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Mol Ther. 2018 Aug 1;26(8):1896-1905. doi: 10.1016/j.ymthe.2018.05.018. Epub 2018 Jun 15.

Autologous CD19-Targeted CAR T Cells in Patients with Residual CLL following Initial Purine Analog-Based Therapy.

Author information

1
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Department of Medicine, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, NY, USA.
8
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
10
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: brentjer@mskcc.org.

Abstract

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m2), followed by escalating doses of 3 × 106, 1 × 107, or 3 × 107 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-α. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation.

KEYWORDS:

CAR T cells; adoptive cellular therapy; chimeric antigen receptors; chronic lymphocytic leukemia; immunotherapy

PMID:
29910179
PMCID:
PMC6094824
[Available on 2019-08-01]
DOI:
10.1016/j.ymthe.2018.05.018

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