Phase II Study of Metastatic Melanoma Using a Chemoradiation Lymphodepleting Conditioning Regimen Followed by Infusion of Anti-Mart-1 and Anti-gp100 TCR-Gene Engineered Lymphocytes and Peptide Vaccines
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Complete Response Rates for Patients With Metastatic Melanoma
研究概览
简要总结
Background:
- Melanoma antigen recognized by T-cells (MART-1) and gp100 are two genes found in melanoma cells. An experimental procedure developed for treating patients with advanced melanoma uses these genes and a type of virus to make special cells called anti-MART-1 and anti-gp100 cells, which are designed to destroy the patient's tumor. The cells are created in the laboratory using the patient's own tumor cells or blood cells.
- The procedure also uses one of two vaccines-the anti-MART-1 peptide or the anti-gp100 peptide-to stimulate cells in the immune system that may increase the effectiveness of the anti-MART-1 and anti-gp100 cells. Both vaccines are made from a virus that is modified to carry a copy of the MART-1 gene or gp100 gene. The virus cannot cause disease in humans.
Objectives:
- To evaluate the safety and effectiveness of anti-MART-1 and anti-gp100 cells and peptide vaccines for treating patients with advanced melanoma.
Eligibility:
- Patients 18 years of age with metastatic melanoma for whom standard treatments, including aldesleukin (IL-2) therapy to boost immune response, have not been effective.
Design:
- Participants have an initial evaluation with complete medical history, as well as scans, x-rays, and other tests as directed by researchers. Most of the treatments for this study will be given on an inpatient basis.
- Before the treatment begins, participants will undergo leukapheresis (removal of selected blood cells) to obtain cells for preparing the anti-MART-1 and anti-gp100 cells, and for later stem cell transplantation.
- Preinfusion treatment: 5 days of chemotherapy and 2 days of total-body irradiation to prepare the immune system for receiving the anti-MART-1 and anti-gp100 cells.
- Infusion of cells, followed by IL-2 treatment to improve immune response. IL-2 is given as a 15-minute infusion through a vein every 8 hours for a maximum of 15 doses (over 5 days).
- After the cell infusion, participants will be divided into two groups and will receive either the gp100 peptide or MART-1 vaccine, given once a week for 3 weeks. Participants will also have stem cell transplantation (from previously collected stem cells) to promote cell survival.
- Periodic follow-up clinic visits after hospital discharge for physical examination, review of treatment side effects, laboratory tests and scans every 1 to 6 months.
详细描述
Background:
- We have engineered human peripheral blood lymphocyte (PBLs) to express a T-cell receptor (TCR) that recognizes human leukocyte antigens (HLAA*0201) restricted epitopes derived from the gp100 or the MART-1 melanoma antigen.
- We constructed single retroviral vectors that contain both Alpha and Beta T cell receptor (TCR) chains and can mediate genetic transfer of this TCR with high efficiency (greater than 30 percent) without the need to perform any selection.
- In co-cultures with HLA-A*0201 positive melanomas these TCR transduced T cells secreted significant amount of interferon-gamma (IFN-y) but no significant secretion was observed in control co-cultures.
- gp100:154-162 TCR or MART-1:27-35 TCR transduced T-cells could efficiently kill HLAA*0201 positive tumors. There was little or no recognition of normal fibroblasts.
- Adoptive transfer of either of these TCR transferred gene modified peripheral blood lymphocyte (PBL) following a nonmyeloablative lymphodepleting regimen could mediate tumor regression in from 13-30 percent of patients with metastatic melanoma though no complete responses were seen.
Objectives:
Primary objectives:
- In cohort 1 and 2, to determine if the administration of both the anti-gp100:154-162 TCR-engineered and anti- MART-1:27-35 TCR-engineered peripheral blood lymphocytes (PBL), aldesleukin and either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide to patients following a chemoradiation lymphodepleting preparative regimen will result in complete tumor regression in patients with metastatic melanoma.
- In cohort 3 and 4, to determine if the administration of both the anti-gp100:154-162 TCR-engineered and anti-MART-1:27-35 TCR-engineered CD8+ peripheral blood lymphocytes (PBL), aldesleukin and either the gp100:154-162 peptide or the MART-1:26-35(27L) peptide to patients following a chemoradiation lymphodepleting preparative regimen will result in complete tumor regression in patients with metastatic melanoma.
- Determine whether the administration of the specific vaccine (the gp100:154-162 peptide or the MART-1:26-35(27L) peptide) can increase the persistence of the specific transferred cells (anti-gp100:154-162 TCR PBL, anti-gp100:154-162 TCR CD8+ PBL, the anti-MART- 1:27-35 TCR PBL, or the anti-MART-1:27-35 TCR CD8+ PBL), respectively.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
TBI 600cGy + PBL + HD IL-2+gp100:154-162
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Montanide ISA 51 VG (Drug)
TBI 600cGy + PBL + HD IL-2+gp100:154-162
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Radiation (Procedure)
TBI 600cGy + PBL + HD IL-2+gp100:154-162
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Aldesleukin (Drug)
TBI 600cGy + PBL + HD IL-2+gp100:154-162
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Fludarabine (Drug)
TBI 600cGy + PBL + HD IL-2+gp100:154-162
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Cyclophosphamide (Drug)
TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L)
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Montanide ISA 51 VG (Drug)
TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L)
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Radiation (Procedure)
TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L)
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Aldesleukin (Drug)
TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L)
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Fludarabine (Drug)
TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L)
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Cyclophosphamide (Drug)
TBI 600cGy+PBL+HD IL-2+MART-1:26-35(27L)
Day 0:Autologous transduced CD8+PBL (anti-gp100:154 TCR PBL and anti-MART-1 F5 TCR PBL) infusion will be administered intravenously over 20 to 30 minutes (minimum 5 x 10e8 and up to a maximum of 2 x 10e11 of each transduced lymphocyte population). One mg of either the gp100:154-162 or the MART-1:26-35(27) emulsified in IFA by deep subcutaneous injection into each thigh to be administered prior to cell infusion and on days 7 and 14. Within 24 hours of cell infusion administration of aldesleukin will be initiated as 720,000 IU/kg/dose IV over 15 minutes every 8 hours for up to 5 days (maximum 15 doses).Radiation: 2Gy of TBI twice on day -2 and once on day -1 (total dose 6 Gy) at a rate of 0.07 Gy/minute.
干预措施: Anti-MART-1 F5 TCR PBL (Genetic)
结局指标
主要结局
Complete Response Rates for Patients With Metastatic Melanoma
时间窗: Every 4-6 weeks after initial treatment regimen. If the patient has stable disease or tumor shrinkage, complete evaluations will be repeated every 1-3 months.
Complete response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response is a disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression is at least a 20% increase in the sum of the LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD.
次要结局
- Toxicity Profile(32 months)
研究者
Steven Rosenberg, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)