H-2 class I knockout, HLA-A2.1-transgenic mice: a versatile animal model for preclinical evaluation of antitumor immunotherapeutic strategies

H-2 class I-negative, HLA-A2.1-transgenic HHD mice were used for a comparat ive evaluation of the immunogenicity of HLA-A2.1-restricted human tumor-ass ociated cytotoxic T lymphocyte (CTL) epitopes. A hierarchy was established among these peptides injected into mice in incomplete Freund's adjuvant whi ch correlates globally with their capacity to bind and stabilize HLA-A2.1 m olecules. Go-injection of a helper peptide enhanced most CTL responses. In contrast, classical HLA class I-transgenic mice which still express their o wn class I molecules did not, in most cases, develop HLA-A2.1-restricted CT L responses under the same experimental conditions. Different monoepitope i mmunization strategies of acceptable clinical usage were compared in HHD mi ce. Recombinant Ty-virus-like particles, or DNA encoding epitopes fused to the hepatitis B virus middle envelope protein gave the best results. Using this latter approach and a melanoma-based polyepitope construct, CTL respon ses against five distinct epitopes could be elicited simultaneously in a si ngle animal. Thus, HHD mice provide a versatile animal model for preclinica l evaluation of peptide-based cancer immunotherapy.