Study of Adoptive Transfer of iNKT Cells Combined With TACE to Treat Advanced HCC

Study Overview
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Brief Summary
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Hepatocellular carcinoma (HCC) is a common disease with high mortality. More than 80% patients are first diagnosed with late-stage and unresectable, their effective drugs and treatments are very limited. invariant Natural Killer T (iNKT) cell exhibit antitumor activity against malignant tumors through producing high levels of cytokines. iNKT cells are abundant in the liver, but defect in liver cancer development. iNKT cells can express homing receptors licensing them specifically to migrate liver, then play key antitumor immunity. We already did a phase I study of autologous infusion of iNKT cells in the treatment of patients with advanced HCC. Safety and feasibility of iNKT infusion was proved. The purpose of this study is to verify the effectiveness of iNKT cells infusion combined with transcatheter arterial chemoembolization (TACE) in treatment of advanced HCC.

Detailed Description
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Patients with advanced HCC will be enrolled and divided into two groups. Patients in experimental group will be treated with TACE combined with iNKT cells infusion. TACE will be performed at 0th and 4th week. iNKT cells will be infused at 1st, 3rd, 5th, 7th, 8th and 12th week. Patients in control group will be treated with TACE at 0th and 4th week. Adverse events（AEs）, overall survival (OS) time and recurrence-free survival (RFS) time, change of immune cells will be monitored.

Official Title
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Study of Adoptive Transfer of Invariant Natural Killer T Cells Combined With Transcatheter Arterial Chemoembolization (TACE) to Treat Advanced Hepatocellular Carcinoma (HCC): Phase II Clinical Trial

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Biological: iNKT cells
* Drug: Cyclophosphamide
* Drug: Human recombinated Interleukin-2
* Procedure: TACE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-80 years. Patients with hepatocellular carcinoma (BCLC, stage C) proved by histopathology or proved by CT or MRI imaging system, relapsed after previous therapy and no effective therapies known at this time. Life expectancy of ≥ 12 weeks. WBC>3.0×10^9/L, LYMPH> 0.8×10^9/L, Hb>85g/L, PLT>50×10^9/L, Cre<1.5×the upper limit of normal value. iNKT>10/mL in peripheral blood mononuclear cell (PBMC). Able to understand and sign the informed consent. Exclusion Criteria: Any uncontrolled systematic disease: hypertension, heart disease, and et al.; Portal vein tumor thrombus, central nervous system tumor metastasis, or combined with other tumors; Receiving radiochemotherapy, local therapy, or targeting drugs within 4 weeks prior to this treatment; Unstable immune systematic diseases or infectious diseases; Combined with AIDS or syphilis; Patients with history of stem cell or organ transplantation; Patients with allergic history to related drugs and immunotherapy; Patients with complications associated with liver diseases: moderate or severe pleural effusion, pericardial effusion, ascites, or gastrointestinal hemorrhage; Pregnant or lactating subjects; Unsuitable subjects considered by clinicians.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TACE+iNKT for unresectable HCC<br>TACE combined with autologous iNKT cells infusion will be applied for patients in experimental group. TACE will be performed at 0th and 4th week. 5×10^8-10^9/m2 iNKT cells will be infused to patients at 1st, 3rd, 5th, 7th, 8th and 12th week. | Biological: iNKT cells<br>* 5×10^8-10^9/m2 iNKT cells will be infused to patients at 1st, 3rd, 5th, 7th, 8th and 12th week.<br>* Other names: invariant Natural Killer T cells;Drug: Cyclophosphamide<br>* CTX will be administered intravenously at a dose of 750mg/m2 2 days before the first iNKT cells infusion.<br>* Other names: CTX;Drug: Human recombinated Interleukin-2<br>* IL-2 will be given at a dose of 25,000 IU/kg/day for 5-14 days after iNKT cells infusion.<br>* Other names: IL-2;Procedure: TACE<br>* TACE will be conducted to all patients at 0th week and 4th week.<br>* Other names: Transcatheter Arterial Chemoembolization;|
| Other: TACE for unresectable HCC<br>TACE will be conducted at 0th week and 4th week. | Procedure: TACE<br>* TACE will be conducted to all patients at 0th week and 4th week.<br>* Other names: Transcatheter Arterial Chemoembolization;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival(OS) | OS is the duration from the date of enrollment to the date of death due to any causes. | 3 months or up to death | 
| Progression-Free Survival(PFS) | PFS is the duration from the date of enrolled into clinical trial to the date of first documentation of tumor progression. | 3 months or up to death | 
| Disease Control Rate (DCR) | DCR is the proportion of patients who had a response rate including complete remission (CR), partial remission (PR) and disease stabilization (SD) evaluated by imaging according to the irRC standard. | 3 months or up to death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunological Monitoring | Frequencies of immune cells such as iNKT cells, natural killer cells (NK) , regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), et al will be analyzed by flow cytometry before and after iNKT infusion. | Frequencies of immune cells will be monitored at 0th, 4th, 8th and 12th week. | 
| Adverse Events(AEs) | The severities of AEs will be divided into 5 levels according to the National Cancer Institute (NCI) Common Terminology Standard for Adverse Events (CTCAE) version 4.03. | The occurrence and severities of AEs will be recorded within 12-13 weeks after iNKT cells infusion. | 
| Alpha-fetoprotein (AFP) | AFP is the best-defined tumor marker for HCC, and it is widely used in clinical settings as an adjuvant diagnostic and prognostic indicator. | 3 months or up to death |