title: Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma.
abstract: BACKGROUND
  To explore the biological activity of EMD 273063 (hu14.18-IL2), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 (IL2), in patients with unresectable, stage IV cutaneous melanoma as measured by induction of immune activation at the tumor site and in peripheral blood.
  
  
  METHODS
  Nine patients were treated with 4 mg/m2 per day of EMD 273063 given as a 4-h intravenous infusion on days 1, 2, and 3 every four weeks (one cycle). Peripheral blood was analyzed for T cell and natural killer cell phenotype and frequency, as well as levels of soluble IL2 receptor (sIL2R), IL10, IL6, tumor necrosis factor alpha and neopterin. Biopsies of tumor metastasis were performed prior to therapy and at day 10 of the first 2 cycles to study lymphocyte accumulation by immunohistochemistry.
  
  
  RESULTS
  Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events. Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients). Best response on therapy was stable disease in 2 patients. There were no objective tumor regressions by standard response criteria. Systemic immune activation was demonstrated by increases in serum levels of sIL2R, IL10, and neopterin. There was evidence of increased tumor infiltration by T cells, but not NK cells, in most post-dosing biopsies, suggesting recruitment of immune cells to the tumor site.
  
  
  CONCLUSIONS
  EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine.
authors.affiliation: University of California, 11-934 Factor Building, UCLA Medical Center, Los Angeles, CA 90095-1782, USA. aribas@mednet.ucla.edu
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: William
authors.initials: W
authors.lastname: Gooding
authors.forename: Andreas
authors.initials: A
authors.lastname: Kovar
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.forename: Oscar
authors.initials: O
authors.lastname: Kashala
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001706:Biopsy; D016207:Cytokines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000473:pathology* / Q000601:surgery / Q000628:therapy*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000473:pathology* / Q000601:surgery / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D007376:Interleukin-2; C493743:lorukafusp alfa