥28 g/L; Total bilirubin ≤2× upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3× ULN; Alkaline phosphatase (ALP) ≤3× ULN; Creatinine ≤1.5× ULN. Coagulation Function: International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN; Activated partial thromboplastin time (APTT) ≤1.5× ULN. Cardiac Function: Echocardiography confirms normal diastolic function; Left ventricular ejection fraction (LVEF) ≥50%; No severe arrhythmia. Pulmonary and Renal Function: No severe lung or kidney disease; No active pulmonary infection; Blood oxygen saturation ≥92% in room air.
• Serum pregnancy test results of women of childbearing age must be negative within 7 days before the first use of the study drug; Fertile men or women with the possibility of becoming pregnant must use a highly effective contraceptive method (such as oral contraceptives, intrauterine devices, abstinence or barrier contraception combined with spermicides) throughout the trial and continue contraception for 12 months after the end of treatment;
• The subjects voluntarily joined the study, signed the informed consent, had good compliance, and cooperated with follow-up.

You may not qualify if:

• Uncontrollable active infection (excluding HBV and/or HCV infections);
• active central nervous system disease, or known concomitant brain metastases with significant neurological/psychiatric symptoms assessed by MMSE;
• Known allergy to 2 or more non-similar foods/drugs, or known allergy to chemotherapy preconditioning drugs (such as cyclophosphamide, fludarabine);
• Any toxicity caused by previous antitumor therapy before chemotherapy preconditioning has not returned to grade 1 or below (CTCAE version 5.0);
• Patients who have participated in or are participating in clinical trials of other drugs/therapies within 4 weeks prior to the first administration of the investigational drug;
• Major surgery had been performed/received within 4 weeks prior to the first administration of the study drug or had not yet recovered from the side effects of the surgery, live vaccination, and radiotherapy within 2 weeks;
• Patients who are taking systemic hormone therapy for immunosuppressive purposes (dose \>10mg/ day prednisone or other equivalent hormone) and continue to use within 2 weeks prior to treatment;
• Pregnant or lactating women;
• A history of other malignancies within the past 5 years, except cured basal cell carcinoma of the skin, squamous cell carcinoma of the skin, early prostate cancer, and cervical carcinoma in situ;
• Active inflammatory bowel disease or digestive tract ulcer;
• HIV antibody or treponema pallidum antibody test results positive;
• A large amount of pleural fluid or ascites accompanied by clinical symptoms that require symptomatic treatment;
• A history of active lung disease (pneumonia, obstructive pulmonary disease, asthma) or active pulmonary tuberculosis;
• suffering from blood system diseases: leukemia, lymph nodes, myelodysplastic syndrome or myeloma;
• Except vitiligo accidental immune deficiency disease or autoimmune disease;

Sponsors & Collaborators

• Eastern Hepatobiliary Surgery Hospital: lead

Study Sites (1)

The Third Affiliated Hospital of Navy Military Medical University

Shanghai, Yangpu District, 200438, China

RECRUITING

Central Study Contacts

Xiaofeng Zhang, Ph.D.

CONTACT

+86 13917412555; zxf_ehbh@126.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: The Vice President of the Clinical Research Institute

Study Record Dates

• First Submitted: March 16, 2025
• First Posted: March 30, 2025
• Study Start: July 30, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): April 7, 2028
• Last Updated: September 3, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)