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 (GVHD) prophylaxis. For patients receiving an unrelated product, total body irradiation is also added to the regimen. To date we have enrolled 16 patients and transplanted 14. 12 of the patients were transplanted using an unrelated donor and we have seen very limited GVHD with only one patient having Grade 2 skin GVHD. We have used cord blood in two cases. One for a patient with P67 deficient CGD and who failed to engraft. The belief is that the Campath impacted negatively with the ability of the more naive T cells in a cord blood graft preventing engraftment, and the protocol has been modified to use ATG in the case of a cord blood product. The other patient to receive cord blood was transplanted for X-linked Severe Combined Immunodeficiency. He was conditioned with ATG instead of Campath and is currently 3 years out with full engraftment, no evidence of graft versus host disease, and normal immune function. We have had three deaths on the protocol, one patient with CGD who died due to renal failure unrelated to transplant and subsequent refusal to continue dialysis. The second patient had leukocyte adhesion deficiency and died due to sepsis, despite evidence of engraftment. This patient had failed a previous transplant, was infected at the time of the transplant, and was also highly alloimmunized from previous granulocyte infusions. The third patient was transplanted for Rag 1 deficiency, tolerated transplant extremely well and engrafted successfully but died due to accidental drug overdose. We have transplanted a number of patients with ongoing infections including fungal osteomyelitis of the spine and/or meninges and in some cases have used granuloctye infusions during the period of transplant-induced neutropenia with no adverse effects. To date, all patients with CGD transplanted with an ongoing infection have done well without any significant morbidity or mortality due to infection progression during the transplant course. Overall our results for the CGD patients in particular are especially promising with an overall survival of 10 of 11, and an overall engraftment rate of 10 of 11. The patient with failure to engraft had autologous recovery and is being considered for a second transplant. We are getting many referrals and anticipate that we will continue to transplant 4-5 patients a year. 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 tested 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 have published this data. Further studies have shown a role for T regulatory cells (Tregs) as part of the mechanism of the drugs effects. We also used a clinically approved adenosine agonist (Regadenosan) in our model in anticipation of setting up a clinical pilot trial;however we have determined that the effects on GVHD are very specific to the A2a receptor. We have now established a new CRADA with PGxHealth, formally Adenosine Therapeutics, to study other formulations of the A2a receptor agonists and have seen similar effects on T regs, both invitro and invivo, by these agonists and have submitted our results for presentation to the American Society of Hematology 2010 meeting. In addition, we have found that rapamycin also works to reduce TH17 cells in our model and we are studying combination drug therapies now in our model. We are continuing to study the mechanisms of these drugs overall and hope eventually to put these into clinical use.
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