title: A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy.
abstract: OBJECTIVE
  Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.
  
  
  METHODS
  Three patients with colon cancer, four with non-Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles.
  
  
  RESULTS
  Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion.
  
  
  CONCLUSIONS
  Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.
authors.affiliation: Metabolism Branch, Laboratory of Pathology, Department of Laboratory Medicine, National Eye Institute, Bethesda, MD 20892-1457, USA.
authors.forename: Deirdre
authors.initials: D
authors.lastname: O'Mahony
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Cate
authors.initials: C
authors.lastname: Quinn
authors.forename: Wendy
authors.initials: W
authors.lastname: Gao
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: Barry
authors.initials: B
authors.lastname: Gause
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Sattva
authors.initials: S
authors.lastname: Neelapu
authors.forename: Margaret
authors.initials: M
authors.lastname: Brown
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: Robert
authors.initials: R
authors.lastname: Nussenblatt
authors.forename: Paul
authors.initials: P
authors.lastname: Albert
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Davis
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: Mike
authors.initials: M
authors.lastname: Petrus
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: John E
authors.initials: JE
authors.lastname: Janik
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D019041:L-Selectin / Q000096:biosynthesis; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D053645:Interleukin-2 Receptor alpha Subunit; D019041:L-Selectin; D017430:Prostate-Specific Antigen