Clinical Safty and Efficacy Study of Infusion of iNKT Cells and CD8+T Cells in Patients With Advanced Solid Tumor

Study Overview
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Brief Summary
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Invariant Natural killer T (iNKT) cells are a unique subset of lymphocytes that express homogeneous TCR recognizing KRN7000 which was up-regulated by many kinds of cancer cells. PD-1+CD8+T cells of patients with advanced tumor are most likely tumor-specified. Our hypothesis is that immunotherapy strategy of infusion of iNKT cells and PD-1+CD8+T cells may decrease the tumor burden and improve overall survival. The purpose of this study is to assess the safety and efficacy of treatment of patients with advanced solid tumor by infusing of iNKT cells and PD-1+CD8+T cells.

Detailed Description
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Treatment of patients with advance solid tumor is great unsolved challenge to the physicians. Efficacy of conventional treatment, such as surgery, radiotherapy and chemotherapy is limited. AS novel therapy, immunotherapy shows great prospects. Human iNKT cells can directly lysis tumor cells by a perforin-dependent mechanism,and intracellular granzyme B expression may also potentiate cell killing. Tumor cells expressing CD1d may be especially susceptible to direct NKT cell lysis. iNKT cells play important role in immune regulation by secreting various cytokines. PD-1+CD8+T cells are most likely tumor-specific in patient with advanced tumor. Expansion method of iNKT cells and PD-1+CD8+T cells in vitro is developed as published in our patent. Infusions of iNKT cells and CD8+T cell have been proved safe in mice. In this clinical trial, the safety and efficacy of the immunotherapy of infusion of iNKT cells and CD8+T cells are assessed.

Official Title
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Phace I and II Study of Immunotherapy Strategy Used iNKT Cells and CD8+T Cells in Patients With Advanced Tumor

Conditions
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Non-small Cell Lung Cancer, Small Cell Lung Cancer, Pancreas Cancer, Hepatocellular Carcinoma, Gastric Cancer, Renal Cell Carcinoma

Intervention / Treatment
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* Biological: Infusion of iNKT cells and CD8+T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytologically diagnosis of advanced lung cancer, or advanced gastric cancer, or advanced pancrease cancer, or hepatocellular carcinoma, or advanced colorectal cancer Patients' tumor tissue (formalin-fixed, paraffin-embedded) must be sufficient for diagnosis of cancer by a certified Laboratory of Pathology Laboratory values within the following ranges prior to receiving treatment of study agent: Hemoglobin≧8.0 g/dL, Neutrophils count≧1E9/L, Lymphocytes count≧lower limit of institutional normal, Platelet count≧50E9/L, Serum creatinine≦2.0 mg/dL, Serum bilirubin≦2 x upper limit of institutional normal, AST/ALT≦2 x upper limit of institutional normal No dyspnea at rest. Oxygen saturation ≥90% on room air No genetic disease Fertile females/males must consent to use contraceptives during participation of the trial. Women of child bearing potential must have a negative pregnancy test prior to receiving treatment of study agent within 7 days Patients must have a Karnofsky performance status greater than or equal to 80% Able and willing to give witnessed, written informed consent form prior to receiving any study related procedure Agrees to participate in long-term follow-up for up to 1 years, if received NKT infusion Exclusion Criteria: Organ dysfunction,such as significant cardiovascular disease, myocardial infarction within the past six months, unstable angina, coronary angioplasty within the past six months, uncontrolled atrial or ventricular cardiac arrhythmias; Child-Pugh C; Renal function failure or uremia; Respiratory failure; Disturbance of consciousness; Renal failure. Suffering from lymphoma or leukemia Serious infections requiring antibiotics, bleeding disorders Patients with myelodysplastic syndrome (MDS) History of immunodeficiency disease or autoimmune disease Positive HIV antigen and antibody, Hepatitis B surface antigen and Hepatitis C PCR within 21 days prior to enrollment Within concurrent chemotherapy Concurrent other medical condition that would prevent the patient from undergoing protocol-based therapy Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dose of study agent Pregnant or breast-feeding patients Can't give informed consent Lack of availability for follow-up assessment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Interventional Model Description: treatment group: receive twice cell infusions in one course of treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment<br>The eligible patient receive the experimental infusion of iNKT cells and CD8+T cells . | Biological: Infusion of iNKT cells and CD8+T cells<br>* The eligible patients receive twice infusions of iNKT cells(1E8 1E10) and CD8+T cells(1E7 1E9) in one course of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events related to the infusion of cells | The incidence of adverse events following infusion of iNKT cells and CD8+T cells | 28 days post-infusion | 
| Objective Response Rate (ORR) | Change of target focus confirmed by CT or MRI | up to 4 months post-infection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic analysis | Hematologic analysis is used to assess the impact of infusion to the cells in blood, including erythrocytes, leukocytes, platelets, T lymphocytes , B lymphocytes, Natural killer cell, NKT, CD4/CD8, and Treg lymphocytes. | Base line, the day before the first infusion in each course of treatment and up to 12 weeks after the treatment | 
| Liver biochemical examination | Liver Biochemical examination is a serological analysis about the metabolites related to the function of liver , such as immunoglobulins, Albumin (ALB), Alanine aminotransferase (ALT), Aspartate Aminotransferase (AST), Prealbumin (PA), total bilirubin (TB), and direct bilirubin (DB). | Base line, the day before the first infusion in each course of treatment and up to 12 weeks after the treatment | 
| Kidney biochemical examination | Kidney Biochemical examination is a serological analysis about the metabolites related to the function of liver, such as Blood urea nitrogen (BUN), Urea (UA), and Crea (Cr). | Base line, the day before the first infusion in each course of treatment and up to 12 weeks after the treatment | 
| Tumor Marker | Tumor Marker | Base line, the day before the first infusion in each course of treatment and up to 12 weeks after the treatment |