title: Phase I study of single, escalating doses of a superantigen-antibody fusion protein (PNU-214565) in patients with advanced colorectal or pancreatic carcinoma.
abstract: To develop a T-cell-based therapy for carcinomas, the superantigen staphylococcal enterotoxin A (SEA) was supplied with tumor specificity by means of a recombinant fusion of the Fab fragment of the monoclonal antibody C242 recognizing human colorectal (CRC) and pancreatic carcinomas (PC). Using this Fab-SEA fusion protein (PNU-214565), potent cytotoxicity by activation of T cells can be obtained in the targeted area. Twenty-one patients with CRC and 3 with PC were treated with single, escalating doses of PNU-214565 to establish the maximum tolerated dose (MTD) and to define toxicities. The doses ranged from 0.01 ng/kg to 4.0 ng/kg with three patients at each dose level, except for the dose of 1.5 ng/kg with which six patients were treated because of dose-limiting toxicity. Adverse events (AE) were transient: 13 patients experienced mild to moderate fever. In one patient, a grade 3 fever was followed by a grade 2 hypotension. Other mild or moderate AEs were fatigue, nausea, vomiting, diarrhea, and abdominal pain. No significant hematological toxicity occurred. Immune activation was highly variable with strong activity in peripheral blood seen only in two patients at the dosage level 1.5 ng/kg. They showed pronounced elevations of interleukin-2 (IL-2), IL-6, tumor necrosis factor-alpha, and interferon-gamma, 3-5 hours after the start of infusion. In one patient, IL-2 and IL-6 increased substantially (2,925 U/mL and 32,000 U/mL) concomitantly with grade 3 fever and transient grade 2 neutropenia, grade 2 lymphopenia, and grade 2 monocytopenia. In conclusion, a single 3-hour infusion of PNU-214565 could be safely administered up to 4 ng/kg. MTD was not determined. Instead, a repeat-dose trial was initiated starting at 0.5 ng/kg, considered safe in this trial, with the objective of defining the MTD.
authors.affiliation: Department of Oncology, Finsen Center, Copenhagen University Hospital, Upjohn, Lund, Sweden.
authors.forename: S E
authors.initials: SE
authors.lastname: Nielsen
authors.forename: J
authors.initials: J
authors.lastname: Zeuthen
authors.forename: B
authors.initials: B
authors.lastname: Lund
authors.forename: B
authors.initials: B
authors.lastname: Persson
authors.forename: J
authors.initials: J
authors.lastname: Alenfall
authors.forename: H H
authors.initials: HH
authors.lastname: Hansen
mesh_terms: D000328:Adult; D000907:Antibodies, Bacterial / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004768:Enterotoxins / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000009:adverse effects / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D018089:Superantigens / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D015295:Antigens, Tumor-Associated, Carbohydrate; D000970:Antineoplastic Agents; C074601:CA 242 antigen; D004768:Enterotoxins; D007140:Immunoglobulin Fab Fragments; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal