Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia
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- 2 September 2015
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 7 (303), 303ra139
- https://doi.org/10.1126/scitranslmed.aac5415
Abstract
Patients with multiply relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. Chimeric antigen receptor (CAR)–modified T cells targeting CD19 have the potential to improve on the low complete response rates with conventional therapies by inducing sustained remissions in patients with refractory B cell malignancies. We previously reported preliminary results on three patients with refractory CLL. We report the mature results from our initial trial using CAR-modified T cells to treat 14 patients with relapsed and refractory CLL. Autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector were infused into patients with relapsed/refractory CLL at doses of 0.14 × 108 to 11 × 108 CTL019 cells (median, 1.6 × 108 cells). Patients were monitored for toxicity, response, expansion, and persistence of circulating CTL019 T cells. The overall response rate in these heavily pretreated CLL patients was 8 of 14 (57%), with 4 complete remissions (CR) and 4 partial remissions (PR). The in vivo expansion of the CAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR. No patient in CR has relapsed. All responding patients developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease was not detectable in patients who achieved CR, suggesting that disease eradication may be possible in some patients with advanced CLL.Keywords
Funding Information
- NIH (1R01CA165206, 1K24 CA117879, R01CA102646, R01CA116660)
- Pennsylvania Department of Health
- Leukemia and Lymphoma Society
This publication has 32 references indexed in Scilit:
- Chimeric Antigen Receptor T Cells for Sustained Remissions in LeukemiaThe New England Journal of Medicine, 2014
- T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trialThe Lancet, 2014
- Current concepts in the diagnosis and management of cytokine release syndromeBlood, 2014
- Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic LeukemiaScience Translational Medicine, 2014
- Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid LeukemiaThe New England Journal of Medicine, 2013
- Targeted Therapy With the T-Cell–Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B-Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free SurvivalJournal of Clinical Oncology, 2011
- Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19Blood, 2010
- Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domainsProceedings of the National Academy of Sciences of the United States of America, 2009
- Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drugJCI Insight, 2008
- Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantationBlood, 2003