title: Rational Combination of Immunotherapies with Clinical Efficacy in Mice with Advanced Cancer.
abstract: In the context of cancer, naïve T cells are insufficiently primed and become progressively dysfunctional. Boosting antitumor responses by blocking PD-1 or CTLA-4 results in durable clinical responses only in a limited proportion of cancer patients, suggesting that other pathways must be targeted to improve clinical efficacy. Our preclinical study in TRAMP mice comparing 14 different immune interventions identified anti-CD40 + IL2/anti-IL2 complexes + IL12Fc as a uniquely efficacious treatment that prevents tolerance induction, promotes priming of sustained, protective tumor-specific CD8(+) T cells, and cures late-stage cancer when given together with adoptively transferred tumor-specific T cells. We propose that improving signals 2 (costimulation) and 3 (cytokines) together with fresh tumor-specific, rather than boosting of dysfunctional preexisting memory, T cells represents a potent therapy for advanced cancer.
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Ali
authors.initials: A
authors.lastname: Bransi
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Oscar Camilo
authors.initials: OC
authors.lastname: Salgado
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Michal
authors.initials: M
authors.lastname: Beffinger
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Karim
authors.initials: K
authors.lastname: Milo
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Karina
authors.initials: K
authors.lastname: Silina
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.affiliation: National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Alexander
authors.initials: A
authors.lastname: Knuth
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. vandenbroek@immunology.uzh.ch.
authors.forename: Maries
authors.initials: M
authors.lastname: van den Broek
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D053208:Kaplan-Meier Estimate; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*