title: Modulation of tumor immunity: a patent evaluation of WO2015026684A1.
abstract: A high percentage of regulatory T cells (Tregs) among tumor-infiltrating lymphocytes weakens the immune response against tumors. The anergy of effector T cells (Teff) can be reversed by immune checkpoint treatment, which inhibits Tregs and boosts the activation of Teff. Both effects can be obtained by triggering the glucocorticoid-induced TNF receptor-related (GITR), a costimulatory molecule expressed by Teff and Tregs, and by inhibiting the programmed cell death (PD)-1 receptor, an inhibitory molecule expressed by Teff. Patent W02015026684A1 provides a method of treating human tumors using a combination of a molecule triggering GITR and another inhibiting PD-1. The treatment approach was tested on three murine models of cancer, and the synergic effect of antihuman antibodies (Abs) in combination was tested in mixed lymphocyte reactions. Immune checkpoint treatment can break tolerance toward tumors and promote tumor rejection. The patented approach is very interesting and might be successful. The combined use of PD-1 antagonists and GITR agonists is synergic and tumor-centered, and adverse events might be less problematic than expected. A crucial point in translating the murine studies to humans is the differences between murine and human GITR and the evidence that some antihuman GITR Abs are not agonists.
authors.affiliation: a Department of Medicine , University of Perugia , San Sisto (PG) , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.affiliation: a Department of Medicine , University of Perugia , San Sisto (PG) , Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Cari
authors.affiliation: a Department of Medicine , University of Perugia , San Sisto (PG) , Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ronchetti
authors.affiliation: a Department of Medicine , University of Perugia , San Sisto (PG) , Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D015195:Drug Design; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000819:agonists* / Q000276:immunology; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D010330:Patents as Topic; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D013045:Species Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D053450:Glucocorticoid-Induced TNFR-Related Protein; D061026:Programmed Cell Death 1 Receptor; C491405:TNFRSF18 protein, human
keywords: GITR (glucocorticoid-induced TNF receptor-related molecule); Immune checkpoint treatment; PD-1 (programmed cell death 1); TILs (tumor-infiltrating lymphocytes); Tregs (regulatory T cells); co-accessory molecules; combination treatment; solid tumors