Pancreatic cancer immunotherapy using a tumor lysate vaccine, engineered to express α-gal epitopes, targets pancreatic cancer stem cells.

Abstract

Pancreatic cancer is a lethal disease that remains one of the most resistant to traditional therapies. Immunotherapy in pancreatic cancer induces the recruitment and activation of T cells that recognize tumor-associated antigens (TAAs); thus, the mechanism differs from that of chemotherapy and radiotherapy. The goal of cancer immunotherapy is to elicit immune responses against autologous tumors, and especially to induce multiple T cell clones against a variety of TAAs. In the present study, we prepared a polyvalent tumor lysate vaccine engineered to express the α-gal epitopes, Galα1-3Galβ1-4 GlcNAc-R (i.e., α-gal tumor lysate), from primary tumors. The vaccine elicited strong antibody production against multiple TAAs in pancreatic cancer cells and induced activation of multiple tumor-specific T cells in α1,3-galactosyltransferase (α1,3GT) knockout (KO) mice. The tumor lysate vaccine exhibited a similar effect on pancreatic cancer stem cells (CSCs) with the CD44+CD24+ phenotype. Furthermore, in vivo experiments using NOD/SCID mice, inoculated with splenocytes from KO mice vaccinated with the α-gal tumor lysate and injected with pancreatic cancer cells, showed successful induction of a marked immune response that resulted in suppression of tumorigenesis and significant improvement in overall survival. In contrast, inoculation of lymphocytes from KO mice vaccinated with control tumor lysate vaccine had no effects on tumor growth and survival. The results of both in vitro and in vivo experiments emphasize the efficiency of tumor lysate vaccines expressing α-gal epitopes in targeting all pancreatic cancer cells, including differentiated cancer cells and pancreatic CSCs. The α-gal tumor lysate vaccine could be the basis for a novel therapeutic approach in human clinical trials.

• Authors: Tsukasa Tanida, Masahiro Tanemura, Eiji Miyoshi, Hiroaki Nagano, Kenta Furukawa, Yuji Nonaka, Hirofumi Akita, Naoki Hama, Hiroshi Wada, Koichi Kawamoto, Shogo Kobayashi, Hidetoshi Eguchi, Masaki Mori, Yuichiro Doki
• Journal: International journal of oncology (Int J Oncol) Vol. 46 Issue 1 Pg. 78-90 (Jan 2015) ISSN: 1791-2423 [Electronic] Greece
• PMID: 25354268 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Cell Extracts
• Epitopes
• alpha-Galactosidase

Topics

• Animals
• Antigens, Neoplasm (immunology)
• Cancer Vaccines (chemical synthesis)
• Cell Extracts (immunology, therapeutic use)
• Epitopes (immunology)
• Genetic Engineering (methods)
• HEK293 Cells
• Humans
• Immunotherapy (methods)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Neoplastic Stem Cells (immunology)
• Pancreatic Neoplasms (immunology, pathology, therapy)
• Tumor Cells, Cultured
• alpha-Galactosidase (genetics, immunology)