title: Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.
abstract: BACKGROUND
  Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma.
  
  
  METHODS
  Thirty-six patients received anti-CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses).
  
  
  RESULTS
  Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti-CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis.
  
  
  CONCLUSIONS
  There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, CRC Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, MD 20814, USA.
authors.forename: Ajay V
authors.initials: AV
authors.lastname: Maker
authors.forename: Giao Q
authors.initials: GQ
authors.lastname: Phan
authors.forename: Peter
authors.initials: P
authors.lastname: Attia
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
authors.forename: Udai S
authors.initials: US
authors.lastname: Kammula
authors.forename: Richard E
authors.initials: RE
authors.lastname: Royal
authors.forename: Leah R
authors.initials: LR
authors.lastname: Haworth
authors.forename: Catherine
authors.initials: C
authors.lastname: Levy
authors.forename: David
authors.initials: D
authors.lastname: Kleiner
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Mavroukakis
authors.forename: Michael
authors.initials: M
authors.lastname: Yellin
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D015551:Autoimmunity; D060908:CTLA-4 Antigen; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000627:therapeutic use*; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008875:Middle Aged; D012878:Skin Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D014057:Tomography, X-Ray Computed
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D000074324:Ipilimumab