Clinical Trials of Allogeneic Transplantation for Inherited Immune Deficiencies

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Abstract

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. [unreadable] 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 four 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 is a 15 year old male with X-SCID and underlying MAI infection who has failed 4 previous attempts an 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 30 days post transplant with full engraftment, and doing well to date. The anticipated date of discharge will be 38 days post transplant. The other two patients are awaiting completion of their work up prior to transplant. [unreadable] 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. We have also begun working on trying to further define the role of dendritic cells in GVHD using this same 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.