Clinical Trials of Allogeneic Transplantation for Inherited Immune Deficiencies

该项目涉及使用造血干细胞移植治疗遗传性免疫缺陷的治疗性临床试验。我们之前报道了使用非消融调节成功实现长期移植和治愈CGD患者，使用hla匹配的兄弟姐妹供体作为造血干细胞移植的来源。这种方法的问题之一是移植物失败率高（30%）或植入率很低。2004年，我们对一名X-CGD患儿进行了随访移植，该患儿获得了高水平的供体T细胞植入，但长期骨髓植入不到1%。我们成功地在淋巴和髓系中永久转化为几乎100%的供体嵌合，仅使用10 mg/kg的丁硫丹进行调节。这有力地支持使用这种方法来挽救低移植，而不是使用完全的骨髓和淋巴消融调节方案来进行这种挽救治疗。

This project involves the conduct of therapeutic clinical trials for the treatment of inherited immune deficiencies using hematopoietic stem cell transplantation. We previously reported the successful use of non-ablative conditioning to achieve successful long term engraftment and cure of CGD patients using HLA-matched sibling donors as the source of the hematopoietic stem cell graft. One of the problems with this approach was the high rate (30%) of graft failure or very low engraftment. In 2004 we performed a follow up transplant on an X-CGD child previously transplanted by us who had achieved high level donor T cell engraftment but less than 1% long term myeloid engraftment. We demonstrated successful permanent conversion to almost 100% donor chimerism in the lymphoid and myeloid lineages using conditioning with only busulfan at 10 mg/kg. This strongly supports the use of this approach to rescue low engraftment rather than using a fully myelo- and lympho-ablative conditioning regimen for such salvage therapy. We have now opened a clinical trial to treat patients with immunodeficiencies using either a matched related, matched unrelated, or cord blood product and a tolerance inducing conditioning regimen consisting of Campath 1-H and busulfan with sirolimus for graft versus host disease prophylaxis. For patients receiving an unrelated product, total body irradiation is also added to the regimen. To date we have enrolled five patients. The first patient, a 32 year old male with X linked CGD and underlying renal dysfunction, received a 10 out of 10 HLA matched bone marrow product from an unrelated donor. The patient had slow engraftment with a prolonged period of neutropenia and thrombocytopenia. In addition he developed renal failure after receiving one dose of ambisome for a presumed fungal infection. Although the patient received a second stem cell product from the same donor, and achieved full engraftment by chimerism analysis, the patient subsequently declined further treatment, specifically dialysis, and subsequently expired due to uremia and hyperkalemia at 95 days post transplant. The second patient was a 15 year old male with X-SCID and underlying MAI infection who has failed 4 previous attempts at unconditioned haplotransplantation. For his conditioning, he received ATG instead of the Campath as he had only a cord blood product available to him and given his underlying T cell deficiency along with a slower T cell recovery associated with cord blood products, it was opted to use a T cell depleting agent with a shorter half life. He otherwise received both the radiation and busulfan and has been maintained on sirolimus as per protocol. The patient is currently one year post transplant with full engraftment, and doing well to date. The patient has almost completely normal T cell function and appears to be developing B cell function requiring less IVIG. The third patient to undergo transplant was a 32 year old female with Leukocyte adhesion deficiency. She was conditioned with Campath, Radiation and busulfan along with the sirolimus using a 9/10 unrelated donor product. At the time of transplant, the patient had ongoing infections with multiple resistant organisms including acinetobacter and open wounds involving her inner thigh and abdomen. The patient had previously undergone transplant using her mother as a haplotype donor, but rejected the graft. Although she showed evidence of initial engraftment, it was decided to infuse a stem cell boost after treating the patient with rituximab due to her high titres of HLA antibodies. She achieved one hundred percent engraftment, but died of multiorgan failure after developing a sepsis like picture. No organisms were cultured at the time of death and no evidence of GVHD was seen at autopsy. The exact cause of death has therefore not been determined. A fourth patient with interferon gamma deficiency was enrolled; however during workup was not deemed to be eligible. The fifth patient to be enrolled has P47 deficient CGD and previously failed a transplant using her HLA matched sister, but her sister is no longer eligible to donate. The patient will undergo a second transplant in the near future using an HLA 10 out of 10 matched unrelated donor as she has continued to have multiple fungal infections including a fungal meningitis. Meanwhile, we have been investigating the use of an adenosine A2a receptor agonist. Prior studies have shown that agonists specific to this receptor improve outcomes in ischemia models of tissue damage. In collaboration with the investigators at the University of Virginia who have supplied a specific agonist known as ATLe146, we have been testing this drug in a murine model of graft versus host disease. We have seen benefit in attenuating the onset and severity of GVHD in our F1-parental transplant model and experiments are undergoing to further elucidate the exact mechanism of its benefit. A manuscript has been prepared and submitted for publication. We have also begun working on trying to further define the role of dendritic cells in GVHD using this same murine transplant model. Finally we are in the process of developing a pre clinical trial to use this drug for the treatment of chronic GVHD and eventually as a prevention of GVHD in the transplant regimen. Using a blister model established in our lab with Dr John Gallin and Kol Zarember, we plan to apply the drug topically to assess its effects on inflammation and cellular responses to damage signals. We are also in the process of establishing a pilot trial in collaboration with the Adenosine Therapeutics to test the adenosine agonist in patients with acute graft versus host disease.