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

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. 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. 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).

Secondary Objectives:

1. 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).
2. 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.

Exploratory Objectives:

1. 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.
2. 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.

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. To improve efficacy, Hi-TCR-T cell retransfusion can be prepared by increasing the cell dose of the target or changing the combination of the target as the disease progresses and evaluated by a multidisciplinary team (MDT).

Safety and efficacy evaluation and exploratory studies were conducted after reinfusion of Hi-TCR-T cells from screening multiple targets:

1. Safety assessment: at baseline, 4, 7, 10, 2, 3, 4, 8, 12, 16, 20, 6, 9 and 12 months after cell therapy;
2. 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;
3. 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.

The start time of the study was defined as the date the first patient was enrolled; The end time of the study was defined as 12 months after the end of medication for the final patient, or all patients died, or all patients had lost follow-up or withdrawn consent (whichever occurred first). The planned recruitment period is 12-18 months.

Conditions

• Advanced Hepatocellular Carcinoma (HCC)

Interventions

BIOLOGICAL

Super Hi-TCR-T cells

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.

Sponsors & Collaborators

• Eastern Hepatobiliary Surgery Hospital

  lead OTHER

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-07-30

Primary Completion

2028-01-01

Completion

2028-04-07

Countries

• China

Study Locations