title: A Systematic Review of Immunotherapy in Urologic Cancer: Evolving Roles for Targeting of CTLA-4, PD-1/PD-L1, and HLA-G.
abstract: BACKGROUND
  Overexpression of immune checkpoint molecules affects tumor-specific T-cell immunity in the cancer microenvironment, and can reshape tumor progression and metastasis. Antibodies targeting checkpoints could restore antitumor immunity by blocking the inhibitory receptor-ligand interaction.
  
  
  OBJECTIVE
  To analyze data and current trends in immune checkpoint targeting therapy for urologic cancers.
  
  
  METHODS
  Systematic literature search for clinical trials in the PubMed and Cochrane databases up to August 2014 according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Endpoints included oncologic results, tumor response rates, safety, and tolerability.
  
  
  RESULTS
  Anti-CTLA-4 monotherapy has demonstrated biochemical responses in prostate cancer. One phase 3 trial assessing ipilimumab efficacy in castration-resistant disease was negative overall. Nevertheless, ipilimumab may significantly improve overall survival compared with placebo in subgroups of patients with favorable prognostic features. In renal cancer, phase 1 trials showed interesting stabilization or long-lasting objective response rates approaching 50% using anti-PD-1/PD-L1 drugs in heavily pretreated metastatic patients. In bladder cancer, one phase 2 trial indicated a good safety profile for ipilimumab as a neoadjuvant drug before radical cystectomy. Overall, immune-related effects such as colitis and dermatitis were common and well tolerated.
  
  
  CONCLUSIONS
  Our systematic review shows that antibodies blocking immune checkpoints offer interesting and long-lasting response rates in heavily pretreated patients with advanced urologic cancers. More promising results are currently provided by anti-CTLA-4 antibodies in prostate cancer and by PD-1/PD-L1 inhibitors in renal cancer. These should encourage new clinical trials of immune therapy combinations and immunotherapy monotherapy combined with conventional anticancer drugs. In bladder cancer, the use of targeted immunotherapy still remains underevaluated; however, preliminary results reported at recent conferences seem encouraging.
  
  
  RESULTS
  Data from studies support the activity and safety of immune checkpoint inhibitors in urologic cancers, alone or in combination with conventional cancer therapies. Encouraging data in other oncologic fields could translate into interesting responses in urological cancers.
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France; University Paris Diderot, Sorbonne Paris Cité, UMR E_5 Institut Universitaire d'Hematologie, Saint-Louis Hospital, Paris, France. Electronic address: edgardo.carosella@cea.fr.
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
authors.affiliation: Urology Department, Saint-Louis Hospital, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Ploussard
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France; University Paris Diderot, Sorbonne Paris Cité, UMR E_5 Institut Universitaire d'Hematologie, Saint-Louis Hospital, Paris, France.
authors.forename: Joel
authors.initials: J
authors.lastname: LeMaoult
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France; University Paris Diderot, Sorbonne Paris Cité, UMR E_5 Institut Universitaire d'Hematologie, Saint-Louis Hospital, Paris, France; Urology Department, Saint-Louis Hospital, Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Desgrandchamps
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D059951:HLA-G Antigens / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology; D058990:Molecular Targeted Therapy; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D059951:HLA-G Antigens; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: CTLA-4; Cancer immunotherapy; Checkpoint; HLA-G; Monoclonal antibodies; PD-1