Major histocompatibility gene therapy: the importance of haplotype and beta 2-microglobulin.
OBJECTIVE
Alloantigen gene therapy with the genes for the Class I major histocompatibility complex (MHC) HLA-B7 and beta 2-microglobulin in HLA-B7-negative patients has potential efficacy in the treatment of head and neck cancer, although the mechanism of response is unclear. Whether tumor regression is due to a response to HLA-B7 in HLA-B7-negative patients (i.e., due to "foreign" antigen) or simply to MHC overexpression is unknown. Therefore, a mouse model was used to compare tumor growth following syngeneic MHC transfection to alloantigenic MHC transfection. The importance of the beta 2-microglobulin gene was also evaluated.


METHODS
Prospective animal study.


METHODS
The head and neck cancer cell line SCC-VII that grows in immunocompetent C3H mice, which are MHC haplotype H2-K, was used. Stable transfections were made with H2-K, H2-K, and beta 2-microglobulin in the SCC-VII cells. To test the importance of MHC "foreignness," mice were injected with SCC-VII cells, SCC-VII plus H2-K plus beta 2-microglobulin transfected cells, and SCC-VII plus H2-K plus beta 2-microglobulin transfected cells. To evaluate beta 2-microglobulin, mice were injected with SCC-VII cells, SCC-VII plus H2-K plus beta 2-microglobulin transfected cells, SCC-VII plusH2-K transfected cells, and SCC-VII plus beta 2-microglobulin transfected cells. Tumor growth in all groups was compared statistically.


RESULTS
Major histocompatibility complex foreignness was a part of the antitumor response. Foreign MHC routinely abrogated tumor growth, whereas syngeneic MHC only slowed tumor growth. beta 2-microglobulin aided the MHC tumor inhibition but did not inhibit tumor without the MHC.


CONCLUSIONS
The antitumor response was greater when the MHC gene used was foreign. beta 2-microglobulin increased the efficacy of MHC gene therapy. Both of these findings are important when designing clinical trials of immunologically based gene therapies for head and neck cancer.
Salamone
Frank N
FN
Departments of Otolaryngology-Head and Neck Surgery, The University of Cincinnati Medical Center, Cincinnati, Ohio, U.S.A. fns99@yahoo.com
Gleich
Lyon L
LL
Li
Ya-Qin
YQ
Stambrook
Peter J
PJ
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005069:Evaluation Studies as Topic; D005805:Genes, MHC Class I / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D015793:HLA-B7 Antigen / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D007519:Isoantigens / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D011446:Prospective Studies; D014162:Transfection; D001613:beta 2-Microglobulin / Q000235:genetics*
D004268:DNA-Binding Proteins; D015793:HLA-B7 Antigen; D007519:Isoantigens; D001613:beta 2-Microglobulin; C072003:Pfdn6 protein, mouse