title: Therapeutic Efficacy of 4-1BB Costimulation Is Abrogated by PD-1 Blockade in a Model of Spontaneous B-cell Lymphoma.
abstract: Combinations of mAbs that target various components of T-cell activation/inhibition may work synergistically to improve antitumor immunity against cancer. In this study, we investigated the therapeutic potential of combining an anticancer vaccination strategy with antibodies targeting an immune stimulatory (4-1BB) and immune inhibitory (PD-1) receptor, in a preclinical model of spontaneously arising c-Myc-driven B-cell lymphoma. In Eμ-myc transgenic mice, we reveal that 4-1BB agonistic mAb treatment alone was sufficient to drive antitumor immunity and prevent disease progression in 70% of mice. When combined with an α-GalCer-loaded, irradiated tumor cell vaccine, 4-1BB mAb treatment led to increased expansion of effector CD8 T-cell populations and protection of long-term surviving mice against tumor rechallenge. Unexpectedly, PD-1 blockade did not provide therapeutic benefit. The T-cell-promoting effects and antitumor activity of 4-1BB mAb were diminished when used simultaneously with a PD-1-blocking mAb. This was associated with a rapid and dramatic reduction in effector CD8+T-cell subsets in the presence of PD-1 blockade. These findings reveal that supporting T-cell activation therapeutically is effective for controlling B-cell lymphomas; however, caution is required when combining antibody-mediated modulation of both costimulatory and coinhibitory T-cell receptors.Cancer Immunol Res; 5(3); 191-7. ©2017 AACR.
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: McKee
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Brianna L
authors.initials: BL
authors.lastname: Doff
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Megan S F
authors.initials: MS
authors.lastname: Soon
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia. s.mattarollo@uq.edu.au.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Mattarollo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage; D007156:Immunologic Memory; D007167:Immunotherapy; D007371:Interferon-gamma / Q000097:blood; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D005699:Galactosylceramides; D061026:Programmed Cell Death 1 Receptor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C493154:alpha-galactosylceramide; D007371:Interferon-gamma