Phase II Study of Metastatic Cancer That Overexpresses p53 Using Lymphodepleting Conditioning Followed by Infusion of Anti-p53 T Cell Receptor (TCR)-Gene Engineered Lymphocytes

National Cancer Institute (NCI)1 个研究点分布在 1 个国家目标入组 12 人开始时间: 2006年10月最近更新: 2011年8月15日

适应症

干预措施

试验速览

阶段: 2 期
状态: 已完成
发起方: National Cancer Institute (NCI)
入组人数: 12
试验地点: 1
主要终点: Clinical Tumor Regression

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Background:

The p53 gene normally suppresses tumor growth, but when it is mutated, or damaged, tumors can grow unchecked.

In cancers where the p53 gene has mutated, an increased level of p53(overexpression of p53) can be measured in the tumor.

Objectives To determine whether advanced cancers that overexpress p53 can be treated effectively with lymphocytes (white blood cells) that have been genetically engineered to contain an anti-p53 protein.

Eligibility Patients 18 years of age and older with metastatic cancer (cancer that has spread beyond the original site) Patient's tumor overexpresses p53 Patient's leukocyte antigen type is HLA-A 0201 Design

Patients undergo the following procedures:

Leukapheresis (on two occasions). This is a method of collecting large numbers of white blood cells. The cells obtained in the first leukapheresis procedure are grown in the laboratory, and the anti-p53 protein is inserted into the cells using an inactivated (harmless)virus in a process called transduction. Cells collected in the second leukapheresis procedure are used to evaluate the effectiveness of the study treatment.

Chemotherapy. Patients are given chemotherapy through a vein (intravenously, IV) for 1 week to suppress the immune system so that the patients immune cells do not interfere with the treatment.

Treatment with anti-p53 cells. Patients receive an IV infusion of the transduced cells containing anti-p53 protein, followed by infusions of a drug called IL-2, which helps boost the effectiveness of the transduced white cells.

Patients may undergo a tumor biopsy (removal of a small piece of tumor tissue). Patients are evaluated with laboratory tests and imaging tests, such as computed tomography (CT) scans 4 to 6 weeks after treatment and then once a month 3 to 4 months to determine the response to treatment.

Patients have blood tests at 1, 3, 6 and 12 months and then annually for the next 10 years.

详细描述

Background:

Human peripheral blood lymphocytes (PBL's) can be engineered to express alpha T-cell receptor that recognizes an human leukocyte antigen serotype witin HLA-A A serotype group) HLA-A2. 1 restricted epitope derived from the p53 protein.

We constructed a single retroviral vector that contains both alpha and existent chains and can mediate genetic transfer of this TCR with high efficacy (less than 30%) without the need to perform any selection.

In co-cultures with HLA-A2 and p53 double positive tumors including melanoma, hepatoma, sarcoma, small-cell lung cancer, esophageal and breast tumors, p53-TCR transduced T cells secreted significant amount of IFN-(but no significant secretion was observed in control co-cultures with either HLA-A2+/p53- or HLA-A2-p53+cell lines.

Additional secretion of cytokines (IL-2, IL-4, IL-10,granulocyte macrophage stimulating factor (GM-CSF),tumor necrosis factor alpha (TNFalpha)) and chemokines (regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein 1 alpha (MIP-1 alpha)) was also observed in co-cultures with HLA-A2+/p53+tumor lines.

研究设计

研究类型: Interventional
分配方式: Non Randomized
干预模型: Parallel
主要目的: Treatment
盲法: None

入排标准

年龄范围: 18 Years 至 —（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•Patients must have metastatic cancer that overexpresses p53 as assessed by immunohistochemistry, as determined by positive staining of tumor sample. when compared to negative controls per procedure in Appendix
•The immunohistochemical staining will be performed in the Pathology Laboratory Center for Cancer Research (CCR), National Cancer Institute (NCI) on fresh or archival tissue and will be supervised by Dr. Maria Merino. The criteria used to determine overexpression will be that used in the Laboratory of Dr. Curt Harris. Ten fields will be evaluated at 40 X magnification and if greater than 5% of cells stain positive, the tumor will be categorized as an overexpressor.
•Patients with melanoma or renal cell cancer must have previously received interleukin-2 (IL-2) and have been either non-responders (progressive disease) or have recurred. Patients with other histologies,not including hematologic malignancies, must have previously received first line and second line or higher systemic standard care(or effective salvage chemotherapy regimens) for metastatic disease,if known to be effective for that disease and have been either non-responders (progressive disease) or have recurred.
•Age greater than or equal to 18 years.
•Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 to
•Life expectancy of greater than three months.
•Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus be less responsive to the experimental and more susceptible to its toxicities).
•Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative.
•Patients must be human leukocyte antigen A(HLA-A) 0201 positive.
•Patients of both genders must be willing to practice birth control for four months after receiving the preparative regimen.
•Absolute neutrophil count greater than 1000/mm^3, and normal white blood cells (WBC) (greater than 3000/mm^3).
•Platelet count greater than 100,000/mm^
•Hemoglobin greater than 8.0 g/dl.
•Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than the upper limit of normal.
•Serum creatinine less than or equal to 1.6 mg/dl.
•Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
•More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo). Six weeks must have elapsed since prior Ipilimumab (MDX-010) therapy to allow antibody levels to decline, and patients who have previously received MDX-010 must have a normal colonoscopy with normal colonic biopsies.
•Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
•A biopsy must be evaluable to evaluate p53 expression and to confirm the diagnosis by the Laboratory of Pathology, CCR, NCI.

排除标准

•Patients requiring systemic steroid therapy
•Patients with active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
•Patients with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and acquired immune deficiency syndrome (AIDS)). Patients with opportunistic infections will be excluded. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
•Patients with history of severe immediate hypersensitivity reaction to any of the agents used in this study.
•Patient is not willing to sign a durable power of attorney.
•Patient is not able to understand and sign the Informed Consent Document.
•Since aldesleukin will be excluded if they have a history of electrocardio- gram (EKG) abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left ventricular ejection fraction (LVEF) less than 45% on a cardiac stress test (stress thallium, stress multi-gated acquisition scan (MUGA), dobutamine echocardiogram, or other stress test).
•Similarly, patients who are greater than or equal to 50 years old with a LVEF less than 45% will be excluded.
•Patients with a prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years) or symptoms of respiratory dysfunction (e.g. grade 2 dyspnea or hypoxia) who do not have a normal pulmonary function test as evidenced by a FEV(1) less than 60% predicted will be excluded.