Patients with ADA SCID may experience autoimmune AEs

Patients with ADA-SCID may experience autoimmune AEs after SCT (and/or during ERT) that are thought to be related to immune dysregulation prior to achieving complete immune reconstitution. The more common autoimmune manifestations include hemolytic anemia, hypothyroidism, and immune thrombocytopenia. Following treatment with GT, HSCT, and/or PEG-ADA, early-onset ADA-SCID patients may have a response (atopy) to common AM966 synthesis such as food or inhalants. Reports of autoimmunity and allergy-related events have also been described in delayed-onset ADA-SCID. Several autoimmune events occurred pre-treatment. The majority of post-GT events occurred within 3-year follow-up, mainly consisted of positive autoantibody tests without associated clinical manifestations, and were consistent with ongoing immune reconstitution. Peripheral blood CD19+ B cells and CD3+ T cells, red blood cell deoxyadenosine nucleotide (dAXP) levels, and anti-CD3 monoclonal antibody (mAb) proliferative responses were similar between patients with and without autoimmune events (data not shown). Autoimmune events are commonly associated with HSCT, PEG-ADA treatment, and the underlying disease state. Importantly, there were no indications that any autoimmune events were specifically attributable to the GT medicinal product. GT with integrating vectors introduces a risk of insertional mutagenesis through activation of proto-oncogenes, the formation of de novo gene expression products, and knockout of tumor suppressor gene function. As a result, leukemic transformation is a leading safety concern for GT. Hematologic malignancies and abnormalities following RV GT have been observed in patients treated for X-linked SCID, chronic granulomatous disease, and Wiskott-Aldrich Syndrome. Importantly, no cases of leukemia have been reported in the cohort described here, despite more than a decade of follow-up in several patients. Moreover, none of the other 22 patients with ADA-SCID who underwent alternative GT regimens over the past decade have developed leukemia. Additional RIS analysis confirmed the existence of several thousand unique insertion sites. As is expected for a pseudo-randomly inserting vector, RIS were detected in areas of known risk. However, clones with these inserts are stable and are not causing clinical safety issues for patients. Insertion site diversity (the number of recovered sites) was comparable to similar gamma retroviral GT trials. All 18 patients who have been treated with RV GT for ADA-SCID are alive, clinically well, and without signs of leukemic transformation. The safety data presented here provide a first-of-its-kind assessment describing detailed short-term and medium-term follow-up, including infections, hepatic events, autoimmune manifestations, and neurologic/hearing impairments. Monitoring of this cohort is ongoing and will be incorporated into a registry for these and future patients, planned in agreement with pharmacovigilance guidelines for GT products. Such a registry is vital to establish the long-term safety of GT for the treatment of patients with ADA-SCID and to allow accurate comparisons of this new treatment with SCT, ERT, and the emerging class of lentiviral-based GT vectors. Long-term safety and efficacy data from the registry will be made publicly available as the cohort matures. The safety data reported here are consistent with those available for the general ADA-SCID population and indicate that GT can safely restore immune function in these patients. Immune reconstitution leads to a decrease in the rate of infections following GT, in many cases to rates similar to those within the general pediatric population. The patients discussed here, for whom other treatment options were limited, safely underwent GT and in most cases corrected the metabolic defect and achieved immune reconstitution.
Materials and Methods
Author Contributions
Conflicts of Interest
Acknowledgments The authors would like to thank all the medical and nurse personnel of the Paediatric Immunohematology and Hematology and Bone Marrow Transplant Unit of San Raffaele Hospital (Milan), the personnel of the SR-Tiget Clinical Trial Office, local referring physicians who helped with patient management, and all patients who participated in this study and their families. The authors thank Luca Biasco and Francesca Dionisio (both of SR-Tiget) for performing the RIS integration studies, and Michela Gabaldo (SR-Tiget) for her continuous support in the alliance between Telethon/San Raffaele and GSK. The authors wish to thank Sam Garthside, Younan Chen, and Andrea Campanile of GSK for statistical, programming, operational, and data management support for the clinical development program. Writing assistance was provided by Molly Nixon of Synchrogenix (funded by GSK). Project management support was provided by Barbara Kravitz of GSK. In addition, the authors acknowledge Miriam Casiraghi, Giuliana Tomaselli, and Samih El Hossary (all of SR-Tiget) for their support to patients. Financial support for these studies was provided to A.A. by the Fondazione Telethon, European Union Project FP7 CELL PID, and GlaxoSmithKline.