A parathyroid-hormone-related-protein (PTH-rP)-specific cytotoxic T cell response induced by in vitro stimulation of tumour-infiltrating lymphocytes derived from prostate cancer metastases, with epitope peptide-loaded autologous dendritic cells and low-do

Bone metastases are one of the most common events in patients with prostate carcinoma. PTH-rP, a protein produced by prostate carcinoma and other epithelial cancers, is a key agent for the development of bone metastases. A PTH-rP-derived peptide, designated PTR-4 was identified, which is capable to bind HLA-A2.1 molecules and to generate PTH-rP-specific cytotoxic T cell (CTL) lines from healthy HLA-A2.1(+) individual peripheral-blood-mononuclear-cells (PBMC). In this model, we investigated the in vitro possibility of generating an efficient PTH-rP specific CTL response by cyclical stimulations with IL-2 and PTR-4 peptide-pulsed autologous dendritic cells (DC), of HLA-A2.1(+) tumour infiltrating lymphocytes (TIL) derived from a patient with metastatic prostate carcinoma. A T cell line generated in this way (called TM-PTR-4) had a CD3(+), CD5(+), CD4(-), CD8(+), CD45(Ro+), CD56(-) immunophenotype and a HLA-A2.1 restricted cytotoxic activity to PTR-4-peptide pulsed CIR-A2 (HLA-A2.1(+)) target cells, PTH-rP(+)/HLA-A2.1(+) CIR-A2 transfected with PTH-rP gene, prostate carcinoma LNCaP cells, and autologous metastatic prostate cancer cells (M-CaP). These lymphocytes were not cytotoxic to HLA-A2.1(+) targets not producing PTH-rP, such as peptide-unpulsed CIR-A2 and colon carcinoma SW-1463, cell lines. Our results provide evidence that PTR-4 peptide-pulsed autologous DC may break the tolerance of human TIL against the autologous tumour by inducing a PTH-rP-specific CTL immune reaction. In conclusion PTR-4 peptide-pulsed autologous DC may be a promising approach for vaccine-therapy and antigen-specific CTL adoptive immunotherapy of hormone-resistant prostrate cancer.

Correale P ，Micheli L ，Vecchio MT ，Sabatino M ，Petrioli R ，Pozzessere D ，Marsili S ，Giorgi G ，Lozzi L ，Neri P ，Francini G ... -  《-》

Induction of tumor-reactive CTL from peripheral blood and tumor-infiltrating lymphocytes of melanoma patients by in vitro stimulation with an immunodominant peptide of the human melanoma antigen MART-1.

Rivoltini L ，Kawakami Y ，Sakaguchi K ，Southwood S ，Sette A ，Robbins PF ，Marincola FM ，Salgaller ML ，Yannelli JR ，Appella E ... -  《JOURNAL OF IMMUNOLOGY》

Tumor-specific and HLA-A2-restricted cytolysis by tumor-associated lymphocytes in human metastatic breast cancer.

Linehan DC ，Goedegebuure PS ，Peoples GE ，Rogers SO ，Eberlein TJ ... -  《JOURNAL OF IMMUNOLOGY》

Generation of human cytolytic T lymphocyte lines directed against prostate-specific antigen (PSA) employing a PSA oligoepitope peptide.

Correale P ，Walmsley K ，Zaremba S ，Zhu M ，Schlom J ，Tsang KY ... -  《JOURNAL OF IMMUNOLOGY》

New epitope peptides derived from parathyroid hormone-related protein which have the capacity to induce prostate cancer-reactive cytotoxic T lymphocytes in HLA-A2+ prostate cancer patients.

Parathyroid hormone-related protein (PTHrP) is produced by cancer cells and has been suggested to be responsible for malignancy-associated hypercalcemia and osteolysis after bone metatsases. Therefore, PTHrP is a promising target in the treatment of metastatic prostate cancer. Seven PTHrP-derived peptides were prepared based on the HLA-A2 binding motif. These peptide candidates were screened by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs), and their ability to be recognized by immunoglobulin G (IgG). Both the PTHrP59-67 and PTHrP42-51 peptides were found to efficiently induce peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A2+ prostate cancer patients with several HLA-A2 subtypes. These CTLs showed HLA-A2-restricted cytotoxicity toward prostate cancer cells. IgG reactive to the PTHrP42-51 peptide was frequently detected in prostate cancer patients. These results indicate that these two new PTHrP peptides will be useful in the peptide-based immunotherapy of HLA-A2+ prostate cancer patients, especially those with bone metastases.

Yao A ，Harada M ，Matsueda S ，Ishihara Y ，Shomura H ，Takao Y ，Noguchi M ，Matsuoka K ，Hara I ，Kamidono S ，Itoh K ... -  《PROSTATE》