Preliminary Results of a Phase 1/2 Clinical Study of Zinc Finger Nuclease-Mediated Editing of BCL11A in Autologous Hematopoietic Stem Cells for Transfusion-Dependent Beta Thalassemia

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.3544-3544
• Main Authors: Smith, Angela R., Schiller, Gary J., Vercellotti, Gregory M, Kwiatkowski, Janet L., Krishnamurti, Lakshmanan, Esrick, Erica B., Williams, David A., Miller, Weston P., Woolfson, Adrian, Walters, Mark C.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-125743

Introduction: Persistently high fetal hemoglobin (HbF) expression can ameliorate severe transfusion-dependent beta thalassemia (TDT). BCL11A, a master regulator of the fetal-to-adult hemoglobin switch, is a rational gene-editing target in beta globinopathies. In pre-clinical studies with human hematopoietic stem cells (HSC), zinc finger nuclease (ZFN)-mediated disruption of the GATA-binding region of the intronic erythroid-specific enhancer (BCL11A ESE) increased endogenous HbF production in erythroid cells while allowing healthy, multi-lineage hematopoiesis. Though allogeneic hematopoietic stem cell transplantation (HSCT) can be curative in TDT, its application is partly limited by donor availability. Autologous transplantation using ex vivo gene-modified HSCs (HSCGT) can circumvent this, and lentiviral vector-mediated beta globin gene addition studies have shown efficacy in TDT. However, the long-term safety of random lentiviral genomic integration in HSCs is uncertain. ST-400 is an investigational cell therapy comprised of autologous CD34+ cells that have undergone high-precision, ZFN-mediated ex vivo editing at BCL11A ESE. The aim of this study is to induce HbF expression in edited erythroid cells. We hypothesized that HSCGT with ST-400 is safe and effective in TDT. Methods: The Thales trial (NCT03432364) is a Phase I/II study of the safety, tolerability and efficacy of ST-400 in adult patients with TDT, defined as undergoing ≥8 annual packed red blood cell transfusion episodes for at least 2 consecutive years before enrollment. After routine leukapheresis following mobilization with G-CSF and plerixafor, autologous collections are enriched for CD34+ cells and transfected with mRNA encoding ZFNs with binding sites flanking the GATA-binding region of BCL11A ESE. ST-400 product is infused following myeloablative busulfan conditioning. The trial will enroll 6 patients who are monitored for safety and efficacy for 3 years post-infusion. Results: Three patients have completed ST-400 manufacturing, and two have been infused. Patient 1 (β0/β0 genotype) received an ST-400 dose of 6.1 x 106 cells/kg. The patient experienced a serious adverse event (SAE) of hypersensitivity during ST-400 infusion considered to be related to the product cryoprotectant, DMSO, that resolved by the end of infusion. The patient had prompt hematopoietic reconstitution (ANC recovery day +14; platelet recovery day +24), with increasing HbF fraction that contributed to stable total hemog