Induction of antitumor response by in vivo allogeneic major histocompatibility complex gene transfer using electroporation.

Abstract

BACKGROUND: Most malignancies lack tumor-associated antigens, which are recognized by T-lymphocytes through major histocompatibility complex (MHC) molecules, and seem to evade host immunological defense. In this study, we investigated whether allogeneic MHC gene transfer into the low-antigenic tumor might induce cell-mediated immunity, and provide an immunotherapeutic effect in vivo. MATERIALS AND METHODS: Mammary adenocarcinoma cells (MAT B III) originated from an F344 rat (RT1A(l)) were transfected with a plasmid DNA encoding RT1A(a) (pcMRT1A) in vitro. Cytolytic T-cell response was then evaluated using F344 splenocytes. Furthermore, pcMRT1A-liposome complex was injected into the MAT B III tumors grown in F344 rats, followed by a series of eight electrical pulses with a electroporator, every other d for total of four times. The tumor size and survival of animals were evaluated thereafter. RESULTS: The expression of RT1A(a) on the tumor cells induced cytolytic T-cell response in vitro. Intratumor injection of pcMRT1A-liposome complex followed by in vivo electroporation markedly generated biological response, including increased interferon-gamma (IFN-gamma) expression and a large number of infiltrated cells in the tumor. Inhibited tumor growth, even complete tumor regression, was observed, resulting in prolonged survival time. CONCLUSIONS: Direct transfer of allogeneic MHC gene into the tumor by in vivo electroporation could induce a cell-mediated immune response against the introduced antigens, resulting in local IFN-gamma production. This initial response may bring about the subsequent immunological response even to the unmodified tumor cells through cytokines such as IFN-gamma, resulting in the marked tumor regression.