Cytokine-Induced Killer Cells Engineered with Exogenous T-Cell Receptors Directed Against Melanoma Antigens: Enhanced Efficacy of Effector Cells Endowed with a Double Mechanism of Tumor Recognition

• DOI: 10.1089/hum.2014.112
• Publication Date: 2015-03-11T05:53:23Z
• Authors: Angela R. Elia; Paola Circosta; Dario Sangiolo; Chiara Bonini; Loretta Gammaitoni; Sara Mastaglio; Pietro Genovese; Massimo Geuna; Fabio Avolio; Giorgio Inghirami; Corrado Tarella; Alessandro Cignetti
• Keywords: 0301 basic medicine; Antigens, Neoplasm; B-Lymphocyte Subsets; Cell Line, Tumor; Cytokines; Genetic Engineering; Humans; Immunotherapy, Adoptive; Leukocytes, Mononuclear; Melanoma; Natural Killer T-Cells; Receptors, Antigen, T-Cell; Molecular Medicine; Molecular Biology; Genetics; Antigens, Neoplasm; B-Lymphocyte Subsets; Cell Line, Tumor; Cytokines; Genetic Engineering; Humans; Immunotherapy, Adoptive; Leukocytes, Mononuclear; Melanoma; Natural Killer T-Cells; Receptors, Antigen, T-Cell; B-Lymphocyte Subsets; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; 3. Good health; 03 medical and health sciences; Antigens, Neoplasm; Cell Line, Tumor; Leukocytes, Mononuclear; Cytokines; Humans; Natural Killer T-Cells; Genetic Engineering; Melanoma

Cytokine-induced killer (CIK) cells consist of a heterogeneous population polyclonal T lymphocytes displaying NK phenotype and HLA-unrestricted cytotoxic activity against broad range tumors. We sought to determine whether transduction CIK with cell receptor (TCR) genes specific for tumor-associated antigens could generate effector endowed double mechanism tumor recognition. HLA-A2-restricted TCR-transduced (TD) directed the melanoma Mart1 NY-ESO1 were generated by lentiviral successfully expanded over 3-4-week period. TD-CIK both CD3(+)/CD56(-) CD3(+)/CD56(+) (31±8% 59±9%, respectively), indicating that major histocompatibility complex (MHC)-restricted MHC-unrestricted be targeted transduction. At end culture, majority unmodified displayed an memory phenotype, without considerable expression replicative senescence exhaustion markers. Functionally, specifically recognized expressing relevant antigen as well maintained their activity. The HLA-A2(+) lines was significantly higher than untransduced counterparts at low effector:target ratio (cytotoxic from 1.9- 4.3-fold counterparts). highly proficient in releasing high amount IFN-γ upon antigen-specific stimulation able recognize primary targets. In conclusion, we showed (1) reproducibility simplicity expansion might solve problem obtaining adequate numbers potent antitumor adoptive immunotherapy; (2) presence terminal effectors less differentiated progenitors confer them long survival vivo; (3) addition MHC-restricted recognition allows not only targeting surface but also wider cytoplasmic or nuclear antigens, involved proliferation survival. are attractive alternative tool development efficient therapeutic strategies.