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High-Affinity HLA-A(*)02.01 Peptides from Parathyroid Hormone-Related Protein Generate In Vitro and In Vivo Antitumor CTL Response Without Autoimmune Side Effects¹

Guido Francini^2,*, Antonio Scardino, Kostas Kosmatopoulos, François A. Lemonnier, Giuseppe Campoccia, Marianna Sabatino^*, Daniele Pozzessere^*, Roberto Petrioli^*, Luisa Lozzi, Paolo Neri, Giuseppe Fanetti, Maria Grazia Cusi and Pierpaolo Correale^*

^* Division of Medical Oncology, Institut National de la Santé et de la Recherche Médicale Unité d’Immunité Cellulaire Antivirale, Institut Pasteur, Paris, France; and Blood Bank and Department of Molecular Biology, Siena University School of Medicine, Siena, Italy

Parathyroid hormone-related protein (PTH-rP), a protein produced by prostate carcinoma and other epithelial cancers, is a key agent in the development of bone metastases. We investigated whether the protein follows the self-tolerance paradigm or can be used as a target Ag for anticancer immunotherapy by investigating the immunogenicity of two HLA-A(*)02.01-binding PTH-rP-derived peptides (PTR-2 and -4) with different affinity qualities. PTH-rP peptide-specific CTL lines were generated from the PBMC of two HLA-A(*)02.01⁺ healthy individuals, stimulated in vitro with PTH-rP peptide-loaded autologous dendritic cells and IL-2. The peptide-specific CTLs were able to kill PTH-rP⁺HLA-A(*)02.01⁺ breast and prostate carcinoma cell lines. The two peptides were also able to elicit a strong antitumor PTH-rP-specific CTL response in HLA-A(*)02.01 (HHD) transgenic mice. The vaccinated mice did not show any sign of side effects due to cell-mediated autoimmunity or toxicity. In this study we describe two immunogenic and toxic-free PTH-rP peptides as valid candidates for the design of peptide-based vaccination strategies against prostate cancer and bone metastases from the most common epithelial malignancies.

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