-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1271 Preliminary Results of UCART19, an Allogeneic Anti-CD19 CAR T-Cell Product in a First-in-Human Trial (PALL) in Pediatric Patients with CD19+ Relapsed/Refractory B-Cell Acute Lymphoblastic LeukemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster I
Saturday, December 9, 2017, 5:30 PM-7:30 PM
Bldg A, Lvl 1, Hall A2 (Georgia World Congress Center)

Waseem Qasim, MD, PhD1*, Oana Ciocarlie1*, Stuart Adams, PHD1*, Sarah Inglott1*, Claire Murphy1*, Christine Rivat1*, Gary Wright1*, Giovanna Lucchini, MD2*, Juliana Silva, MD2*, Kanchan Rao2*, Amina Zinaï, MD3*, Florence Binlich, MD3*, Sandra Dupouy, Pharm.D, Ph.D3*, Jeanne Pauly, PharmD3*, Svetlana Balandraud, MD3*, Frédéric Dubois3*, Cyril Konto, MD4*, Premal Patel, MD, PhD, BSPharm4*, Robert Chiesa1*, Sujith Samarasinghe5*, Havinder Hara1*, Alayna Boyle1*, Jan Chu1*, Danielle Pinner1*, Persis J Amrolia2*, Ajay Vora, MD6, Anupama Rao1*, Philip Ancliffe, MD1* and Paul Veys, MD1*

1Bone Marrow Transplantation Department, Great Ormond Street hospital NHS trust, London, United Kingdom
2Bone Marrow Transplantation Department, Great Ormond Street hospital NHS Trust, London, United Kingdom
3Institut de Recherches Internationales Servier, Suresnes, France
4Pfizer, San Francisco
5Haematology Department, Great Ormond Street hospital NHS trust, London, United Kingdom
6Haematology, Great Ormond Street Hospital, London, United Kingdom

Background

UCART19 is a genetically modified T-cell product manufactured from non-HLA matched healthy donor cells and aims to provide a ready to use, off-the-shelf allogeneic engineered CAR T-cell product. Lentiviral-transduced CAR T-cells express (1) an anti-CD19 CAR (anti-CD19 scFv- 41BB- CD3ζ), and (2) an RQR8 “safety switch” that is intended to allow targeted elimination of RQR8+ cells by rituximab. UCART19 has been additionally modified to disrupt the T-cell receptor alpha constant (TRAC) and CD52 genes. We previously reported the success of this approach in two infants treated under compassionate use who achieved molecular remissions ahead of allogeneic transplantation and remain in remission with follow-up for 18 and 24 months. Here we describe preliminary results of a Phase 1 trial of UCART19 in pediatric patients (pts) with high risk relapsed refractory (R/R) CD19+ B-ALL and no therapeutic options.

Methods

This study evaluates the safety and tolerability of a fixed dose (2x107 total cells or 1.1 to 2.3x106 cells/kg) of UCART19 and its ability to achieve molecular remission at day (D) 28 to enable allogeneic stem cell transplantation (allo-SCT). Up to 10 subjects with R/R B-ALL aged between 6 months and < 18 years, with morphologically confirmed CD19+ B-ALL or an MRD load ≥ 1x10-3 are eligible. The lymphodepletion regimen combines cyclophosphamide and fludarabine with or without alemtuzumab (FC or FCA). UCART19 is administered thereafter (Day 0) as a single dose infusion. If the patient achieves molecular remission, allo-SCT is scheduled within 6 to 12 weeks (wks) after infusion, and trial period continues for a further 12 months before entry into a long-term follow-up study.

Results

As of 24 June 2017, 5 children (3 males and 2 females), including two infant leukaemias, aged between 8 months and 16.4 years had been enrolled and treated. Four pts had received 3 or more previous lines of treatment and 2 had undergone a previous allo-SCT. All patients were unsuitable for or had failed generation of an autologous CAR T-cell product. All had received debulking chemotherapy and/or inotuzumab ozogamicin therapy before UCART19. All pts received lymphodepletion with FCA. No immediate infusion related reaction (IRR) related to UCART19 were reported. All pts experienced reversible cytokine release syndrome (CRS) (1 grade (G) 1, 3 G2, 1 G3), with one child requiring 2 doses of tocilizumab. Time to onset of first CRS symptoms was between D4 and D8. Two pts presented mild neurological symptoms that recovered (within 1 to 3 days) without treatment. Acute skin GvHD G1 was reported in two pts (one with biopsy confirmation) and both recovered with topical steroids. Four children experienced viral complications (CMV, ADV, BK, metapneumovirus) related to lymphodepletion, and all experienced neutropenia, which was prolonged in 2/5 pts. By D28-42, 5/5 pts had achieved complete remission with incomplete blood count recovery albeit with hypoplastic marrows (all patients were MRD negative by flow cytometry or qPCR ). UCART19 were detectable from D7 to at least D28 in all subjects by qPCR and/or flow cytometry and by molecular signatures of T-cell donor chimerism. All proceeded to conditioned allo-SCT between 7 to 9 weeks after UCART19 infusion, with no gene-modified cells detectable thereafter. Two children relapsed 3 months after transplantation (one CD19- and one CD19+) and died 7 and 8 months after UCART19 infusion respectively. One subject died in remission from transplant related complications including thrombotic microangiopathy and BK haemorrhagic cystitis and nephritis. Two subjects remain in molecular remission 2 and 2.5 months post-transplant.

Conclusion

Preliminary results of this first-in-human trial of UCART19 treatment in a high risk R/R B-ALL pediatric population revealed no unexpected toxicities. GvHD seen in 2 patients was mild and self-limiting. Lymphodepletion-related viral complications and persisting neutropenia were encountered. All five treated subjects were rendered either flow or PCR MRD negative enabling allogeneic transplantation to proceed. The trial is ongoing in the UK and further data may be presented (NCT02808442) .

Disclosures: Qasim: Autolus Ltd: Consultancy, Equity Ownership; Miltenyi: Research Funding; Orchard Therapeutics: Consultancy, Equity Ownership; Servier: Research Funding; Bellicum: Research Funding; NIHR: Research Funding; Cellectis: Research Funding. Lucchini: Alexion: Membership on an entity's Board of Directors or advisory committees. Zinaï: Servier: Employment. Binlich: Servier: Employment. Dupouy: Servier: Employment. Pauly: Servier: Employment. Balandraud: Servier: Employment. Dubois: Servier: Employment. Konto: Bristol-Myers Squibb: Employment, Equity Ownership; Pfizer: Employment, Equity Ownership. Patel: Pfizer: Employment, Equity Ownership. Veys: Bellicum: Research Funding; Servier: Research Funding.

Previous Abstract | Next Abstract >>
*signifies non-member of ASH