title: Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers.
abstract: BACKGROUND
  The primary objective was to study the antitumor activity of prolonged subcutaneous dosing of systemic 852A, a Toll-like receptor-7 agonist (TLR-7), in recurrent breast, ovarian and cervix cancer. Secondary objectives included assessment of safety and immune system activation.
  
  
  METHODS
  Adults with recurrent breast, ovarian or cervix cancer failing multiple therapies received 0.6 mg/m(2) of 852A subcutaneously twice weekly for 12 weeks. Doses increased by 0.2 mg/m(2)/week to a maximum of 1.2 mg/m(2). Serum was collected to assess immune activation.
  
  
  RESULTS
  Fifteen patients enrolled: 10 ovarian, 2 cervix and 3 breast. Three completed all 24 injections. There were two grade 2 (decreased ejection fractions), nine grade 3 (1 cardiovascular, 1 anorexia, 3 dehydration, 2 infections, 2 renal) and two grade 4 (hepatic and troponin elevation) unanticipated toxicities. Cardiac toxicities included three cardiomyopathies (2 asymptomatic) and one stress-related non-ST elevated myocardial infarction. Five patients discontinued therapy due to possibly associated side effects. One who had stable disease (SD) following 24 doses received 17 additional doses. A cervix patient with SD following 24 doses received chemotherapy after progressing 3 months later, and remains disease free at 18 months. Immune activation, as evidenced by increased IP-10 and IL-1ra, was observed.
  
  
  CONCLUSIONS
  In this first human experience of a TLR-7 agonist delivered subcutaneously using a prolonged dosing schedule, 852A demonstrated sustained tolerability in some patients. Clinical benefit was modest, but immune activation was seen suggesting further study of antitumor applications is warranted. Because of cardiac toxicity; 852A should be used cautiously in heavily pretreated patients.
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Geller
authors.affiliation: Department of Medicine, MMC 806 420 Delaware St. SE., University of Minnesota, Minneapolis, MN, 55455 USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cooley
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Argenta
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
authors.forename: Levi S
authors.initials: LS
authors.lastname: Downs
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
authors.forename: Linda F
authors.initials: LF
authors.lastname: Carson
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Judson
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, MMC 395 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
authors.forename: Rahel
authors.initials: R
authors.lastname: Ghebre
authors.affiliation: Department of Pediatrics, University of Minnesota, MMC 391 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Weigel
authors.affiliation: Department of Medicine, MMC 806 420 Delaware St. SE., University of Minnesota, Minneapolis, MN, 55455 USA.|Department of Pediatrics, University of Minnesota, MMC 391 420 Delaware St. SE., Minneapolis, MN, 55455 USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.affiliation: Department of Medicine, MMC 806 420 Delaware St. SE., University of Minnesota, Minneapolis, MN, 55455 USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Curtsinger
authors.affiliation: Department of Medicine, MMC 806 420 Delaware St. SE., University of Minnesota, Minneapolis, MN, 55455 USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011804:Quinolines; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; C523097:N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide; D011804:Quinolines; D013449:Sulfonamides; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7
references.citation: Breast Cancer Res Treat. 2005 Nov;94(1):93-4
references.pmid: 16172790
references.citation: J Clin Oncol. 1985 Aug;3(8):1079-85
references.pmid: 3894589
references.citation: Int J Immunopharmacol. 1999 Jan;21(1):1-14
references.pmid: 10411278
references.citation: Exp Dermatol. 2006 May;15(5):331-41
references.pmid: 16630072
references.citation: J Immunol. 1995 Oct 15;155(8):3877-88
references.pmid: 7561094
references.citation: J Immunol. 2005 Feb 1;174(3):1259-68
references.pmid: 15661881
references.citation: J Cutan Pathol. 2005 Apr;32(4):257-62
references.pmid: 15769273
references.citation: Br J Dermatol. 2003 Nov;149 Suppl 66:9-14
references.pmid: 14616338
references.citation: Mol Immunol. 2005 May;42(8):957-68
references.pmid: 15829287
references.citation: Clin Cancer Res. 2008 Feb 1;14(3):856-64
references.pmid: 18245549
references.citation: Nat Immunol. 2002 Feb;3(2):196-200
references.pmid: 11812998
references.citation: J Exp Med. 2002 May 20;195(10):1257-66
references.pmid: 12021306
references.citation: Antimicrob Agents Chemother. 1988 May;32(5):678-83
references.pmid: 2840014
references.citation: Clin Cancer Res. 2007 Dec 1;13(23):7119-25
references.pmid: 18056192
references.citation: FASEB J. 1998 Jun;12(9):705-13
references.pmid: 9619449
references.citation: Annu Rev Immunol. 2002;20:709-60
references.pmid: 11861616
references.citation: Breast Dis. 2002;15:83-90
references.pmid: 15687648
references.citation: J Leukoc Biol. 2004 Feb;75(2):163-89
references.pmid: 14525967
references.citation: Clin Cancer Res. 2001 Oct;7(10):3031-3
references.pmid: 11595691
references.citation: J Clin Pharmacol. 2007 Aug;47(8):962-9
references.pmid: 17660481
references.citation: J Infect Dis. 2001 Mar 15;183(6):844-9
references.pmid: 11237799
references.citation: Vaccine. 2005 Mar 18;23(17-18):2374-8
references.pmid: 15755631