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

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.

• Authors: B J Giantonio, R K Alpaugh, J Schultz, C McAleer, D W Newton, B Shannon, Y Guedez, M Kotb, L Vitek, R Persson, P O Gunnarsson, T Kalland, M Dohlsten, B Persson, L M Weiner
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 15 Issue 5 Pg. 1994-2007 (May 1997) ISSN: 0732-183X [Print] United States
• PMID: 9164211 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antigens, Neoplasm
• Enterotoxins
• HLA-DR Antigens
• Immunoglobulin Fab Fragments
• Immunotoxins
• Interleukin-2
• Recombinant Fusion Proteins
• Superantigens
• Tumor Necrosis Factor-alpha
• enterotoxin A, Staphylococcal

Topics

• Adult
• Aged
• Antibodies, Monoclonal (adverse effects, blood, therapeutic use)
• Antigens, Neoplasm (blood)
• Colonic Neoplasms (immunology, therapy)
• Enterotoxins (adverse effects, blood, therapeutic use)
• Female
• Genotype
• HLA-DR Antigens (genetics)
• Humans
• Immunoglobulin Fab Fragments (adverse effects, blood, therapeutic use)
• Immunotherapy (adverse effects)
• Immunotoxins (therapeutic use)
• Interleukin-2 (blood)
• Lymphocyte Activation
• Male
• Middle Aged
• Pancreatic Neoplasms (immunology, therapy)
• Recombinant Fusion Proteins (adverse effects, blood, therapeutic use)
• Rectal Neoplasms (immunology, therapy)
• Superantigens (immunology)
• Tumor Necrosis Factor-alpha (metabolism)