A Phase 1 Dose-escalation Study Testing the Feasibility and the Tolerance of Infusion of a Specific Third Party Suicide Gene-transduced Anti-HLA-DPB1*0401 CD4+ T Cell Clone in HLA-DPB1*04:01 Positive Tumor Recipients Receiving an Allotransplant From a HLA-DPB1*04:01 Negative Donor.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- determine maximal tolerated dose of infusion of a third party suicide gene-transduced anti-HLA-DPB1*04:01 CD4+ T cell clone in HLA-DPB1*04:01 tumor positive recipients receiving an allo-HSCT from a HLA-DPB1*04:01 negative alternative donor.
研究概览
简要总结
For several decades, allogeneic hematopoietic stem cell trans-plantation (allo-HSCT) has remained an important strategy in the management of patients with high-risk hematological malignancies. The acceptance of umbilical cord blood (UCBT) and haploidentical grafts (Haplo) as viable alternative donors for allo-HSCT has increased the options for patients with no matched donors and now ensures that a donor can be identified for virtually all patients. Relapsed disease is a principal threat to these patients and affects 30-50% of them. The therapeutic options for these relapsing patients are diverse but remain largely ineffective in altering their long-term outcomes. Therefore, pre-emptive treatment post allo-HSCT is considered.
MHC (major histocompatibility complex) class II molecules are a family of molecules normally found only on hematopoietic cells. cell-surface proteins are responsible for the regulation of the immune system in humans and are important in disease defense.
They are the major cause of organ transplant rejections. Different HLA-DPB1 alleles exist in the general population. HLA-DPB1*04:01 is the most frequent (70.5%) while HLA-DPB1*02:01 represents 32% and HLA-DPB1*03:01 20%. In allo-HSCT, the donor and the recipient may express different HLA-DPB1 molecules. HLA-DPB1 matching status has an impact on GVL (graft versus leukemia) and GVHD. In recipients of HSCT, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status of other HLA molecules.. Therefore, one could anticipate that a mismatched of HLA class II could induce a selective GVL reactivity without GVHD.
HLA-DP-expressing B cell and myeloid malignancies can be recognized and lysed by HLA-DP-specific T cells. The majority of leukemic cells (Acute Myeloid Leukemia, Acute Lymphoid Leukemia, Chronic Lymphoid Leukemia) express HLA-DP. A T cell clone recognizing specifically HLA-DPB1*0401 has been developed as a permanent cell line This clone has been demonstrated to be able to kill HLA-DPB1*0401 positive leukemic cells. In addition, this clone harbors a special suicide gene allowing the destruction of the clone in presence of a specific anti-viral drug named ganciclovir.
We hypothesize that infusion of a third party suicide gene-transduced T cell clone directed against HLA-DPB1*401 might protect against possible relapse of hematological malignancies.
We propose to inject iv escalating dose of a third party clone recognizing HLA-DPB1*04:01, 4 to 5 months following transplantation (when immunosuppressive drugs have been discontinued) in patients HLA-DPB1*04:01 positive with a donor HLA-DPB1*04:01 negative to evaluate the feasibility, toxicity, benefits of this immune intervention.
详细描述
Rationale Despite graft-versus-tumor effect, relapse remains one of the main causes of morbidity and mortality in allo-HSCT recipients. Forty to 50% of deaths following allo-HSCT are due to disease relapse. In case of relapse, the prognosis is very poor and disease burden remains a challenge for the use of adoptive cellular therapy alone. The 3 year overall survival (OS) in case of post-transplant relapse is dismal. The post-transplant period is characterized by a prolonged phase of immunodeficiency leading to increased vulnerability to infections and risk of relapse. For this reason, maintenance or pre-emptive therapies for patients in CR (complete remission) are now considered to prevent future relapse. Following allo-HSCT, the recognition by donor T lymphocytes of recipient HLA antigens may result in different consequences. On one side, T cells may recognize antigens present on malignant cells and eradicate residual disease or prevent tumor relapse. On the other side, injection of unselected T cells may induce a graft-versus-host-disease (GVHD).
HLA-DPB1 is one of MHC class II molecule lying centromeric to other class II loci on chromosome 6p21.3. Increase recombination events are found in the region between the HLA-DP loci and other class II loci, explaining the relative lack of linkage disequilibrium (LD) between HLA-DP (* HLA- DP: Human Leucocytes Antigen (DP allele))and the rest of MHC haplotype. For this reason, it is difficult to find a donor matched for DPB1 in addition to other classic HLA molecules. In sibling donors, the rate of incompatibility has been estimated to be as high as 10.9% and in unrelated donors a mismatch rate can be up to 89%. HLA-DPB1 is often not taken into consideration in donor selection. However HLA-DPB1 matching status has an impact on GVL and GVHD. In recipients of HSCT, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status of other HLA molecules. HLA class II molecules expression is mainly restricted to hematopoietic cells. Therefore, one could anticipate that a mismatched of HLA class II could induce a selective GVL reactivity without GVHD. However, HLA class II expression can be upregulated on various tissues following exposure to pro-inflammatory cytokines with a risk of GVHD as it is the case following some conditioning regimens or infections.
