Vector Integration and Efficacy of CD19-Directed CAR T Cell Therapy in Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL)

Abstract CD19-specific Chimeric Antigen Receptor (CTL019)-engineered T-cells provide a breakthrough for personalized cancer therapy. An anti-CD19 CAR gene with 41BB costimulatory domain is delivered into patient T-cells ex vivo using a lentiviral vector, expanded in culture and then reinfused into patients. While dramatically successful for some treatment-refractory cancers, a significant proportion of patients do not experience therapeutic levels of CAR T cell expansion - thus it is important to investigate factors driving successful expansion in responders in more detail. Here we have analyzed sites of lentiviral vector integration in CAR T cells from trials to ALL and CLL, comparing successful and unsuccessful therapy in longitudinal data sets for 40 subjects. The location of each integrated vector marks a cell lineage uniquely allowing the fate mapping of individual CAR-engineered T cells in the infusion product and after adoptive transfer. We found that 81.4% of integrations had occurred in annotated transcription units which is consistent with previous reports for lentiviral vector integration sites. Relatively larger and more diverse populations of CAR-modified T-cells were associated with improved outcome (Chao1 index, p=0.043). Population sizes were also significantly more diverse in the infusion product compared with day 28 post-infusion, and more diverse at this time point when comparing responders with non-responders, or even partial responders with non-responders (p Disclosures Fraietta: Novartis: Patents & Royalties: WO/2015/157252, WO/2016/164580, WO/2017/049166. Porter: Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board; Genentech: Other: Spouse employment. Frey: Servier Consultancy: Consultancy; Novartis: Consultancy. Grupp: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy. Siegel: Novartis: Research Funding. Lacey: Novartis Pharmaceuticals Corporation: Patents & Royalties; Tmunity: Research Funding; Parker Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. June: Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees. Melenhorst: Shanghai UNICAR Therapy, Inc: Consultancy; novartis: Patents & Royalties, Research Funding; Casi Pharmaceuticals: Consultancy; Incyte: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding.