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1021 Gene Therapy for Sickle Cell Anemia Using a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant Shows Promising Correction of the Disease PhenotypeClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 801. Gene Therapy and Transfer: Gene Therapy for Blood Cell Disorders
Hematology Disease Topics & Pathways:
Diseases, Anemias, sickle cell disease, Biological, Therapies, Hemoglobinopathies, gene therapy, Clinically relevant
Monday, December 3, 2018: 6:15 PM
Room 6B (San Diego Convention Center)

Punam Malik, MD1, Michael Grimley, MD2, Charles T. Quinn, MD1,3, Amy Shova, RN4*, Little Courtney, RN4*, Carolyn Lutzko, PhD5*, Theodosia A. Kalfa, MD, PhD1, Omar Niss, MD1, Parinda A Mehta, MD6, Sharat Chandra, MBBS, MD6*, Elke Grassman7*, Johannes C.M. Van der Loo, PhD7*, Scott Witting, MS7*, Diana Nordling7*, Archana Shreshta, PhD7*, Sydney Felker, BS7*, Catherine Terrell, BS7*, Lilith Reeves, MS, MT(ASCP)7*, Devin Pillis, MS8*, Loberg Anastacia7*, Frederic D Bushman, PhD9*, Jennifer Knight-Madden10*, Karen Kalinyak, MD1, Stella M. Davies, PhD, MBBS, MRCP11 and Monika Asnani, PhD12*

1Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
2Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
3Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
4Cancer and Blood Disease Institute, Cincinnati Children's Hospital, Cincinnati, OH
5Cincinnati Children's Hospital Medical Center, Cincinnati, OH
6Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
7Cincinnati Children's Hospital, Cincinnati, OH
8Cincinnati Children's Hospital, Cincinnati
9Department of Microbiology, University of Pennsylvania, Philadelphia, PA
10Caribbean Institute for Health Research, Kingston, Jamaica
11Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
12Carribean Health Research Institute, Kingston, Jamaica

Background: Genetic transfer of an anti-sickling β87-globin lentiviral vector (LV) into hematopoietic stem cells (HSC) followed by myeloablative transplant has cured one child with sickle cell anemia (SCA) (NEJM 2017), although it was not successful in 7 subsequent adult SCA patients, and modifications to intensify ablative conditioning, improve HSC dose, gene transfer are underway (Blood 130 Suppl 1: 527, 2017). Based upon our preclinical data (Blood 2009), we embarked upon a Reduced Intensity Conditioning (RIC) Phase I/II Pilot Study on Gene Transfer in Patients with SCA with a modified γ-Globin LV (NCT02186418), hypothesizing this approach will be safe, feasible and efficacious; Moreover, RIC will have significantly less toxicity, costs, and be implementable in many transplant centers, including those in some of the resource-poor countries, where supportive therapies for myeloablative transplants are unavailable, and where majority of SCA patients exist.

Methods: Adult patients with severe SCA deemed eligible were transfused/erythrocytapheresed prior to HSC collection and transfused for 6 months post-transplant (PT) to Hb>10g/dl and HbS~30%. CD34+ HSC were collected via bone marrow harvest (BMH) and/or plerixafor mobilized Peripheral Blood Stem Collection (PBSC), selected for CD34+ cells and transduced. Patients received a single dose of IV melphalan (140mg/m2 BSA) 36hr prior to infusion of γ-globin modified (GM)-HSC. Patients were monitored for adverse events (AE), engraftment, vector copy number (VCN), modified HbF (HbF*) expression and clinical features of SCA.

Results: Two SCA patients (35yo and 25yo) with HbS-β0 thalassemia genotype were treated. CD34+ HSC were collected via multiple BMH (P1) and BMH+PBSC (P2). Follow up data are available for 6 and 12mo on P1 and P2. P1 received 1x106 CD34+ cells/kgbw [vector copy number (VCN) 0.22], and P2 received 6.9x106 CD34+ cells/kgbw [VCN 0.46]. Time to neutrophil engraftment (ANC ≥ 500) was day 9 and 7 post-transplant (PT) in P1 and P2, respectively, and time to Plt recovery (Plt>50K) was day 14 PT in both. Patients included in this trial had severe disease and continued to have pre-existing chronic pain requiring significant opiates; hence ~80% of the AEs were pain events; other AEs were anticipated transient laboratory AEs associated with melphalan. Following GM-HSC infusion, both patients showed a progressive rise in HbF* (a point mutation in the γ-globin LV allows distinction from endogenous HbF by HPLC) starting from day 30 PT. Since patients had transfused HbA containing RBCs in the initial 6 months, HbF*/(HbF*+HbS) was calculated, and was 20% and 21% in P1 and P2 at day 180 PT and VCN 0.2-0.4, detected in all lineages. Integration site analysis, performed on the infused products (Day 0), at day 30 PT on P1 and P2, and on day 180 PT on P1 demonstrated highly polyclonal pattern of integration. At 1 yr PT, P1 had 20% HbF* (2.1g/dl HbF*, total Hb 10.6) with a stable VCN of 0.2-0.4 in multiple lineages in bone marrow and peripheral blood. The baseline Hb of P1 was 7.5-8.5g/dL prior to transplant. In the preceding 2 years prior to transplant, both patients were admitted for pain crises/acute chest >5-6 times/yr, and had chronic pain requiring chronic opiates. Chronic pain persisted for 4-5 months PT in P1, after which P1 has not required IV opiates, negligible oral opiates and has had no hospital visits/admissions with acute sickle events. P2 has required decreasing amounts of oral opiates for chronic back pain.

Conclusions: Early results from 2 SCA adults treated with a modified γ-globin LV modified autologous HSC following RIC transplant showed excellent safety, feasibility, with minimal post-transplant toxicity, rapid count recovery, and sustained stable genetically modified cells in peripheral blood and bone marrow. The first patient shows significant clinical amelioration of the SCA phenotype at 1 year PT, with 20% vector-derived HbF (HbF*) that has caused amelioration of anemia, near elimination of chronic pain and absence of acute sickle events. The second patient, although still early post-transplant shows a similar HbF* trajectory. Additional study data will demonstrate whether this level of HbF* will provide consistent clinical benefit to patients with severe SCA. These early results, especially following a RIC transpant, are extremely promising; and if sustained, will provide a ‘transportable’ safe and feasible gene therapy for SCA.

Disclosures: Malik: CSL Behring: Patents & Royalties. Quinn: Silver Lake Research Corporation: Research Funding; Amgen: Research Funding; Global Blood Therapeutics: Research Funding.

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