A Phase I/II Open Label Non Randomized Study, Monocentric, Single Arm, Evaluating Safety and Efficacy of Gene Therapy of FHL 3 Caused by Mutations in the Human UNC13D Gene by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced ex Vivo With the UNC13D LV Vector Expressing the UNC13D cDNA
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 5
- 试验地点
- 2
- 主要终点
- Incidence of Transplantation Related Mortality (TRM)
研究概览
简要总结
The investigators propose to replace HLA- partially compatible allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for FHL type 3 patients, with autologous transplantation of immunoselected gene-modified CD34+ cells, combined with transduced autologous T-cell each time this is possible and also to propose this alternative treatment as salvage in case of failure of a previous allogeneic HSCT. This approach should avoid the severe immunological complications (failure to engraft, acute or chronic graft versus host disease (GVHD)) and conditioning toxicities such as severe Veno-Occlusive Disease (VOD). As the clinical manifestations of FHL type 3 patients are triggered by opportunistic viral infections (often EBV) and can be poorly controlled or only transiently controlled by the available drugs , providing the patient after the conditioning with immediately functional autologous cytotoxic T-cells could be key to maintain the control of the viral infection and hopefully its eradication awaiting for the hematopoietic reconstitution . This procedure should avoid any reactivation of the viral infection and thus improving the patients' overall survival and event-free survival while clearing the ongoing triggering infections.
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
- 3 Months 至 45 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient aged from 3 months up to 45 years old.
- •Patient with a FHL caused by mutation of the UNC13D gene.
- •Complete remission is defined by the normalization of clinical and laboratory parameters:
- •Resolution of fever
- •Resolution of splenomegaly or reduced and isolated splenomegaly.
- •Improvement of cytopenia: absolute neutrophil count > 500/µl AND platelets cout > 100 000/ µl (unsupported by transfusion)
- •Normalization of serum fibrinogen level (Fibrinogen ≥1.5g/l)
- •Resolution of hyperferritinemia (Ferritin level < 2000µg/l)
- •Normalization of T-cell activation
- •Patient eligible for an allogeneic HSCT in absence of an HLA geno-identical donor (at diagnostic or 6 months after failure of a previous HSCT (rejection or loss of the graft))
- •Patint or parental, guardian's patient signed informed consent.
- •For patients of childbearing age : willing to use an effective method of contraception* during the trial and for at least 12 months post-infusion
- •Affiliation to Social Security
排除标准
- •Active CNS encephalitis related to HLH
- •Existence of a matched -sibling donor
- •Unwillingness to return for follow-up during the 2 years study and lifelong for off study review.
- •HIV-1 or 2 or HTLV1 infections.
- •Patient on AME (state medical aid) (unless exemption from affiliation)
- •Pregnancy or breast feeding in a post-partum female
- •Diagnosis of significant psychiatric disorder of the subject that could seriously impeded the ability to participate in the study
- •Known allergies, hypersensitivity, or intolerance to any of busulfan, fludarabine, rituximab, G-CSF, plerixafor or excipients, or similar compounds
- •Unable to tolerate general anesthesia and/or apheresis
- •Participation in another clinical study with an investigational drug within 30 days of inclusion.
- •Uncontrolled HLH manifestation
研究组 & 干预措施
MUNC
干预措施: MUNC-CD34 (Genetic)
MUNC
干预措施: MUNC-T3 (Genetic)
结局指标
主要结局
Incidence of Transplantation Related Mortality (TRM)
时间窗: up to 6 months post treatment
Frequency and severity of clinical AEs and laboratory parameters
时间窗: throughout the whole period of the research, up to 60 months
Adverse event will be measured using CTCAE
Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment
时间窗: At 12 months post treatment
Bone marrow analysis and VISA
Detection of Replication -Competent Lentivirus (RCL)
时间窗: at 3, 6 and 12 months post treatment, then yearly up to 60 months
次要结局
- Neutrophil and platelet recovery(throughout the whole period of the research, up to 60 months)
- Quantification of the transgene copy number (VCN) on drug substance at time of cryopreservation, on PBMC, sorted T-CD3+ and sorted NK cells(at 1, 2, 3, 6, 9, 12, 18 and 24 months post treatment)
- Quantification of the UNC13D RNA on PBMC(at 1, 2, 3, 6, 9, 12, 18 and 24 post treatment)
- Quantification of Munc13.4 protein level in the drug substance and on peripheral blood mononuclear cells and on sorted CD3+ and CD56+ cells in function of their number(at 6, 12 and 24 months post treatment)
- Determination of the total number of T-cells and distribution of different subpopulations(at 1, 2, 3, 6, 12, 18 and 24 months post treatment)
- Correction of degranulation function in T-CD3(at 6 months and 24 months post treatment)
- Integration site analyse study(at 24 months post treatment)
- Needs of PICU support(up to 24 months post treatment)
- Endothelial complications(up to 24 months post treatment)
- Infectious diseases(up to 24 months post treatment)
- Estimate of the cost of the complete procedure, from mobilisation to transplant(up to 24 months post treatment)
- stimate of the 24 months total cost(up to 24 months post treatment)