Abstract PR06: T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) produce complete responses and long-term persistence without GVHD in children with relapsed, refractory ALL
Authors: Grupp Stephan A. , Maude Shannon , Aplenc Richard , Barrett David M. , Kalos Michael , Levine Bruce , Lichtman Manuel , Rheingold Susan , Shen Angela , Strait Christine , Teachey David , Wood Patricia A. , June Carl 
Published: May 2015

Abstract
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 recognizing CD19 combined with the CD137 and CD3 zeta intracellular activation domain, 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 study treating 16 children 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. 13/16 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%. 11 pts had relapsed ALL after a prior allogeneic SCT. T cells were collected from the pt, regardless of prior SCT status, though all pts had to be 6 mos s/p SCT with no GVHD or GVHD treatment.
Results: 16 children median age 9.5 y (5-22y) with CD19+ ALL were treated. One child had T cell ALL aberrantly expressing CD19. 14/16 pts had active disease or +MRD after chemotherapy on the day prior to CTL019 cell infusion, while 2 were MRD(-). A median of 4x106 CTL019 cells/kg (1.1-18x106/kg) were infused over 1-3 days. There were no infusional toxicities &gt;grade 2, although 3 pts developed fevers within 24 hrs of infusion and did not receive planned subsequent infusions of CTL019 cells. 13 patients (81%) achieved a CR, including the patient with CD19+ T ALL, 3 did not respond. 10/16 evaluable pts as of August 28, 2013 have ongoing BM CR with median follow up 3.4 mo (1.2-16 mo). Three patients with a CR at 1 month have subsequently relapsed, 1 with CD19(-) disease. All responding pts developed some degree of delayed cytokine release syndrome (CRS) at the time of peak T cell expansion, and a subset experienced transient hypotension and hypoxia. Treatment with tocilizumab, an anti IL6-receptor antagonist, reversed the CRS related hemodynamic or respiratory instability seen, though corticosteroids were used concurrently in some patients. No GVHD was observed, and cells collected from SCT recipients were generally of 100% donor origin. 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 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 that 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 anticytokine 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.
This abstract is also presented as Poster B69.
Citation Format: Stephan A. Grupp, Shannon Maude, Richard Aplenc, David M. Barrett, Michael Kalos, Bruce Levine, Manuel Lichtman, Susan Rheingold, Angela Shen, Christine Strait, David Teachey, Patricia A. Wood, Carl June. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) produce complete responses and long-term persistence without GVHD in children with relapsed, refractory ALL. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr PR06.