Allogeneic MHC gene transfer enhances an effective antitumor immunity in the early period of autologous hematopoietic stem cell transplantation.
OBJECTIVE
In autologous hematopoietic stem cell transplantation (HSCT), lymphopenia-induced homeostatic proliferation of T cells is driven by the recognition of self-antigens, and there is an opportunity to skew the T-cell repertoire during the T-cell recovery by engaging tumor-associated antigens, leading to a break of tolerance against tumors. However, the homeostatic proliferation-driven antitumor responses seem to decline rapidly in association with tumor growth. We hypothesized that a tumor-specific immune response induced by an immune gene therapy could enhance and sustain homeostatic proliferation-induced antitumor immunity.


METHODS
The antitumor effect of allogeneic MHC (alloMHC) gene transfer was examined at the early phase of the immune reconstitution after syngeneic HSCT.


RESULTS
Syngeneic HSCT showed significant tumor growth inhibition of syngeneic colon cancer cells within a period of 30 days; however, the tumor then resumed rapid growth and the survival of the mice was not prolonged. In contrast, when the alloMHC plasmid was intratumorally injected at the early phase after syngeneic HSCT, the established tumors were markedly regressed and the survival of recipient mice was prolonged without significant toxicities, whereas no survival advantage was recognized in recipient mice injected with a control plasmid. This tumor suppression was evident even in the other tumors that were not injected with the alloMHC plasmid. The antitumor response was characterized by the development of tumor-specific T cell- and natural killer cell-mediated cytotoxicities.


CONCLUSIONS
The results suggest the efficacy and safety of integrating intratumoral alloMHC gene transfer with an autologous HSCT for the treatment of solid cancers.
Kobayashi
Akihiko
A
Authors' Affiliations: Section for Studies on Host-Immune Response and Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Hara
Hidehiko
H
Ohashi
Masaki
M
Nishimoto
Takeshi
T
Yoshida
Kimiko
K
Ohkohchi
Nobuhiro
N
Yoshida
Teruhiko
T
Aoki
Kazunori
K
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006183:H-2 Antigens / Q000235:genetics* / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D008285:Major Histocompatibility Complex / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse