title: Big opportunities for small molecules in immuno-oncology.
abstract: The regulatory approval of ipilimumab (Yervoy) in 2011 ushered in a new era of cancer immunotherapies with durable clinical effects. Most of these breakthrough medicines are monoclonal antibodies that block protein-protein interactions between T cell checkpoint receptors and their cognate ligands. In addition, genetically engineered autologous T cell therapies have also recently demonstrated significant clinical responses in haematological cancers. Conspicuously missing from this class of therapies are traditional small-molecule drugs, which have previously served as the backbone of targeted cancer therapies. Modulating the immune system through a small-molecule approach offers several unique advantages that are complementary to, and potentially synergistic with, biologic modalities. This Review highlights immuno-oncology pathways and mechanisms that can be best or solely targeted by small-molecule medicines. Agents aimed at these mechanisms--modulation of the immune response, trafficking to the tumour microenvironment and cellular infiltration--are poised to significantly extend the scope of immuno-oncology applications and enhance the opportunities for combination with tumour-targeted agents and biologic immunotherapies.
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Adams
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
authors.forename: James
authors.initials: J
authors.lastname: Smothers
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
authors.forename: Roopa
authors.initials: R
authors.lastname: Srinivasan
authors.affiliation: GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Hoos
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy / Q000639:trends*; D000074324:Ipilimumab; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000074324:Ipilimumab