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

TitleTailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms.
Publication TypeJournal Article
Year of Publication2018
AuthorsCircosta P, Elia ARita, Landra I, Machiorlatti R, Todaro M, Aliberti S, Brusa D, Deaglio S, Chiaretti S, Bruna R, Gottardi D, Massaia M, Di Giacomo F, Guarini ARita, FoĆ  R, Kyriakides PW, Bareja R, Elemento O, Chichili GR, Monteleone E, Moore PA, Johnson S, Bonvini E, Cignetti A, Inghirami G
Date Published2018

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.

Alternate JournalOncoimmunology
PubMed ID29632712
PubMed Central IDPMC5889202