The frequency of the different HLA-DPB1 alleles in the general population is well known: HLA-DPB1*04:01 is the most frequent (70.5%) HLA-DPB1*02:01 and and HLA-DPB1*03:01 represent 32% and 20% respectively. 96% of leukemic cells could potentially be targeted with only three CTL clones directed against HLA-DPB1*04:01, 03:01 and 02:01.
HLA-DP-expressing B cell and myeloid malignancies can be recognized and lysed by HLA-DP-specific CD4+ cells ( CD4+ : cluster of differentiation 4+). The majority of leukemic cells (AML, ALL, CLL) express HLA-DP. CD4+ cytotoxic T cell (CTL) clones recognizing specifically HLA-DPB1*04:01 can be identified and have been demonstrated to be able to kill HLA-DPB1*04:01 positive leukemic cells.
In addition, it has already been shown that HLA-DP-specific CD4+ T cells can induce graft-versus-leukemia reactivity in the presence or absence of graft-versus-host disease. In this study the presence of HLA-DP-specific CD4+ T cells correlated with the clinical response to DLI.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients HLA-DPB1*04:01 positive, with confirmed diagnosis of hematologic malignancies (AML, Myelodysplasic and myeloproliferative syndrome, ALL, non-Hodgkin's lymphoma, Hodgkin's disease, CLL), undergoing an allo-HSCT using a HLA-DPB1*04:01 negative donor.
- •The graft can be PBSC (peripheric blood stem cells) or bone marrow.
- •Patients aged between 18-75 years.
- •Patients in complete remission or >50% of response (for lymphoma) at time of transplant.
- •have a donor with no contra-indications for mobilization of peripheral blood stem cells using G-CSF (colony-stimulating factors)
- •Affiliation number to the National Health Care System
- •Lack of reactivity of the clone against the donor's cells (PHA-blasts prepared for from PBMCs).
- •For cord blood transplants: cord blood must be HLA-DPB1*04:01 negative and the HLA compatibility (A, B, DR) between the cord blood and the recipient must be 4/6, 5/6 or 6/
- •ECOG <=2 or Karnofsky >60%
- •neutrophils ≥ 1 000 cells /μl and/or platelets ≥ 50 000 cells/μl (growth factor allowed)
排除标准
- •pregnant or breastfeeding woman
- •patient refusing contraception measure
- •Adult patients under guardianship, curatorship or justice protection
- •Patients with post-transplant relapse within the clone injection time (before D100)
- •Karnofsky performance score below 60%or ECOG >2
- •Acute and chronic heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease.
- •Severe liver failure (bilirubin >30 µmoles/L, SGPT (Serum Glutamo-Oxalacetic Transaminase)> 4 X upper limit of normal).
- •Impaired renal function (creatinine clearance < 30 ml/min)
- •Acute GVHD > grade 1
- •Active uncontrolled infection.
- •Denied to provide informed consent
- •Severe neurological or psychiatric disorders as determined by the study physician.
- •Treatment with other investigational drugs following allogeneic transplantation.
研究组 & 干预措施
CTL 19 : T cell therapy
Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg. After study of toxicity of the 4 injected patients, choice has been made to stop the CRM method to choose the dose and to test only 2 doses for each last patients : 100 x 10^4 cells/kg (actual level 5) and 500 x 10^4 cells/kg (choice based on compassionnal injections data at the level 5)
干预措施: CTL 19 (Combination Product)
结局指标
主要结局
determine maximal tolerated dose of infusion of a third party suicide gene-transduced anti-HLA-DPB1*04:01 CD4+ T cell clone in HLA-DPB1*04:01 tumor positive recipients receiving an allo-HSCT from a HLA-DPB1*04:01 negative alternative donor.
时间窗: 4 weeks after CTL injection
the most likely side effects of the injection of the clone is the induction of an acute GVHD (severity measured by organ staging and overall clinical grading). acute GVHD will be evaluated for each patient. Maximal tolerated dose is defined as : none acute GVHD for 3 patients on 3 or for at least 5 patients on 6. A standard phase 1 dose-escalation study will be used: Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg After study of toxicity of the 4 injected patients, choice has been made to stop the CRM method to choose the dose and to test only 2 doses for each last patients : 100 x 10\^4 cells/kg (actual level 5) and 500 x 10\^4 cells/kg (choice based on compassionnal injections data at the level 5)
次要结局
- survival and persistence of the clone injected(6 hours after clone injection, 8 days post-injection, 15 days post-injection, 30 days post-injection, 60 days post-injection, 6 months post injection, 12 months post injection)
- immune reconstitution(day of clone injection, 30 days after clone injection, 60 days after clone injection, 9 months after clone injection, 12 months after clone injection)
- complete remission(12 months post allograft)
- survival(12 months post allograft)
- mortality(12 months post allograft)
- incidence of relapse(12 months post allograft)
- GVHD incidence(12 months post allograft)
- side effects of Clone(12 months post allograft)