Abstract #4159: Identification of novel tumor-associated antigens, Cadherin 3 (CDH3)/P-Cadherin and RAB6KIFL/KIF20A, as targets for anticancer immunotherapy of pancreatic cancer
Authors: Katsunori Imai, Shinya Hirata, Yoshiaki Ikuta, Michiko Harao, Mitsuhiro Inoue, Satoru Senju, Atsushi Irie, Syuichi Nakatsuru, Hidenobu Nakagawa, Takuya Tsunoda, Yusuke Nakamura, Hideo Baba, Yasuharu Nishimura
Journal: Cancer Research (2009)

Pancreatic cancer is one of the common cancers worldwide and shows the worst mortality among malignancies. In spite of recent advances in surgery, chemotherapy and radiotherapy, the prognosis remains poor. Hence, the development of novel therapeutic modalities is an issue of great importance. To establish anticancer immunotherapy, it is important to identify the tumor-associated antigens (TAAs) that are strongly expressed in the tumor cells but not in the normal cells. In this study, to establish an effective anticancer immunotherapy, we tried to identify the useful TAAs of pancreatic cancer. Based on a previous genome-wide cDNA microarray analysis of pancreatic cancer containing 27,648 genes, we focused on Cadherin 3 (CDH3)/P-cadherin and RAB6KIFL/KIF20A as novel candidate TAAs for anticancer immunotherapy. To identify the HLA-A2 (A*0201)-restricted CTL epitopes of CDH3 and KIF20A, we used HLA-A2.1 (HHD) transgenic mice (Tgm). Furthermore, we examined the cytotoxicity against the tumor cells in vitro and in vivo of CTLs specific to CDH3 and KIF20A induced from HLA-A2-positive healthy donors and cancer patients. The expressions of the CDH3 and KIF20A gene in pancreatic cancer tissues were markedly enhanced in all of the pancreatic cancer patients tested (average of the relative expression ratio, 1,900,000 and 32,000; range, 94,900 - 4,890,000 and 15 - 72,000, respectively) and various malignancies including gastric, colorectal, lung, and bladder cancers, but not in their counterparts or in many normal adult tissues based on cDNA microarray analysis. In the experiment using HLA-A2.1 Tgm, we found that the CDH3-4655-663 (FILPVLGAV) and CDH3-7757-765 (FIIENLKAA) peptides, and three KIF20A-derived peptides could induce HLA-A2-restricted CTLs without causing autoimmunity in HLA-A2.1 Tgm. In addition, peptide-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with the autologous peripheral monocyte-derived dendritic cells pulsed with these peptides in HLA-A2-positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both HLA-A2 and CDH3 or KIF20A. Furthermore, the adoptive transfer of the CDH3-specific CTLs could inhibit the tumor growth of human cancer cells engrafted into nonobese diabetic/severe combined immunodeficiency mice. These results suggest that CDH3 and KIF20A are novel TAAs useful for immunotherapy against a broad spectrum of malignancies including pancreatic cancer. Based on the findings of this study, we are now planning to take this study forward to the next stage, a phase I clinical trial of peptide-based anticancer immunotherapy.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4159.