Allogeneic MHC gene transfer enhances antitumor activity of allogeneic hematopoietic stem cell transplantation without exacerbating graft-versus-host disease.
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/2-->BALB/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/c-->BALB/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.
Ohashi
Masaki
M
Genetics Division, National Cancer Center Research Institute, Department of Surgery, Keio University School of Medicine Tokyo, Japan.
Kobayashi
Akihiko
A
Hara
Hidehiko
H
Miura
Yoshiaki
Y
Yoshida
Kimiko
K
Kushida
Miwa
M
Ikarashi
Yoshinori
Y
Mandai
Masaki
M
Kitajima
Masaki
M
Yoshida
Teruhiko
T
Aoki
Kazunori
K
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D020350:Graft vs Tumor Effect / Q000187:drug effects / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D066298:In Vitro Techniques; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation / Q000276:immunology; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014184:Transplantation, Homologous / Q000276:immunology; D014185:Transplantation, Isogeneic / Q000276:immunology
D015395:Histocompatibility Antigens Class I