NCT01457131终止1 期
Phase I/II Study of Metastatic Cancer That Expresses NY-ESO-1 Using Lymphodepleting Conditioning Followed by Infusion of Gene Engineered Lymphocytes Cotransduced With Genes Encoding IL-12 and Anti-NY ESO-1 TCR
适应症
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- To evaluate the safety of the IL-12 and anti-NY-ESO-1 engineered PBL in patients receiving a non-myeloablative conditioning regimen, and to determine if patients with metastatic cancer will have clinical tumor regression following this regimen.
研究概览
简要总结
Background:
- A new cancer treatment involves collecting white blood cells from an individual, modifying them to secrete IL-2 and target the ESO-1 protein expressed on some cancers, and returning them to the body. The cells may then be able to seek out the cancer cells and destroy them. Some kinds of cancer contain a protein called ESO-1, which is found on the surface of the cells. Doctors want to modify white blood cells to have an anti-ESO-1 effect, and use them to treat the cancer that has the ESO-1. In addition to adding genes that target the ESO-1 protein to the cells, the genes for IL-12 are added to the cells. IL-12 is a protein that stimulates the immune system. This type of therapy is called gene transfer.
Objectives:
- To test the safety and effectiveness of anti-ESO-1/IL-12 white blood cells against metastatic cancer.
Eligibility:
- Individuals at least 18 years of age who have metastatic cancer that expresses ESO-1 and has not responded to standard treatments.
Design:
- Participants will be screened with a medical history and physical exam. They will also have blood tests and imaging studies.
- Participants will have leukapheresis about a month before the treatment to collect white blood cells.
- They will have chemotherapy 5 days before the treatment to suppress the immune system, and prepare the body for the anti-ESO-1/IL-12 cells.
- The anti-ESO-1/IL-12 cells will be given as an infusion.
- Participants will be monitored in the hospital during their recovery from the treatment.
- Participants will have regular followup exams every 1 to 6 months. The exams will include blood tests, imaging studies, and other studies.
Due to toxicities seen with the regimen, it was decided not to pursue the phase 2 portion of the study.
详细描述
Background:
- In prior trials we have shown that adoptive transfer of lymphocytes, transduced with a T cell receptor (TCR) that recognizes the NY-ESO-1 antigen, can mediate regression of metastatic cancer, though responses are often transient, and complete responses are rare.
- Interleukin-12 (IL-12) is an important immunostimulatory cytokine. We have constructed a retroviral vector that contains an inducible single chain IL-12 driven by an NFAT responsive promoter which can be used to mediate transfer of this gene into anti-tumor lymphocytes. This construct enables the secretion of IL-12 following stimulation of the TCR.
- Transduction of the IL-12 gene into mouse anti-tumor lymphocytes results in a profound increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice. These cells have a profound advantage in inducing anti-tumor responses because very few cells are needed and there is no requirement for the concomitant administration of interleukin-2 (IL-2) as is the case for conventional cell transfer immunotherapies.
- Based on these studies we have now used a retrovirus that encodes an inducible human single chain IL-12 driven by an NFAT responsive promoter and a retrovirus that encodes an anti-NY-ESO-1 TCR to cotransduce autologous lymphocytes for the treatment of patients with metastatic cancer that expresses the NY-ESO-1 antigen.
Objectives:
Primary objectives:
- To evaluate the safety of the administration of IL-12 and anti-NY-ESO-1 engineered lymphocytes in patients receiving a non-myeloablative conditioning regimen.
- To determine if the administration of the transduced lymphocytes to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Metastatic cancer that expresses ESO as assessed by one of the following methods: RT-PCR on tumor tissue, or by immunohistochemistry of resected tissue, or serum antibody reactive with ESO. Metastatic cancer diagnosis will be confirmed by the Laboratory of Pathology at the NCI.
- •Patients with melanoma or renal cell cancer must have previously received high dose IL-2 and have been either non-responders (progressive disease) or have recurred. Patients with other histologies, must have previously received 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.
- •Greater than or equal to 18 years of age.
- •Willing to sign a durable power of attorney
- •Able to understand and sign the Informed Consent Document
- •Clinical performance status of ECOG 0 or
- •Life expectancy of greater than three months.
- •Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after receiving the preparative regimen.
- •Patients must be HLA-A*0201 positive
- •Seronegative for 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 treatment and more susceptible to its toxicities.)
- •Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
- •Hematology:
- •Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim.
- •WBC (> 3000/mm(3)).
- •Platelet count greater than 100,000/mm(3).
- •Hemoglobin greater than 8.0 g/dl.
- •Serum ALT/AST less or equal to 2.5 times 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 any prior anti-CTLA4 antibody therapy to allow antibody levels to decline.
- •Patients who have previously received any anti-CTLA4 antibody and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.
排除标准
- •Previous treatment with IL-
- •Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
- •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.
- •Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
- •Concurrent opportunistic infections (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).
- •Concurrent systemic steroid therapy.
- •History of severe immediate hypersensitivity reaction to any of the agents used in this study.
- •History of coronary revascularization or ischemic symptoms
- •Any patient known to have an LVEF less than or equal to 45%.
- •Documented LVEF of less than or equal to 45% tested in patients with:
- •History of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block
- •Age greater than 60 years old
- •Documented FEV1 less than or equal to 60% predicted tested in patients with:
- •A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).
- •Symptoms of respiratory dysfunction
结局指标
主要结局
To evaluate the safety of the IL-12 and anti-NY-ESO-1 engineered PBL in patients receiving a non-myeloablative conditioning regimen, and to determine if patients with metastatic cancer will have clinical tumor regression following this regimen.
时间窗: 4 years
次要结局
- To determine the in vivo survival of cotransduced gene-engineered cells.(4 years)
研究者
研究点 (1)
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