Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-VEGFR2 Gene Engineered CD8+ Lymphocytes
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Number of Participants With a Response to Therapy
研究概览
简要总结
Background:
The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients metastatic cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient s white blood cells with a retrovirus that has the gene for anti-vascular endothelial growth factor receptor (VEGFR2) incorporated in the retrovirus.
Objectives:
- To determine a safe number of these cells to infuse and to see the safety and effectiveness of cell therapy using anti-VEGFR2 gene modified tumor white blood cells to treat recurrent or relapsed cancer.
Eligibility:
- Individuals greater than or equal to 18 years of age and less than or equal to 70 years of age who have been diagnosed with metastatic cancer that has not responded to or has relapsed after standard treatment.
Design:
- Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed
- Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-VEGFR2 cells. {Leukapheresis is a common procedure which removes only the white blood cells from the patient.}
- Treatment: Once their cells have grown the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-VEGFR2 cells and aldesleukin. They will stay in the hospital for about4 weeks for the treatment.
- Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.
详细描述
Background:
- We have constructed a single retroviral vector that contains a chimeric T cell receptor (CAR) that recognizes the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), which can be used to mediate genetic transfer of this CAR with high efficiency (> 50%) without the need to perform any selection. Administration of VEGFR2 CAR transduced cells inhibited tumor growth in several different models in different mouse strains.
- In co-cultures with VEGFR2 expressing cells, anti-VEGFR2 transduced T cells secreted significant amounts of interferon (IFN) gamma with high specificity.
Objectives:
Primary objectives:
- To evaluate the safety of the administration of anti-VEGFR2 CAR engineered cluster of differentiation 8 (CD8)+ peripheral blood lymphocytes in patients receiving a non- myeloablative conditioning regimen, and aldesleukin.
- Determine if the administration of anti-VEGFR2 CAR engineered CD8+ peripheral blood lymphocytes and aldesleukin 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
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Cohort 1 (1x10(6) cells (high dose IL-2)
Patients will receive (1x10(6) cells plus high dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort 1 (1x10(6) cells (high dose IL-2)
Patients will receive (1x10(6) cells plus high dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort 1 (1x10(6) cells (high dose IL-2)
Patients will receive (1x10(6) cells plus high dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort 1 (1x10(6) cells (high dose IL-2)
Patients will receive (1x10(6) cells plus high dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort 2 (3x10(6) cells (high dose IL-2)
Patients will receive (3x10(6) cells plus high dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort 2 (3x10(6) cells (high dose IL-2)
Patients will receive (3x10(6) cells plus high dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort 2 (3x10(6) cells (high dose IL-2)
Patients will receive (3x10(6) cells plus high dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort 2 (3x10(6) cells (high dose IL-2)
Patients will receive (3x10(6) cells plus high dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort 3 (1x10(7) cells (high dose IL-2)
Patients will receive (1x10(7) cells plus high dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort 5 (1x10(8) cells (high dose IL-2)
Patients will receive (1x10(8) cells plus high dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort 3 (1x10(7) cells (high dose IL-2)
Patients will receive (1x10(7) cells plus high dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort 3 (1x10(7) cells (high dose IL-2)
Patients will receive (1x10(7) cells plus high dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort 3 (1x10(7) cells (high dose IL-2)
Patients will receive (1x10(7) cells plus high dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort 4 (3x10(7) cells (high dose IL-2)
Patients will receive (3x10(7) cells plus high dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort 4 (3x10(7) cells (high dose IL-2)
Patients will receive (3x10(7) cells plus high dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort 4 (3x10(7) cells (high dose IL-2)
Patients will receive (3x10(7) cells plus high dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort 4 (3x10(7) cells (high dose IL-2)
Patients will receive (3x10(7) cells plus high dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort 5 (1x10(8) cells (high dose IL-2)
Patients will receive (1x10(8) cells plus high dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort 5 (1x10(8) cells (high dose IL-2)
Patients will receive (1x10(8) cells plus high dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort 5 (1x10(8) cells (high dose IL-2)
Patients will receive (1x10(8) cells plus high dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort 6 (3x10(8) cells (high dose IL-2)
Patients will receive (3x10(8) cells plus high dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort 6 (3x10(8) cells (high dose IL-2)
Patients will receive (3x10(8) cells plus high dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort 6 (3x10(8) cells (high dose IL-2)
Patients will receive (3x10(8) cells plus high dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort 6 (3x10(8) cells (high dose IL-2)
Patients will receive (3x10(8) cells plus high dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort 7 (1x10(9) cells (high dose IL-2)
Patients will receive (1x10(9) cells plus high dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort 7 (1x10(9) cells (high dose IL-2)
Patients will receive (1x10(9) cells plus high dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort 7 (1x10(9) cells (high dose IL-2)
Patients will receive (1x10(9) cells plus high dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort 7 (1x10(9) cells (high dose IL-2)
Patients will receive (1x10(9) cells plus high dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort 8 (1x10(9) cells (low dose IL-2)
Patients will receive (1x10(9) cells plus low dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort 8 (1x10(9) cells (low dose IL-2)
Patients will receive (1x10(9) cells plus low dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort 8 (1x10(9) cells (low dose IL-2)
Patients will receive (1x10(9) cells plus low dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort 8 (1x10(9) cells (low dose IL-2)
Patients will receive (1x10(9) cells plus low dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort 9 (3x10(9) cells (low dose IL-2)
Patients will receive (3x10(9) cells plus low dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort 9 (3x10(9) cells (low dose IL-2)
Patients will receive (3x10(9) cells plus low dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort 9 (3x10(9) cells (low dose IL-2)
Patients will receive (3x10(9) cells plus low dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort 9 (3x10(9) cells (low dose IL-2)
Patients will receive (3x10(9) cells plus low dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort10(1x10(10) cells (low dose IL-2)
Patients will receive (1x10(10) cells plus low dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort10(1x10(10) cells (low dose IL-2)
Patients will receive (1x10(10) cells plus low dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort10(1x10(10) cells (low dose IL-2)
Patients will receive (1x10(10) cells plus low dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort10(1x10(10) cells (low dose IL-2)
Patients will receive (1x10(10) cells plus low dose aldesleukin
干预措施: Fludarabine (Drug)
Cohort11(3x10(10) cells (low dose IL-2)
Patients will receive (3x10(10) cells plus low dose aldesleukin
干预措施: Anti-VEGFR2 CAR CD8 plus PBL (Biological)
Cohort11(3x10(10) cells (low dose IL-2)
Patients will receive (3x10(10) cells plus low dose aldesleukin
干预措施: Cyclophosphamide (Drug)
Cohort11(3x10(10) cells (low dose IL-2)
Patients will receive (3x10(10) cells plus low dose aldesleukin
干预措施: Aldesleukin (Biological)
Cohort11(3x10(10) cells (low dose IL-2)
Patients will receive (3x10(10) cells plus low dose aldesleukin
干预措施: Fludarabine (Drug)
结局指标
主要结局
Number of Participants With a Response to Therapy
时间窗: 5 years
Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment starts or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD.
次要结局
- Number of Participants With Serious and Non-Serious Adverse Events(Date treatment consent signed to date off study, approximately, 33 months and 25 days)
- In Vivo Survival of Chimeric T Cell Receptor (CAR) Gene-engineered Cells(6 years)
研究者
Steven Rosenberg, M.D.
Principal Investigator
National Cancer Institute (NCI)