title: A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells.
abstract: Anti-CD20 monoclonal antibodies (mAb) such as rituximab have been proven to be highly effective at improving outcome in B-cell malignancies. However, many patients ultimately relapse and become refractory to treatment. The glycoengineered anti-CD20 mAb obinutuzumab was developed to induce enhanced antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis and direct cell death and was shown to lead to improved outcomes in a randomized study in B-CLL. We hypothesized that immune stimulation through Toll-like receptor 7 (TLR7) agonism in combination with obinutuzumab would further enhance lymphoma clearance and the generation of long-term antitumor immune responses. Here we demonstrate, in syngeneic human CD20 (hCD20)-expressing models of lymphoma, that systemic administration of a TLR7 agonist (R848) increases responses when administered in combination with obinutuzumab and protects against disease recurrence. Depletion studies demonstrate that primary antitumor activity is dependent on both NK cells and CD4+T cells but not on CD8+T cells. However, both CD4+and CD8+T cells appear necessary for the generation of protective immunological memory. Importantly, increased tumor-free survival post obinutuzumab and R848 combination therapy was seen in hCD20 transgenic mice, which express hCD20 on normal B cells. These findings provide a rationale for clinical testing of obinutuzumab in combination with systemically administered TLR7 agonists to further improve outcome.
authors.affiliation: Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, University of Manchester, Christie Hospital, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Cheadle
authors.affiliation: Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, University of Manchester, Christie Hospital, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: G
authors.initials: G
authors.lastname: Lipowska-Bhalla
authors.affiliation: Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, University of Manchester, Christie Hospital, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Dovedi
authors.affiliation: Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, University of Manchester, Christie Hospital, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: E
authors.initials: E
authors.lastname: Fagnano
authors.affiliation: Roche Pharmaceutical Research &Early Development, Roche Innovation Center Zurich, Zurich, Switzerland.
authors.forename: C
authors.identifier: 0000-0001-7594-7280
authors.initials: C
authors.lastname: Klein
authors.affiliation: Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, University of Manchester, Christie Hospital, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Honeychurch
authors.affiliation: Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, University of Manchester, Christie Hospital, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: T M
authors.initials: TM
authors.lastname: Illidge
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D000069283:Rituximab / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007093:Imidazoles; D051199:Toll-Like Receptor 7; D000069283:Rituximab; C543332:obinutuzumab; C402365:resiquimod