Journal of Clinical Oncology, Vol 15, 1994-2007, Copyright © 1997 by American Society of Clinical Oncology

ARTICLES

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

BJ Giantonio, RK Alpaugh, J Schultz, C McAleer, DW Newton, B Shannon, Y Guedez, M Kotb, L Vitek, R Persson, PO Gunnarsson, T Kalland, M Dohlsten, B Persson and LM Weiner
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

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.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				H. Borghaei, K. Alpaugh, G. Hedlund, G. Forsberg, C. Langer, A. Rogatko, R. Hawkins, S. Dueland, U. Lassen, and R. B. Cohen Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., September 1, 2009; 27(25): 4116 - 4123. [Abstract] [Full Text] [PDF]

				A. J. Brosnahan, M. J. Mantz, C. A. Squier, M. L. Peterson, and P. M. Schlievert Cytolysins Augment Superantigen Penetration of Stratified Mucosa J. Immunol., February 15, 2009; 182(4): 2364 - 2373. [Abstract] [Full Text] [PDF]

				S. Ren, D. S. Terman, G. Bohach, A. Silvers, C. Hansen, H. Colt, and S. A. Sahn Intrapleural Staphylococcal Superantigen Induces Resolution of Malignant Pleural Effusions and a Survival Benefit in Non-Small Cell Lung Cancer Chest, November 1, 2004; 126(5): 1529 - 1539. [Abstract] [Full Text] [PDF]

				J. D. Cheng, J. S. Babb, C. Langer, S. Aamdal, F. Robert, L. R. Engelhardt, O. Fernberg, J. Schiller, G. Forsberg, R. K. Alpaugh, et al. Individualized Patient Dosing in Phase I Clinical Trials: The Role of Escalation With Overdose Control in PNU-214936 J. Clin. Oncol., February 15, 2004; 22(4): 602 - 609. [Abstract] [Full Text] [PDF]

				K. Kawakami, M. Kawakami, S. R. Husain, and R. K. Puri Targeting Interleukin-4 Receptors for Effective Pancreatic Cancer Therapy Cancer Res., July 1, 2002; 62(13): 3575 - 3580. [Abstract] [Full Text] [PDF]

				O. Christ, S. Matzku, C. Burger, and M. Zoller Interleukin 2-Antibody and Tumor Necrosis Factor-Antibody Fusion Proteins Induce Different Antitumor Immune Responses in Vivo Clin. Cancer Res., May 1, 2001; 7(5): 1385 - 1397. [Abstract] [Full Text]

				O. Christ, S. Seiter, S. Matzku, C. Burger, and M. Zoller Efficacy of Local versus Systemic Application of Antibody-Cytokine Fusion Proteins in Tumor Therapy Clin. Cancer Res., April 1, 2001; 7(4): 985 - 998. [Abstract] [Full Text]