title: Committing Cytomegalovirus-Specific CD8 T Cells to Eliminate Tumor Cells by Bifunctional Major Histocompatibility Class I Antibody Fusion Molecules.
abstract: Tumor cells escape immune eradication through multiple mechanisms, including loss of antigenicity and local suppression 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 decorated with pMHCI-IgGs containing a HLA-A*0201 molecule associated with a CMV-derived peptide, are specifically eliminated through engagement of antigen-specific CD8(+) T cells isolated from peripheral blood mononuclear cell preparations of CMV-infected humans. These CD8(+) T cells act without additional expansion, preactivation, or provision of costimulatory 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.
authors.affiliation: Large Molecule Research, Roche Innovation Center Penzberg, Roche Pharma Research and Early Development, Penzberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Schmittnaegel
authors.affiliation: Discovery Oncology, Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Zurich, Switzerland.
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
authors.affiliation: Large Molecule Research, Roche Innovation Center Penzberg, Roche Pharma Research and Early Development, Penzberg, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Hoffmann
authors.affiliation: Large Molecule Research, Roche Innovation Center Penzberg, Roche Pharma Research and Early Development, Penzberg, Germany.
authors.forename: Guy
authors.initials: G
authors.lastname: Georges
authors.affiliation: Large Molecule Research, Roche Innovation Center Penzberg, Roche Pharma Research and Early Development, Penzberg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Mundigl
authors.affiliation: Discovery Oncology, Roche Innovation Center Zurich, Roche Pharma Research and Early Development, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Large Molecule Research, Roche Innovation Center Penzberg, Roche Pharma Research and Early Development, Penzberg, Germany. hendrik.knoetgen@roche.com.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Knoetgen
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000906:Antibodies; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D010455:Peptides