title: The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment.
abstract: Traditional treatment modalities for advanced cancer (radiotherapy, chemotherapy, or targeted agents) act directly on tumors to inhibit or destroy them. Along with surgery, these modalities are predominantly palliative, with toxicity and only modest improvements in survival in patients with advanced solid tumors. Accordingly, long-term survival rates for most patients with advanced cancer remain low, thus there is a need for cancer treatments with favorable benefit and toxicity profiles that can potentially result in long-term survival. The immune system plays a critical role in the recognition and eradication of tumor cells ("immune surveillance"), and immunotherapies based on this concept have been used for decades with some success against a few tumor types; however, most immunotherapies were limited by a lack of either substantial efficacy or specificity, resulting in toxicity. We now have a greater understanding of the complex interactions between the immune system and tumors and have identified key molecules that govern these interactions. This information has revitalized the interest in immunotherapy as an evolving treatment modality using immunotherapeutics designed to overcome the mechanisms exploited by tumors to evade immune destruction. Immunotherapies have potentially complementary mechanisms of action that may allow them to be combined with other immunotherapeutics, chemotherapy, targeted therapy, or other traditional therapies. This review discusses the concepts and data behind immunotherapies, with a focus on the checkpoint inhibitors and their responses, toxicities, and potential for long-term survival, and explores promising single-agent and combination therapies in development.
  
  
  CONCLUSIONS
  Immunotherapy is an evolving treatment approach based on the role of the immune system in eradicating cancer. An example of an immunotherapeutic is ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipilimumab is approved for advanced melanoma and induced long-term survival in a proportion of patients. The programmed death-1 (PD-1) checkpoint inhibitors are promising immunotherapies with demonstrated sustained antitumor responses in several tumors. Because they harness the patient's own immune system, immunotherapies have the potential to be a powerful weapon against cancer.
authors.affiliation: Levine Cancer Institute, Charlotte, North Carolina, USA; University of Washington, Seattle, Washington, USA Gregory.K.Pennock@carolinashealthcare.org.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Pennock
authors.affiliation: Levine Cancer Institute, Charlotte, North Carolina, USA; University of Washington, Seattle, Washington, USA.
authors.forename: Laura Q M
authors.initials: LQ
authors.lastname: Chow
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human
keywords: CTLA-4; Checkpoint inhibitors; Combination; Immunotherapy; PD-1; Survival