학술논문
Tailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms
Document Type
article
Author
Paola Circosta; Angela Rita Elia; Indira Landra; Rodolfo Machiorlatti; Maria Todaro; Sabrina Aliberti; Davide Brusa; Silvia Deaglio; Sabina Chiaretti; Riccardo Bruna; Daniela Gottardi; Massimo Massaia; Filomena Di Giacomo; Anna Rita Guarini; Robin Foà; Peter W. Kyriakides; Rohan Bareja; Olivier Elemento; Gurunadh R. Chichili; Emanuele Monteleone; Paul A. Moore; Syd Johnson; Ezio Bonvini; Alessandro Cignetti; Giorgio Inghirami
Source
OncoImmunology, Vol 7, Iss 4 (2018)
Subject
Language
English
ISSN
2162-402X
2162402X
2162402X
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.