title: Optimising anti-tumour CD8 T-cell responses using combinations of immunomodulatory antibodies.
abstract: Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. In particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD8+ T cells but produced fewer IFN-gamma-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.
authors.affiliation: Tenovus Research Laboratory, Cancer Sciences Division, Southampton University School of Medicine, Tremona Road, Southampton, UK.
authors.forename: Juliet C
authors.initials: JC
authors.lastname: Gray
authors.forename: Ruth R
authors.initials: RR
authors.lastname: French
authors.forename: Sonya
authors.initials: S
authors.lastname: James
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
authors.forename: Peter W
authors.initials: PW
authors.lastname: Johnson
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D053262:Receptors, OX40 / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology* / Q000628:therapy; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D019496:Cancer Vaccines; D053645:Interleukin-2 Receptor alpha Subunit; D053262:Receptors, OX40; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D010047:Ovalbumin