title: Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies.
abstract: OBJECTIVE
  ALT-801 is a bifunctional fusion protein comprising interleukin-2 (IL-2) linked to a soluble, single-chain T-cell receptor domain that recognizes a peptide epitope (aa264-272) of the human p53 antigen displayed on cancer cells in the context of HLA-A*0201 (p53+/HLA-A*0201). We evaluated the safety, pharmacokinetics, and pharmacodynamics of ALT-801 in p53+/HLA-A*0201 patients with metastatic malignancies.
  
  
  METHODS
  p53+/HLA-A*0201 patients were treated with ALT-801 on a schedule of four daily 15-minute intravenous infusions, then 10 days rest and four more daily infusions. Cohorts of patients were treated at 0.015, 0.040, and 0.080 mg/kg/dose.
  
  
  RESULTS
  Four, 16, and 6 patients were treated at the 0.015, 0.04, and 0.08 mg/kg cohorts, respectively. Two dose-limiting toxicities (a grade 4 transient thrombocytopenia and a myocardial infarction) in the 0.08 mg/kg cohort established the maximum tolerated dose (MTD) at 0.04 mg/kg. Patients treated at the MTD experienced toxicities similar to those associated with high-dose IL-2 but of lesser severity. The serum half-life of ALT-801 was 4 hours and ALT-801 serum recovery was as expected based on the dose administered. ALT-801 treatment induced an increase of serum IFN-γ but not TNF-α. Response assessment showed 10 subjects with stable disease at at least 11 weeks, and in one who had melanoma metastasis, there is an ongoing complete absence of identifiable disease after resection of radiographically identified lesions.
  
  
  CONCLUSIONS
  This first-in-man study defines an ALT-801 regimen that can be administered safely and is associated with immunologic changes of potential antitumor relevance.
authors: Departments of Genitourinary Oncology and Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. mayer.fishman@moffitt.org
authors: Mayer N
authors: MN
authors: Fishman
authors: John A
authors: JA
authors: Thompson
authors: Gregory K
authors: GK
authors: Pennock
authors: Rene
authors: R
authors: Gonzalez
authors: Luz M
authors: LM
authors: Diez
authors: Adil I
authors: AI
authors: Daud
authors: Jeffery S
authors: JS
authors: Weber
authors: Bee Y
authors: BY
authors: Huang
authors: Shamay
authors: S
authors: Tang
authors: Peter R
authors: PR
authors: Rhode
authors: Hing C
authors: HC
authors: Wong
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000939:Epitopes / Q000276:immunology; D005260:Female; D005334:Fever / Q000139:chemically induced; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007262:Infusions, Intravenous; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000009:adverse effects / Q000235:genetics / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000276:immunology
chemical_list: C572627:ALT-801; D000939:Epitopes; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma