title: Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer.
abstract: BACKGROUND
  The FDA recently approved an anti-CTLA-4 antibody (Iplimumab) for the treatment of metastatic melanoma. This decision was based on Phase III results, which demonstrate that blocking this immune checkpoint provides a survival advantage in patients with advanced disease. As a single agent, ipilimumab is also being clinically evaluated in advanced (metastatic, castrate-resistant) prostate cancer and two randomized, placebo-controlled Phase III studies have recently completed accrual.
  
  
  METHODS
  We used a well-described genetically engineered mouse (GEM), autochronous prostate cancer model (Pro-TRAMP) to explore the relative sequencing and dosing of anti-CTLA-4 antibody when combined with a cell-based, GM-CSF-secreting vaccine (GVAX).
  
  
  RESULTS
  Our results show that combined treatment results in a dramatic increase in effector CD8 T cells in the prostate gland, and enhanced tumor-antigen directed lytic function. These effects are maximized when CTLA-4 blockade is applied after, but not before, vaccination. Additional experiments, using models of metastatic disease, show that incorporation of low-dose cyclophosphamide into this combined treatment regimen results in an additional pre-clinical benefit.
  
  
  CONCLUSIONS
  Together these studies define a combination regimen using anti-CTLA-4/GVAX immunotherapy and low-dose chemotherapy for potential translation to a clinical trial setting.
authors.affiliation: Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Wada
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jackson
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Hung-Rong
authors.initials: HR
authors.lastname: Yen
authors.forename: Derese
authors.initials: D
authors.lastname: Getnet
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Harris
authors.forename: Monica V
authors.initials: MV
authors.lastname: Goldberg
authors.forename: Tullia C
authors.initials: TC
authors.lastname: Bruno
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grosso
authors.forename: Nicholas
authors.initials: N
authors.lastname: Durham
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D019496:Cancer Vaccines / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000074324:Ipilimumab; D008113:Liver Neoplasms / Q000473:pathology / Q000628:therapy; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D000074324:Ipilimumab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide
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