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Immune Responses of Breast Cancer Patients to Mutated Epidermal Growth Factor Receptor (EGF-RvIII, EGF-R, and de2–7 EGF-R)¹

Enkhtsetseg Purev^*, Dewei Cai^*, Eric Miller, Rolf Swoboda^*, Ted Mayer, Andres Klein-Szanto, Francesco M. Marincola^¶, Rosemarie Mick^||, Laszlo Otvos^*, William Wunner^*, Brigitte Birebent^*, Rajasekharan Somasundaram^*, Carol J. Wikstrand, Darell Bigner, Angela DeMichele^#, Geza Acs^**, Jesse A. Berlin^|| and Dorothee Herlyn^2,*

^* The Wistar Institute, Philadelphia, PA 19104; Virtua Memorial Hospital, Burlington County, Mt. Holly, NJ 08060; Albert Einstein Medical Center, Philadelphia, PA 19141; Fox Chase Cancer Center, Philadelphia, PA 19111; ^¶ Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892; Departments of ^|| Biostatistics and Epidemiology, ^# Medicine, and ^** Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; and Duke University, Durham, NC 27710

Mutated epidermal growth factor receptor (EGF-RvIII, EGF-R, and de2–7 EGF-R) is the result of an 801-bp deletion within the extracellular domain of wild-type EGF-R and is expressed by breast carcinomas, but not by normal breast tissues. EGF-RvIII is expressed both on the surface and in the cytoplasm of tumor cells. Thus, EGF-RvIII is a potential tumor-specific target for both Abs and T cells. However, it is not known whether breast cancer patients can raise immune responses to EGF-RvIII expressed by their tumors. The demonstration of EGF-RvIII-specific immune responses in patients would suggest that immunization of patients with EGF-RvIII vaccines is feasible, because these vaccines may boost a pre-existing immune response. We have evaluated humoral and cellular immune responses to EGF-RvIII in 16 breast cancer patients and three healthy donors. Seven of 16 patients developed EGF-RvIII-specific Abs that bound to isolated EGF-RvIII protein or the protein expressed by EGF-RvIII-transfected mouse fibroblasts. The Abs that bound to EGF-RvIII did not bind to wild-type EGF-R, and anti-EGF-RvIII Abs were not found in the sera of healthy donors. Three patients had EGF-RvIII peptide-specific lymphoproliferative responses, and two of these patients also had humoral immune responses. Humoral and cellular immune responses correlated with EGF-RvIII expression by patients’ tumors in most cases. These studies demonstrate that breast cancer patients specifically recognize EGF-RvIII with an overall immune response rate of 50%, suggesting that patients may benefit from vaccination against EGF-RvIII, boosting pre-existing immune responses.

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