title: A phase II trial of intraperitoneal interleukin-2 in patients  with platinum-resistant or platinum-refractory ovarian cancer.
abstract: Ovarian cancer patients with persistent (platinum-resistant) or progressive (platinum-refractory) disease respond poorly to second line chemotherapy and have low survival expectancy. New and improved therapeutic approaches are needed and immune biologics are one possibility. Interleukin-2 (IL-2) is a T-cell growth factor believed to be important in anti-tumor immunity. We performed a phase II clinical trial with intraperitoneal (IP) recombinant IL-2 administered in weekly infusions of 6 x 10(5) IU/m2. Thirty-one subjects were sequentially entered into the study and clinical responses were surgically confirmed in 24 patients. The primary end point of this study was clinical response with immunologic measurements as secondary end points. The IP regimen was generally well tolerated. Of the 24 patients assessed for response, there were 6 (4 complete, 2 partial) responses for an overall response rate of 25.0% [95% confidence interval (CI) of 11-45]. The median survival of the 31 patient cohort was 2.1 years (95% CI of 1.3-4.4), but for the 6 patients with responses the median survival has not been reached (range 24-120+ months). Eosinophil and lymphocyte numbers were continuously monitored during treatment. Peripheral blood eosinophils were markedly increased at the completion of treatment (p < 0.0001) and associated with increased circulating eotaxin (p = 0.03). We also found significant associations between changes in CD3 counts and survival (p = 0.05) and between IFNγ- secreting CD8 T cells at early time points and survival (p = 0.04). This study provides important evidence for IP IL-2 in platinum-resistant ovarian cancer and identifies several immune correlates of survival.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, 300 Halket Str, Pittsburgh, PA 15213, USA.
authors.forename: Anda M
authors.initials: AM
authors.lastname: Vlad
authors.forename: Raluca A
authors.initials: RA
authors.lastname: Budiu
authors.forename: Diana E
authors.initials: DE
authors.lastname: Lenzner
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Julia A
authors.initials: JA
authors.lastname: Thaller
authors.forename: Kelly
authors.initials: K
authors.lastname: Colonello
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Crowley-Nowick
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kelley
authors.forename: Fredric V
authors.initials: FV
authors.lastname: Price
authors.forename: Robert P
authors.initials: RP
authors.lastname: Edwards
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004802:Eosinophilia / Q000276:immunology; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008214:Lymphocytes / Q000276:immunology; D008218:Lymphocytosis / Q000276:immunology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality; D017671:Platinum Compounds / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007376:Interleukin-2; D017671:Platinum Compounds; D011994:Recombinant Proteins
references.citation: J Clin Oncol. 1999 Jul;17(7):2105-16
references.pmid: 10561265
references.citation: Int J Cancer. 1993 Apr 22;54(1):8-15
references.pmid: 8386711
references.citation: N Engl J Med. 2003 Jan 16;348(3):203-13
references.pmid: 12529460
references.citation: Oncology. 1994 Jan-Feb;51(1):59-62
references.pmid: 8265104
references.citation: N Engl J Med. 1985 Dec 5;313(23):1485-92
references.pmid: 3903508
references.citation: N Engl J Med. 1996 Dec 26;335(26):1950-5
references.pmid: 8960474
references.citation: J Immunol. 2007 Sep 1;179(5):2832-43
references.pmid: 17709497
references.citation: Histol Histopathol. 1997 Jul;12(3):807-12
references.pmid: 9225164
references.citation: Gynecol Oncol. 1998 Jun;69(3):226-9
references.pmid: 9648592
references.citation: Oncogene. 2008 Jan 7;27(2):190-9
references.pmid: 18176600
references.citation: Cancer Cell. 2008 Jun;13(6):507-18
references.pmid: 18538734
references.citation: Cancer Biother. 1993 Summer;8(2):123-36
references.pmid: 7804353
references.citation: J Clin Oncol. 1992 Sep;10(9):1479-84
references.pmid: 1517791
references.citation: Eur J Immunol. 1997 Dec;27(12):3507-16
references.pmid: 9464841
references.citation: Anticancer Drugs. 2006 Jan;17(1):1-12
references.pmid: 16317284
references.citation: Nat Rev Cancer. 2008 Aug;8(8):579-91
references.pmid: 18596824
references.citation: Cancer Res. 2000 Mar 15;60(6):1515-20
references.pmid: 10749115
references.citation: Expert Rev Mol Diagn. 2008 May;8(3):301-14
references.pmid: 18598109
references.citation: Biochem Biophys Res Commun. 1997 Jul 18;236(2):299-301
references.pmid: 9240429
references.citation: Cancer. 1996 Feb 1;77(3):436-40
references.pmid: 8630949
references.citation: J Clin Oncol. 1995 Mar;13(3):688-96
references.pmid: 7884429
references.citation: Cancer Immunol Immunother. 2004 Aug;53(8):729-39
references.pmid: 15088127
references.citation: Hum Pathol. 1996 Sep;27(9):904-11
references.pmid: 8816884
references.citation: Vaccine. 2008 Sep 15;26(39):4984-90
references.pmid: 18625281
references.citation: J Exp Med. 2001 Mar 19;193(6):F23-6
references.pmid: 11257144
references.citation: Urol Int. 2000;64(1):3-8
references.pmid: 10782024
references.citation: J Immunol. 1997 Nov 1;159(9):4593-601
references.pmid: 9379061
references.citation: Langenbecks Arch Surg. 2009 Jan;394(1):115-21
references.pmid: 18670745
references.citation: Br J Cancer. 1993 Jan;67(1):163-71
references.pmid: 7678979
references.citation: Haematologica. 2000 Mar;85(3):298-303
references.pmid: 10702820
references.citation: J Clin Oncol. 2001 Feb 15;19(4):1001-7
references.pmid: 11181662
references.citation: Br J Cancer. 2002 Jul 15;87(2):194-201
references.pmid: 12107842
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18538-43
references.pmid: 16344461
references.citation: J Clin Oncol. 1997 Nov;15(11):3399-407
references.pmid: 9363872
references.citation: J Korean Med Sci. 2007 Sep;22 Suppl:S122-8
references.pmid: 17923738
references.citation: J Clin Invest. 1991 Sep;88(3):825-32
references.pmid: 1885772
references.citation: CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30
references.pmid: 15661684
references.citation: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references.pmid: 15761078
references.citation: J Clin Oncol. 2001 Jul 15;19(14):3312-22
references.pmid: 11454878
references.citation: Ann Surg Oncol. 2007 Apr;14(4):1295-304
references.pmid: 17225981
references.citation: N Engl J Med. 2004 Dec 9;351(24):2519-29
references.pmid: 15590954
references.citation: Cancer. 2000 Apr 1;88(7):1544-8
references.pmid: 10738211
references.citation: Br J Cancer. 1999 May;80(3-4):407-11
references.pmid: 10408846
references.citation: Med Oncol. 1995 Jun;12(2):69-77
references.pmid: 8535664
references.citation: Oncology. 2001;61(2):91-101
references.pmid: 11528247
references.citation: N Engl J Med. 2006 Jan 5;354(1):34-43
references.pmid: 16394300
references.citation: Mod Pathol. 2009 Mar;22(3):393-402
references.pmid: 19060844
references.citation: N Engl J Med. 2008 Jun 19;358(25):2698-703
references.pmid: 18565862