In vivo induction of tumor-specific CTL against CEA-antigens and MAGE-3 antigens expressed on human lung adenocarcinoma by using CEA gene therapy

Abstract

5140

In previous study we showed synergistic effect of IL-6 related genes (IL-6 gene, IL-6 receptor gene and gp130 gene) on the induction of CTL against human cancer cells using SCID-PBL/hu experimental model. In this model IL-6 related genes were administered in vivo using adenovirus vector into SCID-PBL/hu mice bearing human cancers, and induced CTL activity against human tumor cells (lung cancer, stomach cancer, colon cancer) and significant prolonged survival of mice was observed. IL-6 related genes (IL-6 gene+IL-6 receptor(R) gene+gp130 gene) were injected intraperitoneally(i-p) into SCID-PBL/hu mice in vivo by using this experimental model (SCID mice given PBL from lung cancer patient and autologous lung cancer cells). Furthermore, the in vivo generation of human CTL against MAGE-3 peptide (9 amino acids) when SCID-PBL/hu were treated with the MAGE-3 peptide capable of binding HLA-A24 and IL-6 related genes. The human CTL activity generated in vivo from spleen cells, mesenteric lymph node cells and peritoneal exudate cells (PEC) in these SCID-PBL/hu mice was exerted against the human target cells expressed HLA-A24, but not HLA-A2. Furthermore, the in vivo human CTL against CEA antigen were generated when SCID-PBL/hu were treated with CEA genes by using adenovirus vector. The human CD8 positive CTL activity generated in vivo from spleen cells in these SCID-PBL/hu mice was exerted against the human CEA- positive tumor cells expressed the same HLA- A24 as the donor of human PBL possessed. Therefore, it was demonstrated that these human CTL generated in vivo in SCID-PBL/hu mice were antigen specific and HLA-restricted. To our knowledge, it is quite difficult to generate the in vivo CTL against tumor associate antigens in human treated with several kinds of cancer vaccines (tumor associated antigens vaccines). MAGE-3 antigens and CEA antigens were expressed on 30∼40% of human lung cancers and almost of lung adenocarcinoma in Japan. Therefore, the SCID-PBL/hu model using CEA gene or peptides of tumor associated antigens might provide a powerful weapon for developing new cancer vaccines against human lung cancers. (Co-worker: Kazuto Takesako: Takara-shuzo Central Institute, Izumu Saito: Tokyo University) (Grant sponsor: Ministry of Health Labor and Welfare, Japan (Second Term Comprehensive 10-year Strategy for Cancer Control: Grant number: H-14gan-033)