title: A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma.
abstract: OBJECTIVE
  Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy.
  
  
  RESULTS
  There was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients (95% CI, 40%-93%), an abscopal response was seen in 89% (95% CI, 68%-100%). The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% (95% CI, 10%-70%) and 50% (95% CI, 19%-81%), respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses.
  
  
  METHODS
  Twelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks.
  
  
  CONCLUSIONS
  Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.
authors.affiliation: Division of Oncology, Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Ray
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Williams
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Meek
authors.affiliation: School of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Randy C
authors.initials: RC
authors.lastname: Bowen
authors.affiliation: Division of Oncology, Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA.
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Grossmann
authors.affiliation: Section of Surgical Oncology, Division of General Surgery Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA.
authors.forename: Robert H I
authors.initials: RH
authors.lastname: Andtbacka
authors.affiliation: Department of General Surgery, Intermountain Medical Center, Murray, UT, USA.
authors.forename: Tawnya L
authors.initials: TL
authors.lastname: Bowles
authors.affiliation: Section of Surgical Oncology, Division of General Surgery Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA.|Department of General Surgery, Intermountain Medical Center, Murray, UT, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Hyngstrom
authors.affiliation: Department of Dermatology, Oregon Health & Science University-Knight Cancer Institute, Portland, OR, USA.
authors.forename: Sancy A
authors.initials: SA
authors.lastname: Leachman
authors.affiliation: Division of Oncology, Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Grossman
authors.affiliation: Division of Oncology, Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA.
authors.forename: Glen M
authors.initials: GM
authors.lastname: Bowen
authors.affiliation: Division of Oncology, Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Holmen
authors.affiliation: Division of Oncology, Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: VanBrocklin
authors.affiliation: Department of Radiation Oncology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Gita
authors.initials: G
authors.lastname: Suneja
authors.affiliation: Division of Oncology, Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA.
authors.forename: Hung T
authors.initials: HT
authors.lastname: Khong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D000074324:Ipilimumab / Q000008:administration & dosage* / Q000009:adverse effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014589:Utah
chemical_list: D007376:Interleukin-2; D000074324:Ipilimumab
keywords: abscopal effect; immunotherapy; interleukin-2; intratumoral; ipilimumab