Major Histocompatibility Gene Therapy: The Importance of Haplotype and β2-Microglobulin

Objectives/Hypothesis Alloantigen gene therapy with the genes for the Class I major histocompatibility complex (MHC) HLA‐B7 and β2‐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 β2‐microglobulin gene was also evaluated. Study Design Prospective animal study. Methods The head and neck cancer cell line SCC‐VII that grows in immunocompetent C3H mice, which are MHC haplotype H2‐Kk, was used. Stable transfections were made with H2‐Kb, H2‐Kk, and β2‐microglobulin in the SCC‐VII cells. To test the importance of MHC “foreignness,” mice were injected with SCC‐VII cells, SCC‐VII plus H2‐Kb plus β2‐microglobulin transfected cells, and SCC‐VII plus H2‐Kk plus β2‐microglobulin transfected cells. To evaluate β2‐microglobulin, mice were injected with SCC‐VII cells, SCC‐VII plus H2‐Kb plus β2‐microglobulin transfected cells, SCC‐VII plusH2‐Kb transfected cells, and SCC‐VII plus β2‐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. β2‐microglobulin aided the MHC tumor inhibition but did not inhibit tumor without the MHC. Conclusion The antitumor response was greater when the MHC gene used was foreign. β2‐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.