Early Response Data for Pediatric Patients with Non-Hodgkin Lymphoma Treated with CD19 Chimeric Antigen Receptor (CAR) T-Cells
Authors: Rivers Julie , Annesley Colleen , Summers Corinne , Finney Olivia , Pulsipher Michael A. , Wayne Alan S. , Park Julie R. , Jensen Michael C. , Gardner Rebecca 
Published: October 2019

Abstract
Background:Pediatric patients with relapsed or refractory CD19+non-Hodgkin lymphoma (NHL) have poor outcomes despite use of chemotherapy and hematopoietic stem cell transplant (HSCT). Clinical trials of CD19 CAR T-cells have demonstrated efficacy in salvaging adult patients with relapsed and refractory NHL.
Objectives:The objectives of this analysis is to assess the safety, toxicity, feasibility and efficacy of SCRI-CAR19v1 for pediatric patients with relapsed or refractory NHL.
Design/Methods:The ongoing phase 2 trial (NCT02028455) has enrolled and treated 8 pediatric subjects with CD19+NHL. Subjects underwent apheresis, with their CD4 and CD8 T cell subsets prepared immunomagnetically. T cells were stimulated with anti-CD3xCD28 bead stimulation, and then transduced with a SIN lentiviral vector to direct co-expression of the FMC63scFv:IgG4hinge:CD28tm:4-1BB:ζ CAR and the selection/tracking/suicide construct EGFRt. The transduced cells were propagated using recombinant human cytokines to numbers suitable for clinical use. Subjects received lymphodepletion of fludarabine and cyclophosphamide followed by 1x106CD19 CAR T-cells/kg as a 1:1 ratio of CD4 and CD8 cells. Response was assessed at 3 and 9 weeks. Adverse events were graded according to CTCAEv4 except cytokine release syndrome (CRS) was graded according to Lee et al.
Results: Treated subjects had relapsed or refractory diffuse large B cell lymphoma (DLBCL) (4/8), Burkitt's lymphoma (2/8), gray zone B cell lymphoma (1/8), primary mediastinal B cell lymphoma (PMBCL) (1/8), and ranged from 4-18 years old. Two subjects received prior hematopoietic stem cell transplant (HSCT); the subject with PMBCL received auto- and allogeneic HSCT and a subject with Burkitt's received autologous HSCT. Five subjects received prior immunotherapy with brentuximab, nivolumab, rituximab, and/or obinutuzumab. One subject had received ibrutinib. No subject had received prior CAR T-cells. CD4 and CD8 products were successfully manufactured and infused for all subjects. All subjects had expansion of CAR T-cells in the peripheral blood, bone marrow and CSF, with ongoing persistence at last check (range 14 days - 9 months). Toxicity information through day 30 revealed the occurrence of mild CRS in 4 subjects (grade 1 n=3, grade 2 n=1), and one case of severe CRS (grade 3). Mild neurotoxicity was observed in 2 subjects (grade 1 n=1, grade 2 n=1) with no occurrence of severe neurotoxicity. Response assessment at 3 weeks (n=6) revealed anti-tumor responses in 5 subjects, including complete response (CR) by week 9 (n=2, both DLBCL). CR was not sustained in either subject despite ongoing CAR T cell persistence. One of these subjects had a PET avid lesion proven by biopsy to be necrotic tissue but subsequently developed CD19+recurrence at that site. The other subject developed a new CD19+site of disease at six months; however, achieved a 2nd CR 3 weeks after receiving a second infusion of the originally manufactured CAR T-cells. One partial response (PR) subject experienced clearance of marrow disease with stable lymphoma but developed CD19 negative progression at 9 weeks. Updated enrollment, toxicity and response assessments will be presented.
Conclusion:SCRI-CAR19v1 therapy demonstrates efficacy in pediatric patients with relapsed and refractory NHL and appears to be well tolerated with less severe toxicities than observed for pediatric patients with CD19+leukemia. Persistence of the CAR T-cells is excellent with no early loss of CAR T-cell engraftment reported to date. Although early responses were observed, these were not durable perhaps reflecting biologic/immunologic differences between B cell lymphomas in children in comparison to NHL in adults.

Disclosures
Pulsipher: Adaptive Biotech: Consultancy, Research Funding; Amgen: Honoraria; CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Park:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jensen:Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.