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Results of the First Phase I Clinical Trial of the Novel Ii-Key Hybrid Preventive HER-2/neu Peptide (AE37) Vaccine

Jarrod P. Holmes, Linda C. Benavides, Jeremy D. Gates, Mark G. Carmichael, Matthew T. Hueman, Elizabeth A. Mittendorf, James L. Murray, Asna Amin, Dianna Craig, Eric von Hofe, Sathibalan Ponniah, George E. Peoples

From the Department of Medicine, Division of Hematology and Medical Oncology, Naval Medical Center San Diego, San Diego, CA; Department of Surgery, General Surgery Service, Brooke Army Medical Center, Fort Sam Houston; The University of Texas, M.D. Anderson Cancer Center, Houston, TX; Department of Medicine, Hematology and Medical Oncology Service, Walter Reed Army Medical Center, Washington, DC; Cancer Vaccine Development Program, United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD; Joyce Murtha Breast Care Center, Windber Medical Center, Windber, PA; and Antigen Express, Worchester, MA

Corresponding author: COL George E. Peoples, MD, FACS, Department of Surgery, General Surgery Service, Brooke Army Medical Center, 3851 Roger Brooke Dr, Fort Sam Houston, TX, 78234; e-mail: george.peoples{at}amedd.army.mil

Purpose HER-2/neu is overexpressed in breast cancer and is the source of immunogenic peptides. CD4⁺ T-helper peptides for HER-2/neu are being evaluated in vaccine trials. The addition of Ii-Key, a four–amino-acid LRMK modification, increases vaccine potency when compared with unmodified class II epitopes. We present the results of the first human phase I trial of the Ii-Key hybrid HER-2/neu peptide (AE37) vaccine in disease-free, node-negative breast cancer patients.

Patients and Methods The dose escalation trial included five dose groups, to determine safety and optimal dose of the hybrid peptide (100 µg, 500 µg, 1,000 µg) and granulocyte-macrophage colony-stimulating factor (GM-CSF; range, 0 to 250 µg). In the event of significant local toxicity, GM-CSF (or peptide in absence of GM-CSF) was reduced by 50%. Immunologic response was monitored by delayed-type hypersensitivity and [³H]thymidine proliferative assays for both the hybrid AE37 (LRMK-positive HER-2/neu:776-790) and AE36 (unmodified HER-2/neu:776-790).

Results All 15 patients completed the trial with no grade 3 to 5 toxicities. Dose reductions occurred in 47% of patients. In the second group (peptide, 500 µg; GM-CSF, 250 µg), all patients required dose reductions, prompting peptide-only inoculations in the third group. The vaccine induced dose-dependent immunologic responses in vitro and in vivo to AE37, as well as AE36.

Conclusion The hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER-2/neu–specific immune responses, even without the use of an adjuvant. This trial represents the first human experience with the Ii-Key modification, and to our knowledge, AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.

Supported by the United States Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences; the Department of Clinical Investigation, Walter Reed Army Medical Center; and Antigen Express Inc.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army, the Department of the Navy, or the Department of Defense.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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