title: Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition.
abstract: Combinatorial approaches of immunotherapy hold great promise for the treatment of malignant disease. Here, we examined the potential of combining an immune checkpoint inhibitor and trifunctional bispecific antibodies (trAbs) in a preclinical melanoma mouse model using surrogate antibodies of Ipilimumab and Catumaxomab, both of which have already been approved for clinical use. The specific binding arms of trAbs redirect T cells to tumor cells and trigger direct cytotoxicity, while the Fc region activates accessory cells eventually giving rise to a long-lasting immunologic memory. We show here that T cells redirected to tumor cells by trAbs strongly upregulate CTLA-4 expression in vitro and in vivo. This suggested that blocking of CTLA-4 in combination with trAb treatment enhances T-cell activation in a tumor-selective manner. However, when mice were challenged with melanoma cells and subsequently treated with antibodies, there was only a moderate beneficial effect of the combinatorial approach in vivo with regard to direct tumor destruction in comparison to trAb therapy alone. By contrast, a significantly improved vaccination effect was obtained by CTLA-4 blocking during trAb-dependent immunization. This resulted in enhanced rejection of melanoma cells given after pre-immunization. The improved immunologic memory induced by the combinatorial approach correlated with an increased humoral antitumor response as measured in the sera and an expansion of CD4+ memory T cells found in the spleens.
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Deppisch
authors.affiliation: Trion Research GmbH, Martinsried, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruf
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Eißler
authors.affiliation: Trion Research GmbH, Martinsried, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Lindhofer
authors.affiliation: Institut für Molekulare Immunologie, Helmholtz-Zentrum München, Germany.|AG Translationale Molekulare Immunologie, Helmholtz-Zentrum München, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mocikat
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods*; D000074324:Ipilimumab / Q000008:administration & dosage / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D013154:Spleen / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D000074324:Ipilimumab; C522419:catumaxomab
keywords: CTLA-4; T-cell activation; cancer immunotherapy; melanoma; tumor antigen