A Phase II Study Using the Administration of Autologous T-Cells Engineered Using the Sleeping Beauty Transposon/Transposase System to Express T-Cell Receptors Reactive Against Mutated Neoantigens in Patients With Metastatic Cancer
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Response rate
研究概览
简要总结
Background:
A person s white blood cells can be modified in a lab to recognize certain changes in their tumor. Many of these cells are collected from the person, modified, then given back to the person. This may help treat some cancers.
Objective:
To learn if a person s white blood cells modified with T-cell receptors can cause solid tumors to shrink.
Eligibility:
People ages 18-70 who have cancer of the gastrointestinal tract, genitourinary tract, ovary, breast, or lung that has spread, or who have glioblastoma.
Design:
Participants will be screened and have their cells prepared for treatment in another protocol.
Participants will be hospitalized one week before treatment. They will stay approximately 3 - 4 weeks after treatment.
Participants will get the modified white blood cells and chemotherapy through an IV catheter, which is a small plastic tube inserted in a vein.
Participants will take drugs by mouth to prevent infection. They will receive filgrastim as a shot or injection under the skin.
Participants will have tests before, during, and after treatment:
Heart, blood, and urine tests
Chest X-ray
Physical exam
Scans: They will lie in a machine that takes pictures of the body.
Possible apheresis: The participant s blood is removed through a needle in an arm. The blood goes through a machine that removes the white blood cells. The rest of the blood is returned through a needle in the other arm.
Participants will have visits about 6 and 12 weeks after treatment. If they are responding to treatment, they will then have visits every 3-6 months for 3 years. Then they will join another study and be followed about 12 more years.
详细描述
Background:
- The administration of autologous tumor infiltrating lymphocytes (TIL) can mediate complete, durable regressions in 20-25% of patients with metastatic melanoma. Recent studies have shown that these TIL predominantly recognize unique mutated neoantigens expressed by the cancer not shared by other melanomas.
- Administration of bulk autologous TIL to patients with a variety of other solid cancers, including cancers of the gastrointestinal tract and genitourinary tract, have little if any therapeutic impact.
- Recent studies in the Surgery Branch, NCI, have shown that TIL from non-melanoma solid cancers can also contain T-cells reactive against non-shared unique mutated neoantigens expressed in the cancer. The frequency of these T-cells is very low (often < 0.1%) and it is thus difficult to isolate and grow mutation reactive T-cells to levels required for effective therapy.
- In several patients with chemo-refractory metastatic epithelial cancers, we were able to grow an enriched population of neoantigen reactive TIL and administration of these cells mediated several partial regressions of metastatic disease and one complete regression of all metastatic breast cancer now lasting more than 3 years.
- We have now developed approaches to identify these rare neoantigen reactive T-cells from common non-melanoma cancers, to isolate their T-cell receptors (TCR), and to genetically engineer autologous peripheral blood lymphocytes (PBL) using the Sleeping Beauty system to express these TCRs with high efficiency. The neoantigen TCR gene- modified cells can recognize and destroy the autologous cancer in vitro.
- We are now proposing a clinical protocol to treat patients with refractory solid cancers using the adoptive transfer of autologous PBL transposed with genes encoding TCRs that recognize unique mutated neoantigens expressed by the cancer.
Objective:
-To determine the rate of objective response (using RECIST v1.1 criteria) of patients with solid cancers who receive autologous PBL that have been genetically modified with genes encoding TCRs that recognize mutated neoantigens in the autologous cancer using the Sleeping Beauty system.
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 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
1/Sleeping Beauty
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Sleeping Beauty Transposed PBL + high- or low-dose aldesleukin.
干预措施: Fludarabine (Drug)
1/Sleeping Beauty
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Sleeping Beauty Transposed PBL + high- or low-dose aldesleukin.
干预措施: Cyclophosphamide (Drug)
1/Sleeping Beauty
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Sleeping Beauty Transposed PBL + high- or low-dose aldesleukin.
干预措施: Aldesleukin (Drug)
1/Sleeping Beauty
Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Sleeping Beauty Transposed PBL + high- or low-dose aldesleukin.
干预措施: Sleeping Beauty Transposed PBL (Biological)
结局指标
主要结局
Response rate
时间窗: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion
Percentage of patients who have a clinical response to treatment (objective tumor regression)
次要结局
- Immune monitoring(6 weeks (+/-2 weeks) following administration of the cell product)
- Safety and tolerance(6 weeks (+/- 2 weeks) following administration of the cell product)
- Phenotypic and functional characteristics of PBL(2-4 years post cell infusion)