Research Article Committing Cytomegalovirus-Specific CD8 T Cells to Eliminate Tumor Cells by Bifunctional Major Histocompatibility Class I Antibody Fusion Molecules

Tumor cells escape immune eradication through multiple mechanisms, including loss of antigenicity and local suppres-sion of effector lymphocytes. To counteract these obstacles, we aimed to direct the unique cytomegalovirus (CMV)-specific immune surveillance against tumor cells. We developed a novel generation of fusion proteins composed of a tumor antigen–specific full immunoglobulin connected to a single major histocompatibility class I complex bearing a covalently linked virus-derived peptide (pMHCI–IgG). Here, we show that tumor antigen–expressing cancer cells, which are deco-rated with pMHCI–IgGs containing a HLA-A0201 molecule associated with a CMV-derived peptide, are specifically elim-inated through engagement of antigen-specific CD8þ T cells isolated from peripheral blood mononuclear cell preparations of CMV-infected humans. These CD8þ T cells act without additional expansion, preactivation, or provision of costimu-latory signals. Elimination of tumor cells is induced at similar concentrations and with similar time kinetics as those seen with bispecific T-cell engagers (BiTE). However, while BiTE-like reagents indiscriminately activate T cells through binding to the T-cell receptor complex, pMHCI–IgGs selectively engage antigen-specific, constantly renewable, differentiated effector cytotoxic T lymphocytes to tumor cells, thereby representing a novel class of anticancer immunotherapeutics with potentially improved safety and efficacy profiles. Cancer Immunol Res; 3(7); 1–13. 2015 AACR