Safety Study of Adoptive Transfer of Autologous IKDC-like Cells

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety of adoptive transferring autologous IKDC-like cells

Detailed Description
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Cancer immunosurveillance in mice and human protects the host from outgrowth of tumor cells. This may establish a sufficient rationale for cancer immunotherapy that aims to control or eradicate tumor by an induction of effective anti-tumor immunity. The interest in developing cancer immunotherapy has intensified by the recent trials results showing durable responses in approximately 20% of patients who received various kinds of immunotherapy including adoptive transfer of tumor-specific T cells, cancer vaccines, and T cell response checkpoint blockade inhibition. Discoveries to date, natural killer (NK) cell function positively associates with reduction of cancer risk and with better survival of gastrointestinal stromal tumor patients. Interferon-producing killer dendritic cells (IKDCs) are a subpopulation of NK cells discovered in the mouse spleen, which can lyse tumor cells and acquire antigen presentation cell (APC) activity. We found putative IKDCs in human peripheral blood mononuclear cells (PBMCs); meanwhile, we also developed a method to expand IKDC-like cells from murine bone marrow and human PBMC ex vivo. The expanded human IKDC-like cells are cytotoxic toward several human leukemia cell lines and are capable to activate allogeneic T cells. For the in vivo anti-tumor activity, we found that two transfers of syngeneic murine IKDC-like cells reduced tumor burden in B16/OVA and B16/F10 melanoma and Lewis lung carcinoma models, and enhanced interferon (IFN)-γ production by the splenocytes of the tumor-bearing mice. Moreover, six transfers of IKDC-like cell significantly prolonged the survival of mice bearing B16/F10 melanoma. Based on these preclinical results, we hypothesize anti-tumor activity of human IKDC-like cells. We thus propose a phase 1 clinical trial to assess the safety of autologous IKDC-like cell therapy in metastatic cancer patients for determination of the maximum tolerated dose, and to monitor the immune parameters in patients before and after the IKDC-like cell transfer to investigate the therapeutic mechanism and biomarkers.

Official Title
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An Immunotherapy for Metastatic Cancer Patients by Adoptive Transfer of Autologous IKDC-like Cells - Phase 1 Clinical Trial

Conditions
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Neoplasm Metastasis

Intervention / Treatment
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* Biological: autologous IKDC-like cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed metastatic/recurrent non-hematological cancer, stage IV at study entry. Age: 21-75 years. ECOG performance status 0-1. Patients must have at least one measurable lesion. Patients' disease must have failed at least one-line of standard chemotherapy/targeted therapy or other treatment in the metastatic setting. Patients' estimated life expectancy is more than 3 months. Patients who refuse chemotherapy, or who are physiologically unsuitable for chemotherapy or any other standard therapy per investigator's discretion will be considered eligible for this trial. Patients must have adequate bone marrow function, defined as WBC ≥ 3500/mm3, neutrophil ≥ 1500/mm3, lymphocyte ≥ 1,000/mm3, and platelet ≥ 100,000/mm3. Patients must have adequate liver and renal function, defined as serum alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 5 times normal, bilirubin ≤ 1.5 times normal range, and creatinine ≤ 1.5 times upper normal limit. All patients should have documentation of negative result of penicillin test. Women or men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. All patients must be informed of the investigational nature of this study and must sign and give written informed consent. Exclusion Criteria: Subjects with metastatic cancer in disease progression (expected survival time < 3 months). Subjects who have had chemotherapy less than 4 weeks before the start of trial. Subjects who received IFN-γ or GM-CSF less than 4 weeks before the start of trial. Subjects who are HIV, HBV, or HCV positive. Patients who have central nervous system metastasis except for those whose CNS disease have been treated with radiotherapy (Disease-free > 6 months) and/or surgery and have been stable for at least two weeks. Patients who have active acute or chronic infection (at the discretion of the investigator). Pregnant or breast-nursing women. Patients who have active cardiac disease requiring therapy for failure, angina, arrhythmia, or infarction within the preceding 6 months (exception: any patient whose cardiac failure is compensated on medications). Subjects who have received corticosteroids or other immunosuppressive agents less than 4 weeks before starting trial. Subjects who have asthma and/or are on treatment for asthma. Subjects with history of autoimmune disease, such as lupus, multiple sclerosis, Ankylosing Spondylitis, Systemic Sclerosis. Subjects with a history of other systemic disease.. History of neoplastic disease within the last 5 years except for carcinoma in situ of the cervix, superficial bladder cancer or basal/squamous cell carcinoma of the skin. Subjects who present with open wounds.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 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: 3+3 statistics model
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: autologous IKDC-like cell<br>Received autologous IKDC-like cells | Biological: autologous IKDC-like cells<br>* Subject received autologous IKDC-like cells every 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of subject with Grade 3 or above adverse events that received autologous IKDC-like cells, graded according to NCI-CTCAE v4.03 | I. Safety is evaluated by assessment of does-limiting toxicity (DLT) according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 or above. II. DLT is defined as follows: Any Grade 3 or above toxicity regarding general disorders or immune disorders defined by NCI-CTCAE is determined by the investigator to be possibly related in causality to the treatment. Fever, chillness, flu-like symptoms, or infusion-related reactions of grade 3 or more are to be counted as DLT only if they remain at grade 3 or more for more than three days despite of adequate symptomatic medications.. III. The maximum tolerated dose (MTD) of autologous IKDC-like cell will be determined via a 3+3 traditional design. | Through study complete, an average about 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer immunotherapy, IFN-γ-producing killer dendritic cell-like cells, Natural killer cells