Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T-cell Transfusion to Withdraw Immunosuppressive Drugs From Recipients of a Previous HLA Matched Living Donor Kidney Transplantation .
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Percentage of patients no longer dependent on immunosuppressive drugs to maintain normal renal function.
研究概览
简要总结
The study will determine whether patients with functioning Human Leukocyte Antigen (HLA) matched kidney transplants for at least one year and who want to discontinue immunosuppressive drugs can be treated with Total Lymphoid Irradiation (TLI) and rabbit Anti-Thymocyte Globulin (rATG) and an HLA matched donor hematopoietic progenitor cell infusion such that their drugs are successfully withdrawn while maintaining normal renal function.
详细描述
This is a single-center, open-label study in adult renal transplant patients.Twenty five patients with functioning HLA matched living donor kidney transplants will receive TLI, rATG and an infusion of cluster of differentiation (CD)34+ (Stem/Progenitor cells) selected granulocyte colony-stimulating factor (G-CSF) mobilized blood cells combined with CD3+ T cells (Stem/ Progenitor cells) from their transplant donors.Transplant recipients will have their maintenance Immunosuppressive drugs adjusted for four weeks before starting the TLI and ATG conditioning regimen. Mycophenolate Mofetil (MMF) will be maintained at 0.5 gm twice a day per day during this four week period during TLI and ATG treatments, and increased to 1 gram twice a day immediately after the completion of TLI at day 14.
MMF will be tapered starting 6 (six) months later. Tacrolimus levels will be targeted to blood trough levels of 4-6 ng/ml in the month before the start of the conditioning regimen. This target would be increased to 8-10 ng/ml at the start of the TLI and ATG conditioning regimen. At serial time points (1) graft function will be monitored. (2) chimerism will be measured in recipient white blood cell subsets, (3) protocol biopsies of the graft will be obtained. An attempt will be made to discontinue Tacrolimus at 12 months if (1) chimerism is detectable for least 180 days after the CD34+ and CD3+ cell infusion, (2) there is no Graft Versus Host Disease (GVHD), (3) there is stable graft function without clinical rejection episodes and (4) lack of histological rejection on protocol biopsies.
Recipients will be given the target dose of ≥ 8 x 10^6 CD 34 + cells/Kg and a dose of 5x10^6 CD3+ cells/Kg.The dose would be sequentially increased to 10, 15 and 25 x 10^6 CD3+ cells/Kg if fewer than 4 of 5 consecutive patients achieve whole blood chimerism of ≥ 30 % at 60 days. If 4 of 5 patients achieve this level of chimerism, then all subsequent enrolled patients will receive this dose.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All consenting adults of age 18 years and older with previous HLA matched sibling living donor renal transplants who still have their HLA- matched kidney donor available, and who have no history of acute or chronic rejection.
- •Patients who agree to participate in the study and sign an Informed Consent
- •The HLA-matched donor meets the Stanford Bone Marrow Transplant criteria for stem cell donation, agrees to participate and has signed an Informed Consent.
- •The pair is confirmed to be HLA-matched (2 haplo type match) as determined by the histocompatibility laboratory at Stanford.
- •Patients who have no known contraindication to the administration of rabbit ATG or radiation
- •Males and females of reproductive potential who agree to practice a reliable form of contraception for at least 18 months post transplant.
排除标准
- •Known allergy to ATG or a known allergy to rabbit proteins.
- •History of malignancy with the exception of non-melanoma skin malignancies.
- •Pregnant women or nursing mothers.
- •Serological evidence of HIV, Hepatitis B (HepBsAg+) or Hepatitis C infection.
- •Leukopenia (with a white blood cell count < 3000/mm3) or thrombocytopenia (platelet count < 100,000/mm3)
- •Previous history of acute or chronic rejection of the kidney transplant or recurrence of the original disease.
- •Screening kidney biopsy demonstrating acute or chronic rejection, recurrence of original disease or interstitial fibrosis/Tubular Atrophy (IF/TA) score greater than 1.
研究组 & 干预措施
Immune tolerance, Kidney transplantation
Intervention: HLA matched living donor recipients of a functioning kidney transplant graft at one year will receive hematopoietic cell transplantation and Total lymphoid irradiation. The intervention is intended to induce immune tolerance such as to allow withdrawal of the immunosuppressive drugs. Immune tolerance is achieved through the development of donor/recipient mixed chimerism following combined kidney and hematopoietic stem cell transplantation from the living donor.
干预措施: Hematopoietic cell transplantation (Biological)
Immune tolerance, Kidney transplantation
Intervention: HLA matched living donor recipients of a functioning kidney transplant graft at one year will receive hematopoietic cell transplantation and Total lymphoid irradiation. The intervention is intended to induce immune tolerance such as to allow withdrawal of the immunosuppressive drugs. Immune tolerance is achieved through the development of donor/recipient mixed chimerism following combined kidney and hematopoietic stem cell transplantation from the living donor.
干预措施: Total Lymphoid irradiation (Radiation)
结局指标
主要结局
Percentage of patients no longer dependent on immunosuppressive drugs to maintain normal renal function.
时间窗: six months to up to five years post stem cell transplant
A patient will be considered no longer dependent if able to maintain normal renal function after coming off immunosuppressive medications.
次要结局
- Percentage of patients experiencing biopsy proven rejection episodes requiring treatment requiring corticosteroids.(One year to five years)
- Percentage of patients experiencing graft loss.(One year to five years)
研究者
Stephan Busque
Professor for Surgery
Stanford University