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Allogeneic MHC Gene Transfer Enhances Antitumor Activity of Allogeneic Hematopoietic Stem Cell Transplantation without Exacerbating Graft-versus-Host Disease

Authors' Affiliations: ¹ Genetics Division, ² Section for Studies on Host-Immune Response, and ³ Pharmacology Division, National Cancer Center Research Institute, ⁴ Department of Surgery, Keio University School of Medicine Tokyo, Japan, and ⁵ Department of Obstetrics and Gynecology, Kyoto University Hospital, Kyoto, Japan

Requests for reprints: Kazunori Aoki, Section for Studies on Host-Immune Response, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, 104-0045 Tokyo, Japan. Phone: 81-3-3542-2511; Fax: 81-3-3541-2685; E-mail: kaoki{at}gan2.res.ncc.go.jp.

Enhancement of the specific antitumor activity of allogeneic hematopoietic stem cell transplantation (alloHSCT) against solid cancers is a major issue in the clinical oncology. In this study, we examined whether intratumoral allogeneic MHC (alloMHC) gene transfer can enhance the recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. In minor histocompatibility antigen–mismatched alloHSCT (DBA/2BALB/c: H-2^d) recipients, alloMHC gene (H-2K^b) was transduced directly into a s.c. tumor of CT26 colon cancer cells. Because CT26 cells have an aggressive tumorigenicity in syngeneic BALB/c mice, an H-2K^b gene transfer provides only a limited antitumor effect after syngeneic (BALB/cBALB/c) HSCT. By contrast, the H-2K^b gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors without gene transduction. In vitro cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to the H-2K^b gene transfer. Graft-versus-host disease was not exacerbated serologically or clinically in the treated mice, demonstrating that alloMHC gene transfer enhances the antitumor effects of alloHSCT without exacerbating graft-versus-host disease. This combination strategy has important implications for the development of therapies for human solid cancers.

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