[ Visit Client Website ]

Before you can access ASH's online program, you must agree to the following:
  • Abstracts submitted to the ASH Annual Meeting are considered embargoed from the time of submission.
  • The media, companies and institutions issuing press releases, and others are required to abide by the embargo policies governing the Society’s annual meeting. Read ASH’s embargo policy for more information.
-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.

67 T Cells Engineered With a Chimeric Antigen Receptor (CAR) Targeting CD19 (CTL019) Produce Significant In Vivo Proliferation, Complete Responses and Long-Term Persistence Without Gvhd In Children and Adults With Relapsed, Refractory ALLClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Novel Immune-Based Therapies and Novel Targets
Sunday, December 8, 2013: 5:00 PM
La Nouvelle Ballroom C (Ernest N. Morial Convention Center)

Stephan A Grupp, MD, PhD1,2, Noelle V. Frey, MD3,4, Richard Aplenc, MD, PhD5,6, David M Barrett, MD/PhD1*, Anne Chew, PhD7*, Michael Kalos, PhD7, Bruce L. Levine, PhD7, Manuel Litchman, MD8*, Shannon L Maude, MD, PhD1, Susan R. Rheingold6, Angela Shen, MD8*, Christine Strait1*, David T. Teachey, MD9*, Patricia A. Wood, MD, PhD8, David Porter, MD2 and Carl H. June, MD7

1Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
2Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
3Hematologic Malignancies Program, Hematology-Oncology Division, University of Pennsylvania, Philadelphia, PA
4Abramson Cancer Center, Philadelphia, PA
5Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA
6Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA
7Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
8Novartis Pharmaceuticals Corporation, East Hanover, NJ
9Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA

BACKGROUND

CARs combine a single chain variable fragment (scFv) of an antibody with intracellular signaling domains into a single chimeric protein. We previously reported on CTL019 cells expressing a CAR with intracellular activation plus costimulatory domains. Infusion of these cells results in 100 to 100,000x in vivo proliferation, durable anti-tumor activity, and prolonged persistence in pts with B cell tumors, including 1 sustained CR in a patient with ALL (Grupp, et al. NEJM 2013).  We now report on outcomes and longer follow up from our pilot studies treating 20 pts (16 children and 4 adults) with relapsed, refractory ALL. 

METHODS

T cells were lentivirally transduced with a CAR composed of anti-CD19 scFv/4-1BB/CD3ζ, activated/expanded ex-vivo with anti-CD3/anti-CD28 beads, and then infused into pts with relapsed or refractory CD19+ ALL.  17/20 pts received lymphodepleting chemotherapy the week prior to CTL019 infusion. The targeted T cell dose range was 107 to 108 cells/kg with a transduction efficiency (TE) of 11-45%. On the adult protocol, the target dose was 5 x 10total cells split over 3 days with a TE of 6-31%. 11 pts had relapsed ALL after a prior allogeneic SCT.  T cells were collected from the pt, regardless of prior SCT status, and not from allo donors. All pts s/p allo SCT had to be 6 mos s/p SCT with no GVHD or GVHD treatment.

RESULTS

16 children median age 9.5 y (5-22y) and 4 adults median age 50y (26-60y) with CD19+ ALL were treated. One child had T cell ALL aberrantly expressing CD19. 14/16 pediatric pts had active disease or +MRD after chemotherapy on the day prior to CTL019 cell infusion, while 2 were MRD(-). 3 of 4 adults had active disease prior to lymphodepleting chemotherapy, while 1 was in morphologic CR. Lymphodepleting chemotherapy varied with most receiving a Cytoxan-containing regimen the week prior to CTL019. A median of 3.7x106 CTL019 cells/kg (0.7-18x106/kg) were infused over 1-3 days.

There were no infusional toxicities >grade 2, although 5 pts developed fevers within 24 hrs of infusion and did not receive planned subsequent infusions of CTL019 cells.  14 patients (82%) achieved a CR, including the patient with CD19+ T ALL, 3 did not respond, and 3 are pending evaluation. 11/17 evaluable pts have ongoing BM CR with median follow up 2.6 mo (1.2-15 mo).  Three patients with a CR at 1 month have subsequently relapsed, 1 with CD19(-) disease. Median follow-up as of August 1, 2013 was 2.6 mo (1-15 mo) for all pts.

All responding pts developed some degree of delayed cytokine release syndrome (CRS), concurrent with peak T cell expansion, manifested by fever, with variable degrees of myalgias, nausea, anorexia. Some experienced transient hypotension and hypoxia.  Detailed cytokine analysis showed marked increases from baseline values of IL6 and IFNγ (both up to 1000x), and IL2R, with mild or no significant elevation in systemic levels of TNFα or IL2. Treatment  for CRS was required for hemodynamic or respiratory instability in 7/20 patients and was rapidly reversed in all cases with the IL6-receptor antagonist tocilizumab (7 pts), together with corticosteroids in 4 pts. Although T cells collected from the 11 pts who had relapsed after allo SCT were generally 100% of donor origin, no GVHD has been seen. Persistence of CTL019 cells detected by flow cytometry and/or QPCR in pts with ongoing responses continued for 1-15 months after infusion, resulting in complete B cell aplasia during the period of CTL019 persistence.  Pts have been treated with IVIg without any unusual infectious complications. One child who entered a CR subsequently developed MDS with a new trisomy 8 in ALL remission and has gone to SCT, and 1 child developed a single leukemia cutis lesion at 6 mo, still BM MRD(-).

CONCLUSIONS:

CTL019 cells are T cells genetically engineered to express an anti-CD19 scFv coupled to CD3ζ signaling and 4-1BB costimulatory domains.  These cells can undergo robust in-vivo expansion and can persist for 15 mo or longer in pts with relapsed ALL.  CTL019 therapy is associated with a significant CRS that responds rapidly to IL-6-targeted anti-cytokine treatment.  This approach has promise as a salvage therapy for patients who relapse after allo-SCT, and collection of tolerized cells from the recipient appears to have a low risk of GVHD. CTL019 cells can induce potent and durable responses for patients with relapsed/refractory ALL. Multicenter trials are being developed to test this therapy for ALL in the phase 2 setting.

Disclosures: Grupp: Novartis: Research Funding. Chew: Novartis: Patents & Royalties. Levine: Novartis: cell and gene therapy IP, cell and gene therapy IP Patents & Royalties. Litchman: Novartis Phamaceuticals: Employment, Equity Ownership. Rheingold: Novartis: Research Funding. Shen: Novartis Pharmaceuticals: Employment, Equity Ownership. Wood: Novartis Pharmaceuticals: Employment, Equity Ownership. June: Novartis: Patents & Royalties, Research Funding.

Previous Abstract | Next Abstract >>

*signifies non-member of ASH