Background: In order to address the previously recognized limitation of autologous T cells modified to express chimeric antigen receptor (CAR) targeting CD19 in patients (pts) with chemotherapy refractory and relapsed CLL (Brentjens RJ et al., Blood 2011), we designed a phase I trial wherein CLL pts with residual disease following the first-line chemotherapy will receive the CD19-targeted CAR⁺ T cells as a consolidative therapy. Methods: Pts with CLL who have achieved either partial (PR) or complete response (CR) with detectable minimal residual disease (MRD) to the first-line therapy consisting of 6 cycles of pentostatin, cyclophosphamide and rituximab (PCR) were enrolled. Autologous T cells were transduced with a retroviral vector encoding the anti-CD19 scFv linked to CD28 co-stimulatory and CD3ζ signaling domains (19-28z). Pts received cyclophosphamide conditioning therapy followed by 3 escalating doses of CAR⁺ T cells. Response was assessed at 3 months according to the NCI-WG criteria. Results: 7 pts have received the CAR⁺ T cells in 3 dose cohorts (3x10⁶ - 3x10⁷ CAR⁺ T cells/kg). 6 pts had unmutated IgHV and 2 pts had del11q. All 7 pts achieved PR following the PCR chemotherapy. 4 pts had palpable lymphadenopathy (1 pt with bulky lymph nodes) prior to the T cell infusion. Median follow-up was 11 months (range, 3 – 17 mos). No DLT was observed. Mild and self-limiting cytokine release syndrome (CRS) was observed in 3 pts, and there was a positive correlation between the development of CRS and the CAR⁺ T cell persistence. 1 pt achieved CR; 2 pts achieved CR in the bone marrow (1 MRD negative CR) but had progressive disease in lymph node only; 3 pts achieved PR; and 1 pt had progressive disease but this pt had rapidly rising ALC at the time of T cell infusion. Conclusions: Autologous CD19-targeted CAR⁺ T cells appear to be safe and have promising anti-tumor efficacy in pts with high-risk CLL undergoing first-line chemoimmunotherapy. Our findings suggest that the CD19-targeted CAR⁺ T cells are more effective in eradicating disease in the marrow versus lymph nodes, and further studies are being conducted to better understand the mechanism of resistance. Clinical trial information: NCT01416974.