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Oncoimmunology. 2018 Feb 8;7(4):e1341032. doi: 10.1080/2162402X.2017.1341032. eCollection 2018.

Tailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms.

Author information

1
Molecular Biotechnology Center, University of Torino, Italy, and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
2
Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
3
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
4
Department of Medical Sciences, University of Torino, Torino, Italy; Flow Cytometry and Cell Sorting Facility, Human Genetics Foundation, Torino, Italy.
5
Division of Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.
6
University Division of Hematology and Cell Therapy, University of Torino, Ospedale Mauriziano, Torino, Italy.
7
Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, New York, USA[2] Institute for Precision Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York, USA.
8
MacroGenics Inc., 9640 Medical Center Drive, Rockville, MD, USA.
9
MacroGenics Inc., 9704 Medical Center Drive, Rockville, MD, USA.
10
Department of Pathology, NYU Cancer Center, New York University School of Medicine, New York, NY.

Abstract

Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4+ cells into cytotoxic effectors required the presence of CD8+ cells. Serial exposures to DART led to the exponential expansion of CD4 + and CD8 + cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma.

KEYWORDS:

B-cell malignancies; CIK cells; DART CD19xCD3; PDTX; bispecific antibodies

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