INITIAL SAFETY AND EFFICACY RESULTS WITH A SINGLE DOSE OF AUTOLOGOUS CRISPR-CAS9 MODIFIED CD34+ HEMATOPOIETIC STEM AND PROGENITOR CELLS IN TRANSFUSION-DEPENDENT Β-THALASSEMIA AND SICKLE CELL DISEASE
Author(s): ,
Selim Corbacioglu
Affiliations:
Paediatric Haemotology, Oncology and Step Cell Transplantation,Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine,Regensburg,Germany
,
Maria Domenica Cappellini
Affiliations:
Department of Clinical Sciences and Community, University of Milan,IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital,Milan,Italy
,
John Chapin
Affiliations:
CRISPR Therapeutics,Cambridge,United States
,
Nicole Chu-Osier
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
,
Christine Marie Fernandez
Affiliations:
CRISPR Therapeutics,Cambridge,United States
,
Juergen Foell
Affiliations:
Paediatric Haemotology, Oncology and Stem Cell Transplantation,Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine,Regensburg,Germany
,
Josu de la Fuente
Affiliations:
Imperial College Healthcare NHS Trust, Hammersmith Hospital,London,United Kingdom
,
Stephan Grupp
Affiliations:
Department of Pediatrics,University of Pennsylvania Perelman School of Medicine,Philadelphia,United States
,
Tony W Ho
Affiliations:
CRISPR Therapeutics,Cambridge,United States
,
Antonis Kattamis
Affiliations:
Division of Pediatric Hematology-Oncology, First Dept of Pediatrics,University of Athens,Athens,Greece
,
Julie Lekstrom-Himes
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
,
Franco Locatelli
Affiliations:
IRCCS Ospedale Pediatrico Bambino Gesù,Rome,Italy
,
Yimeng Lu
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
,
Mariane de Montalembert
Affiliations:
Hôpital Universitaire Necker-Enfants Malades,Paris,France
,
Damiano Rondelli
Affiliations:
University of Illinois at Chicago,Chicago,United States
,
Ainsley Ross
Affiliations:
CRISPR Therapeutics,Cambridge,United States
,
Niraj Shanbhag
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
,
Sujit Sheth
Affiliations:
Division of Pediatric Hematology/Oncology,Weill Cornell Medicine,New York,United States
,
Sandeep Soni
Affiliations:
Lucile Packard Children's Hospital,Palo Alto,United States
,
Martin Steinberg
Affiliations:
Boston University,Boston,United States
Haydar Frangoul
Affiliations:
The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers,Nashville,United States
EHA Library. Corbacioglu S. 06/12/20; 295100; S280
Selim Corbacioglu
Selim Corbacioglu
Contributions
Abstract
This abstract is embargoed until Friday, June 12, 08:30 CEST.

Abstract: S280

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Immunotherapy - Clinical

Background
BCL11A is a transcription factor and key component of the hemoglobin (Hb) switch that regulates the repression of g-globin chain production occurring early in the post-natal period, leading to the production of adult HbA. Suppression of BCL11A is associated with increases in fetal Hb (HbF). In both transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD), HbF upregulation may reduce or eliminate the need for transfusion therapy and, in SCD, may reduce vaso-occlusive crises (VOCs).

Aims
To induce HbF production in erythrocytes, we used ex vivo CRISPR-Cas9–based gene editing to disrupt BCL11A in hematopoietic stem and progenitor cells (HSPCs), producing CTX001. CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) are multi-center, first-in-human studies of edited patient cells (CTX001) in TDT and SCD, respectively. Here, we present initial results from the first 2 patients treated with CTX001.

Methods
Patients (18-35 y of age) with TDT receiving packed red blood cell (pRBC) transfusions of ≥100 mL/kg/y or ≥10 units/y in the previous 2 y and those with severe SCD defined as ≥2 VOCs/y in the previous 2 y were eligible. Peripheral CD34+ HSPCs were collected by apheresis after mobilization with G-CSF (filgrastim) and plerixafor (TDT) or plerixafor alone (SCD). CD34+ cells were edited with CRISPR-Cas9 using a guide RNA specific for the erythroid enhancer region of BCL11A. Prior to CTX001 infusion on Day(D)+1, patients received myeloablative conditioning with busulfan. Patients were monitored for stem cell engraftment/hematopoietic recovery, adverse events (AEs), Hb production, hemolysis, HbF and F-cell expression, pRBC transfusion requirements (TDT), and VOCs (SCD).

Results
Data are presented for 1 patient with TDT (β0+ [IVS-I-110]) with an annualized pRBC transfusion history of 34 units/y over 2 y prior to consent; follow-up post-CTX001: 12 mo) and 1 patient with SCD (βSS with 7 VOCs/y, annualized over 2 y prior to consent; follow-up post-CTX001: 6 mo). The patient with TDT achieved engraftment of neutrophils (D+33) and platelets (D+37). Two serious AEs (SAEs) occurred, both considered unrelated to CTX001: veno-occlusive liver disease (related to busulfan) and pneumonia in the presence of neutropenia; both resolved. The last pRBC transfusion was on D+30; in the 12 mo post-CTX001 infusion, phlebotomy for iron reduction occurred on D+98, D+147, D+170, D+191. The patient with SCD achieved neutrophil and platelet engraftment on D+30. Following CTX001 infusion, 3 SAEs (sepsis while neutropenic, cholelithiasis, and abdominal pain) occurred; all considered unrelated to CTX001. No VOCs have occurred since CTX001 infusion. For both patients, the safety profile was generally consistent with busulfan myeloablation and autologous hematopoietic stem cell transplantation. Markers of intravascular hemolysis demonstrated significant improvement. Total Hb, HbF and F-cell expression increased over time in both patients (Figure).

