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Identification of Interleukin-13 Receptor 2 Peptide Analogues Capable of Inducing Improved Antiglioma CTL Responses

Departments of ¹ Neurological Surgery, ² Surgery, and ³ Dermatology and Immunology, University of Pittsburgh School of Medicine; ⁴ Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ⁵ Department of Neurosurgery, Kanagawa Cancer Center, Kanagawa, Japan

Requests for reprints: Hideho Okada, Department of Neurological Surgery, University of Pittsburgh School of Medicine, G12a The Hillman Cancer Center, 5117 Center Avenue, Pittsburgh, PA 15213-1863. Phone: 412-623-1111; Fax: 412-623-4747; E-mail: okadah{at}upmc.edu.

Restricted and high-level expression of interleukin-13 receptor 2 (IL-13R2) in a majority of human malignant gliomas makes this protein an attractive vaccine target. We have previously described the identification of the IL-13R2_345-353 peptide as a human leukocyte antigen-A2 (HLA-A2)–restricted CTL epitope. However, as it remains unclear how efficiently peptide-based vaccines can induce specific CTLs in patients with malignant gliomas, we have examined whether analogue epitopes could elicit heteroclitic antitumor T-cell responses versus wild-type peptides. We have created three IL-13R2 analogue peptides by substitutions of the COOH-terminal isoleucine (I) for valine (V) and the NH₂-terminal tryptophan (W) for either alanine (A), glutamic acid (E), or nonsubstituted (W; designated as 1A9V, 1E9V, and 9V, respectively). In comparison with the native IL-13R2 epitope, the analogue peptides 9V and 1A9V displayed higher levels of binding affinity and stability in HLA-A2 complexes and yielded an improved stimulatory index for patient-derived, specific CTLs against the native epitope expressed by HLA-A2⁺ glioma cells. In HLA-A2-transgenic HHD mice, immunization with the peptides 9V and 1A9V induced enhanced levels of CTL reactivity and protective immunity against an intracranial challenge with IL13R2-expressing syngeneic tumors when compared with vaccines containing the native IL-13R2 epitope. These findings indicate highly immunogenic IL-13R2 peptide analogues may be useful for the development of vaccines capable of effectively expanding IL-13R2-specific, tumor-reactive CTLs in glioma patients. (Cancer Res 2006; 66(11): 5883-91)

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