Strong induction of in vivo human CTL against tumor cells using novel IL-2 Receptor γ-chain disrupted NOD-SCID-PBL/hu mice

Abstract

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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 CB17-SCID-PBL/hu experimental model. In this model IL-6 related genes were administered in vivo using adenovirus vector into CB17-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-2 receptor γ-chain disrupted NOD-SCID mice have little activity of NK cell. Therefore, IL-2 receptor γ-chain disrupted NOD-SCID [IL-2R(−/−) SCID] mice were used for the construction of SCID-PBL/hu. The engraftment of human T cell in IL-2R(−/−) SCID is very stronger than that in CB17-SCID mice. IL-6 related genes (IL-6 gene+IL-6 receptor(R) gene+gp130 gene) were injected intraperitoneally (i-p) into IL-2R(−/−) SCID-PBL/hu mice in vivo by using this experimental model [IL-2R(−/−)SCID mice given PBL from healthy volunteer and CESS human cancer cells]. Forty percent of spleen cells in these IL-2R(−/−) SCID-PBL/hu mice were CD3⁺ human T cell. Two weeks after the immunization with CESS cells, 50% of cytotoxic activity against CESS cells was detected in spleen cells at an E/T ratio of 10:1. The CTL activity in the spleen cells from IL-2R(−/−) SCID-PBL/hu was extremely higher (more than 100 fold) than that from CB-17 SCID-PBL/hu. Cytotoxic activity against CESS cells in these mice were exerted by CD4^-CD8⁺CD3⁺human T cells. Furthermore, significant CTL activity in vivo was observed in mesenteric lymph node cells, peritoneal exudates cells and PBL as well as spleen cells. 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). Therefore, the IL-2R(−/−) SCID-PBL/hu model using gene encoding lung cancer associated antigens or peptides of tumor associated antigens might provide a powerful weapon for developing new cancer vaccines against human lung cancers. (Co-worker: 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)