Conclusion
The first 2 patients treated with CTX001 demonstrated successful engraftment. The patient with TDT has been transfusion free since D+30 after CTX001 infusion (12.4 g/dL HbF at 12 mo). The patient with severe SCD has had no VOCs in the 6 mo following CTX001 infusion (HbF 47.3% of total Hb at 6 mo). This is the first scientific report of patients with a human genetic disease treated successfully with CRISPR-Cas9 and indicates that CTX001 is a promising approach for the treatment of hemoglobinopathies. Data will be updated for the presentation.

Submitted on behalf of the CLIMB THAL-111 and CLIMB SCD-121 Investigators.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Beta thalassemia, Hemoglobin, Sickle cell disease

This abstract is embargoed until Friday, June 12, 08:30 CEST.

Abstract: S280

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Immunotherapy - Clinical

Background
BCL11A is a transcription factor and key component of the hemoglobin (Hb) switch that regulates the repression of g-globin chain production occurring early in the post-natal period, leading to the production of adult HbA. Suppression of BCL11A is associated with increases in fetal Hb (HbF). In both transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD), HbF upregulation may reduce or eliminate the need for transfusion therapy and, in SCD, may reduce vaso-occlusive crises (VOCs).

Aims
To induce HbF production in erythrocytes, we used ex vivo CRISPR-Cas9–based gene editing to disrupt BCL11A in hematopoietic stem and progenitor cells (HSPCs), producing CTX001. CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) are multi-center, first-in-human studies of edited patient cells (CTX001) in TDT and SCD, respectively. Here, we present initial results from the first 2 patients treated with CTX001.

Methods
Patients (18-35 y of age) with TDT receiving packed red blood cell (pRBC) transfusions of ≥100 mL/kg/y or ≥10 units/y in the previous 2 y and those with severe SCD defined as ≥2 VOCs/y in the previous 2 y were eligible. Peripheral CD34+ HSPCs were collected by apheresis after mobilization with G-CSF (filgrastim) and plerixafor (TDT) or plerixafor alone (SCD). CD34+ cells were edited with CRISPR-Cas9 using a guide RNA specific for the erythroid enhancer region of BCL11A. Prior to CTX001 infusion on Day(D)+1, patients received myeloablative conditioning with busulfan. Patients were monitored for stem cell engraftment/hematopoietic recovery, adverse events (AEs), Hb production, hemolysis, HbF and F-cell expression, pRBC transfusion requirements (TDT), and VOCs (SCD).

Results
Data are presented for 1 patient with TDT (β0+ [IVS-I-110]) with an annualized pRBC transfusion history of 34 units/y over 2 y prior to consent; follow-up post-CTX001: 12 mo) and 1 patient with SCD (βSS with 7 VOCs/y, annualized over 2 y prior to consent; follow-up post-CTX001: 6 mo). The patient with TDT achieved engraftment of neutrophils (D+33) and platelets (D+37). Two serious AEs (SAEs) occurred, both considered unrelated to CTX001: veno-occlusive liver disease (related to busulfan) and pneumonia in the presence of neutropenia; both resolved. The last pRBC transfusion was on D+30; in the 12 mo post-CTX001 infusion, phlebotomy for iron reduction occurred on D+98, D+147, D+170, D+191. The patient with SCD achieved neutrophil and platelet engraftment on D+30. Following CTX001 infusion, 3 SAEs (sepsis while neutropenic, cholelithiasis, and abdominal pain) occurred; all considered unrelated to CTX001. No VOCs have occurred since CTX001 infusion. For both patients, the safety profile was generally consistent with busulfan myeloablation and autologous hematopoietic stem cell transplantation. Markers of intravascular hemolysis demonstrated significant improvement. Total Hb, HbF and F-cell expression increased over time in both patients (Figure).

Conclusion
The first 2 patients treated with CTX001 demonstrated successful engraftment. The patient with TDT has been transfusion free since D+30 after CTX001 infusion (12.4 g/dL HbF at 12 mo). The patient with severe SCD has had no VOCs in the 6 mo following CTX001 infusion (HbF 47.3% of total Hb at 6 mo). This is the first scientific report of patients with a human genetic disease treated successfully with CRISPR-Cas9 and indicates that CTX001 is a promising approach for the treatment of hemoglobinopathies. Data will be updated for the presentation.

Submitted on behalf of the CLIMB THAL-111 and CLIMB SCD-121 Investigators.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Beta thalassemia, Hemoglobin, Sickle cell disease

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