title: Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer.
abstract: OBJECTIVE
  To establish the maximum-tolerated dose (MTD) and define the toxicities of a single-dose infusion of PNU-214565, a recombinant Escherichia coli-derived fusion protein of Staphylococcal enterotoxin A (SEA) and the Fab-fragment of the C242 monoclonal antibody in patients with advanced colorectal and pancreatic carcinomas. To investigate the capability of PNU-214565 to induce a superantigen (SAg) response resulting in cytokine production and tumor regression.
  
  
  METHODS
  Twenty-one patients (age range, 39 to 76 years; median, 64; 12 men, nine women; 18 colorectal, three pancreatic cancers) were treated with a single 3-hour infusion of PNU-214565, with doses ranging from 0.01 to 1.5 ng/kg. All patients had prior chemotherapy and a good performance status Eastern Cooperative Oncology Group [ECOG] performance status [PS] = 0 [n = 10]; PS = 1 [n = 11]), 10 had prior radiation, and 18 had prior surgery.
  
  
  RESULTS
  Fever and hypotension were the most common toxicities. Fever of any grade occurred in 16 of 21 patients (76%): four of 21 (19%) with grade 2 and two of 21 (9.5%) with grade 3. Hypotension of any grade occurred in 13 of 21 (62%): four of 21 with grade 2 and one of 21 (5%) with grade 3. Interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF alpha) induction correlated with toxicity. In the two patients with grade 3 fever, peak IL-2 and TNF alpha levels were 2.9 IU/mL and 165 pg/mL, and 8.3 IU/mL and 245 pg/mL, respectively. Transient, > or = 50% decreases in circulating monocytes were observed in 17 of 21 patients as early as 0.5 hours (median time, 2 hours) from the start of infusion. Decreases (mean 33%) in circulating lymphocytes were observed in seven of 21 patients. All three patients with grade 3 toxicity were treated at the 0.5-ng/kg dose. The significance of baseline anti-SEA, human antimouse antibody (HAMA), CA242-soluble antigen levels, and T-cell receptor variable beta region (TCR V beta) subsets and histocompatibility leukocyte antigen-DR (HLA-DR) genotypes was assessed as possible predictors of toxicity. All toxicities were transient and easily managed. No grade 3 toxicity occurred at the higher dose levels.
  
  
  CONCLUSIONS
  PNU-214565, a SAg-based tumor targeted therapy, is safe when given as a single 3-hour infusion at doses up to 1.5 ng/kg. The MTD for a single dose was not determined. The safety of a repeated dose schedule is currently under investigation, beginning with doses determined to be safe in this trial.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Giantonio
authors.forename: R K
authors.initials: RK
authors.lastname: Alpaugh
authors.forename: J
authors.initials: J
authors.lastname: Schultz
authors.forename: C
authors.initials: C
authors.lastname: McAleer
authors.forename: D W
authors.initials: DW
authors.lastname: Newton
authors.forename: B
authors.initials: B
authors.lastname: Shannon
authors.forename: Y
authors.initials: Y
authors.lastname: Guedez
authors.forename: M
authors.initials: M
authors.lastname: Kotb
authors.forename: L
authors.initials: L
authors.lastname: Vitek
authors.forename: R
authors.initials: R
authors.lastname: Persson
authors.forename: P O
authors.initials: PO
authors.lastname: Gunnarsson
authors.forename: T
authors.initials: T
authors.lastname: Kalland
authors.forename: M
authors.initials: M
authors.lastname: Dohlsten
authors.forename: B
authors.initials: B
authors.lastname: Persson
authors.forename: L M
authors.initials: LM
authors.lastname: Weiner
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000097:blood; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D004768:Enterotoxins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D007167:Immunotherapy / Q000009:adverse effects; D000922:Immunotoxins / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000097:blood; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D012004:Rectal Neoplasms / Q000276:immunology / Q000628:therapy*; D018089:Superantigens / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D004768:Enterotoxins; D006684:HLA-DR Antigens; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; C026066:enterotoxin A, Staphylococcal