Clinical Trials of Allogeneic Transplantation for Inherited Immune Deficiencies

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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. In 2007 we initiated a clinical protocol using busulfan, Campath and low dose TBI and treated 44 patients with CGD, 39 of whom received an unrelated donor graft. and the results were recently published in the Journal of Clinical Immunology. (Parta et al. JCI). Overall our results for the CGD patients in particular are especially promising with an overall survival of 38 out of 47 and an overall long term engraftment rate of 35 out of 38 evaluable. We are also the only centre to have transplanted patients with the P40 form of CGD demonstrating complete reversal of refractory colitis in this unique subset. In follow up to that study we have opened a new protocol modeling on our previous results using a higher cell dose and post transplant cyclophosphamide to mitigate the increased risk of GvHD from the higher cell dose. At this point, we have enrolled 6 patients on this protocol with one death early due to his underlying progressive pulmonary disease. One patient did not receive the post transplant cyclophosphamide due to a low cell dose and although had early engraftment, rejected at day 85. He remains alive and well. The other four patients are doing well with only one patient having mild GvHD of the skin to date. At the end of 2014, we also initiated a clinical trial using haploidentical donors and transplanted a patient with no matched donors available. This patient had an ongoing infection refractory to all standard therapy involving the heart and we therefore proceeded with a parental graft and using post-transplant cyclophosphamide. We obtained good engraftment with only limited graft versus host disease. This patient is now almost 2 years out with complete resolution of his infection and has been described in publication. (J Clin Immunol. 2015 Oct;35(7):675-80). We enrolled a total of 7 patients on this protocol but experienced severe GvHD in the last three patients with two of the patients succumbing to complications related to GvHD. The third patient is doing well having recovered from the GvHD. This protocol is now closed and an amendment is being prepared to continue with haploidentical transplants but with lmodifications to try to decrease the incidence of severe GvHD. In order to determine the outcomes of transplant for CGD in general, we have become a part of the Primary Immune Deficiency Treatment Consortium ( J Allergy Clin Immunol. 2014 Feb;133(2):335-47) and have initiated a collaborative protocol to review the results of transplant done for CGD in North America. We have enrolled over 100 previously transplanted patients and are preparing a manuscript on some of the data accrued from these patients. We have also been obtaining stool samples pre and post transplant for microbiome analysis, which is a substudy being done in collaboration with Emilia Falcone (NIAID) and Julie Segre (NHGRI). In related laboratory pre-clinical studies, we have been investigating the use of an adenosine A2a receptor agonist to prevent or treat graft versus host disease (GVHD). Prior studies have shown that agonists specific to this receptor improve outcomes in ischemia models of tissue damage. We have seen benefit in attenuating the onset and severity of GVHD in our F1-parental transplant model and have published this data in the Journal of Leukocyte Biology. Further studies have shown a role for T regulatory cells (Tregs) as part of the mechanism of the drugs effects. We have now established a CRADA with Lewis and Clark Pharmaceuticals (formally Adenosine Therapeutics/PgxHealth/Forest Labs) to study other formulations of the A2a receptor agonists and have seen similar effects on Tregs, both in vitro and in vivo, by these agonists. This data was published in the Journal of Immunology (J Immunol. 2013 Jan 1;190(1):458-68) More recently, we have published a new method to assess these agonists in a more rapid and efficient manner prior to beginning in vivo murine studies (Sci Rep. 2017 Mar 20;7:44816). We also had a collaboration with Gabriel Dvesklar of UHSUS to study Pregnancy Specific Glycoprotein -1 (PSG-1) as an immunomodulator and a possible therapy for GvHD. Preliminary in vitro and in vivo studies have been promising with reduced GvHD seen in our mouse models treated with the protein. Dr Sharma has presented some of this data at the annual American Society of Hematology (ASH) meeting and we have published one paper with some of our analysis of these compounds and a second manuscript is in preparation regarding its use in our GvHD murine models. (PLoS One.2016 Jul 7;11(7)) Finally, we have been evaluating some of the effects of GvHD on the brain in a project involving, Sarah Bryant, an IRTA who worked in the lab until this summer and who has submitted an abstract to the ASH meeting.