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
| Autor: | P O Gunnarsson, B Persson, Bruce J. Giantonio, L Vitek, B Shannon, R Persson, Y Guedez, M Kotb, C. McAleer, T Kalland, M Dohlsten, Duane W. Newton, Louis M. Weiner, R K Alpaugh, Josephine Schultz |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Adult
Male Cancer Research Pancreatic disease Genotype medicine.drug_class Colorectal cancer Recombinant Fusion Proteins medicine.medical_treatment Lymphocyte Activation Monoclonal antibody Enterotoxins Immunoglobulin Fab Fragments Antigens Neoplasm Superantigen medicine Humans Aged Chemotherapy Superantigens Performance status Rectal Neoplasms Tumor Necrosis Factor-alpha business.industry Immunotoxins Antibodies Monoclonal HLA-DR Antigens Middle Aged medicine.disease Pancreatic Neoplasms PNU-214565 medicine.anatomical_structure Oncology Colonic Neoplasms Immunology Cancer research Interleukin-2 Female Immunotherapy business Pancreas |
| Zdroj: | Journal of Clinical Oncology. 15:1994-2007 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.1997.15.5.1994 |
| Popis: | PURPOSE 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. PATIENTS AND 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. CONCLUSION 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. |
| Databáze: | OpenAIRE |
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