title: Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer.
abstract: Many advances in the treatment of cancer have been driven by the development of targeted therapies that inhibit oncogenic signaling pathways and tumor-associated angiogenesis, as well as by the recent development of therapies that activate a patient's immune system to unleash antitumor immunity. Some targeted therapies can have effects on host immune responses, in addition to their effects on tumor biology. These immune-modulating effects, such as increasing tumor antigenicity or promoting intratumoral T cell infiltration, provide a rationale for combining these targeted therapies with immunotherapies. Here, we discuss the immune-modulating effects of targeted therapies against the MAPK and VEGF signaling pathways, and how they may synergize with immunomodulatory antibodies that target PD1/PDL1 and CTLA4. We critically examine the rationale in support of these combinations in light of the current understanding of the underlying mechanisms of action of these therapies. We also discuss the available preclinical and clinical data for these combination approaches and their implications regarding mechanisms of action. Insights from these studies provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of cancer.
authors.affiliation: Department of Oncology, Amgen, Inc, Thousand Oaks, CA, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hughes
authors.affiliation: Department of Oncology, Amgen, Inc, Thousand Oaks, CA, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Caenepeel
authors.affiliation: Department of Oncology, Amgen, Inc, South San Francisco, CA, USA. Electronic address: lawrenw@amgen.com.
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D003131:Combined Modality Therapy; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D042461:Vascular Endothelial Growth Factor A; D048049:Extracellular Signal-Regulated MAP Kinases