Αβ T-Cell/CD19 B-Cell Depleted Haploidentical Stem Cell Transplantation: A New Platform for Curing Rare and Monogenic Disorders

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched donor, either related or unrelated, has been extensively used to treat patients with genetic disorders. However, only 25% of patients eligible to receive allogeneic HSCT have an HLA-identical sibling, and an HLA-matched unrelated donor can be identified for less than 60% of other patients. Mismatched HSCT has been associated with a high risk of graft loss, graft-versus-host disease (GvHD), and transplant-related mortality. Graft manipulation strategies have been used over the last decade to reduce these risks. HLA-haploidentical HSCT after ab T-cell/CD19 B-cell depletion (abhaplo-HSCT) has been shown to be effective in curing up to 90% of children with a variety of non-malignant disorders [Bertaina A, Blood 2014]. However, a scarcity of data are available for patients with rare and complex genetic diseases, including Tregopathies, an emerging new class of primary immunodeficiencies. Here we report preliminary data on the single center experience developed at Lucile Packard Children's Hospital, Stanford, CA, USA on the use of abhaplo-HSCT for rare and complex monogenic diseases (Table 1). All the cell products were manufactured at the Laboratory for Cell and Gene Medicine (LCGM) at Stanford (Table 2). Between 05/2018 and 08/2019, 5 patients with complex monogenic disorders were referred to our Center for HSCT including: a 23 year-old with Fanconi Anemia, two with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and two with Schimke Immuno-Osseous Dysplasia (SIOD). Remarkably, all these patients were previously considered not eligible for a HSCT, and one of the IPEX patients was in palliative care. At a median follow-up of 240 days (range 39-520), all patients are alive and disease-free. One patient (SIOD) developed Grade I/stage II skin only graft-versus-host disease (GvHD), while none of the evaluable patients had developed chronic GvHD. Five months after abhaplo-HSCT and with 100% of the circulating T cells being donor derived, the first SIOD patient received a living kidney transplant from the stem cell donor (mother) using minimal immunosuppression with tacrolimus and steroid. Four weeks after the kidney transplant all immunosuppression was stopped, and the patient remains off immunosuppression 12 weeks post-kidney transplantation. Our preliminary data on the use of abhaplo-HSCT in patients with rare and complex monogenic diseases provide a strong rationale for expanding this therapeutic approach to diseases not previously considered as an indication for allogeneic HSCT, to patients in very poor clinical condition and to patients requiring both HSCT and solid organ transplant.