A phase II, dose-optimization trial of autologous T cells genetically engineered to express anti-CD19 chimeric antigen receptor (CART-19) in patients with relapsed or refractory (r/r) CD19+ chronic lymphocytic leukemia (CLL)

TPS7132 Background: The poor prognosis and lack of effective treatment options for patients with r/r CLL highlight the need for novel therapies in this setting. CD19 is a promising anticancer target because it is broadly expressed on normal and malignant B cells through several stages of maturation but absent on pluripotent stem cells. CART-19 (CTL019) therapy involves adoptive transfer of autologous T cells genetically modified via lentiviral transduction to express chimeric antigen receptors (CAR) designed to target CD19+ cells. CART-19 cells express a CD19 antigen recognition domain combined with intracellular signaling domains, CD137 (4-1BB) and CD3-zeta, which mediate cytolytic T-cell activity. In patients with r/r CLL, CART-19 therapy showed potent antileukemic activity with long-term persistence of transduced cells at doses from 1.4 × 107 to 1.1 × 109 CART-19 cells. As of August 2012, 3 of 8 evaluable CLL patients achieved CR (two > 24 months and one > 5 months) and remain in CR with detectable CART-19 cells. Two patients had PR lasting 3 and 5 months, and 3 patients did not respond (Porter et al. NEJM. 2011; Kalos et al. Sci Transl Med. 2011; Porter et al. ASH 2012). Here, we describe a study to determine the optimal dose of CART-19 cells (NCT01747486). Methods: Adults with relapsed or persistent CLL or SLL after ≥ 2 previous therapies will undergo leukapheresis to obtain T cells, which will be stimulated, expanded, and lentivirus transduced ex vivo to express the CD19/4-1BB/CD3-zeta CAR. Patients will undergo lymphodepletion chemotherapy prior to infusion of CART-19 cells. In stage I of the II-stage trial, 30 patients will be randomized 1:1 and receive either 1-5 × 108 or 1-5 × 107 CART-19 T cells. The optimal dose in stage I will be selected based on clinical responses, feasibility, and tolerability. In stage II, 8 additional patients will be enrolled into the selected dose cohort. Study objectives are to determine the efficacy (CR rate within 3 months) and safety (CTCAE v 4.0) of each dose, in vivo CART-19 expansion, and manufacturing feasibility. Three patients have been enrolled as of January 2013. Clinical trial information: NCT01747486.