Suicide Gene Therapy for Donor Lymphocytes Infusion After Allogeneic Hematopoietic Stem Cell Transplantation: a Phase I/II Clinical Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 2
- 主要终点
- Incidence of "severe" GHVD (acute grade >II or chronic extensive) following DLI-TK and treatment with GCV
研究概览
简要总结
The main complications of allogeneic hematopoietic stem cell transplantation (HSCT) include graft-versus-host disease (GVHD) and poor immune reconstitution leading to severe infections and leukemia relapse. Mature donor T-cells present in the transplant facilitate T-cell reconstitution but also induce GVHD, which itself impairs immune reconstitution. We have developed a strategy of alloreactive T-cell depletion, using T-cells expressing the Herpes simplex thymidine kinase (TK) suicide gene combined with a ganciclovir (GCV) treatment. This system permits the selective elimination of dividing TK+ T-cells in vivo. To test this hypothesis in preclinical settings, we have previously developed several experimental models of GVHD using TK+ T-cells in mice. The demonstration that a preventive treatment with GCV administered close to the time of HSCT could control GVHD brought the proof of concept. We now propose a clinical trial to test whether donor lymphocytes infusion (DLI) using TK-transduced cells permits to induce a graft-versus-tumor (GVT) effect for treatment of relapse after HSCT, while GVHD can be controlled by GCV treatment.
详细描述
DLI-TK is administered either after failure of 1 or several previous standard (std-) DLI of, defined after a minimal follow-up of 2 months after the last injection. To prepare DLI-TK, donor T-cells are transduced with a retroviral vector encoding TK. Transduced cells are selected using a CliniMACS device (MYLTENYI). In case of previous std-DLI received, the DLI-TK cell dose is adjusted to be below or equal to the maximal cell dose previously received in std-DLI. No comparison is planned in the analysis.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Hematological malignancy.
- •Previous allogeneic hematopoietic stem cell transplantation.
- •Relapse diagnosed at the molecular, cytogenetic, or cytological level.
- •Failure of a previous stdILD or inclusion in first intention without previous stdDLI.
- •Age > 18 years and < 70 years at the time of inclusion. For patients between 15 and 18 years of age, a case-per case inclusion will be studied.
- •Performance status considered on the score Eastern Cooperative Oncology Group (ECOG) <
- •Life expectation 1-month-old superior.
- •Signed written informed consent.
- •Negative human chorionic gonadotropin (HCG) in the 7 days preceding the inclusion for women in age of procreation.
- •Membership of the French national insurance.
排除标准
- •Grade >II acute GVHD or chronic extensive GVHD at the time of inclusion.
- •Patient receiving an immunosuppressive treatment for GVHD treatment at the time of inclusion.
- •Dysfunction of liver (alanine aminotransferase / aspartate transaminase (ALAT/ASAT) > 5 N, or bilirubin > 50 µM), or of the renal function (creatinine clearance < 30 ml / min).
结局指标
主要结局
Incidence of "severe" GHVD (acute grade >II or chronic extensive) following DLI-TK and treatment with GCV
时间窗: during the 12 months of follow-up
Incidence of "severe" GHVD (acute grade \>II or chronic extensive) following DLI-TK and treatment with GCV
次要结局
- The incidence of GVHD of any grade after DLI-TK(during the 12 months of follow-up)
- The anti-tumoral efficiency of DLI-TK to treat the relapse of the hematological malignancy(during the 12 months of follow-up)
- The survival and the survival without disease after DLI-TK(during the 12 months of follow-up)