title: Evaluating combinations of costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy.
abstract: Combinatory strategies are becoming of increasing interest in cancer immunotherapy. Costimulation by individual members of the immunoglobulin-like (Ig)- and TNF superfamily have already shown promising antitumor potential, thus prompting the exploration of their synergistic abilities in combinatorial approaches. Here, we pursued a targeted strategy with antibody-fusion proteins composed of a tumor-directed antibody and the extracellular domain of the costimulatory ligand B7.1, 4-1BBL, OX40L, GITRL or LIGHT, respectively. Costimulatory activity was assessed in an experimental setting where initial T cell activation was induced by a bispecific antibody (tumor-related antigen × CD3). Advantage of combined targeted costimulation was shown for either B7.1 or 4-1BBL with OX40L, GITRL, LIGHT and 4-1BBL in terms of T cell proliferation and IFN-γ release. Since encouraging results were obtained by the combination of B7.1 and 4-1BBL, we adapted the model system for a time-shift setting. Here, enhanced proliferation and granzyme B expression as well as reduced PD-1 expression on the T cell population demonstrated the benefit of costimulation-assisted restimulation. Finally, the antitumor potential of this combinatorial setting was confirmed in vivo in a lung metastasis mouse model. Thus, combinatorial approaches with costimulatory antibody-ligand fusion proteins seem a promising strategy to be further investigated for cancer immunotherapy.
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Hornig
authors.forename: Katharina
authors.initials: K
authors.lastname: Reinhardt
authors.forename: Vanessa
authors.initials: V
authors.lastname: Kermer
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kontermann
authors.forename: Dafne
authors.initials: D
authors.lastname: Müller
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology; D000818:Animals; D018033:Antibodies, Bispecific / Q000235:genetics / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D018033:Antibodies, Bispecific; D018122:B7-1 Antigen; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D053804:Granzymes