Mouse tumor cells transfected with syngeneic MHC class II and costimulatory molecule genes are therapeutic vaccines in mice provided they do not co-express the class II- associated Invariant chain (Ii). We previously demonstrated that the vaccine cells present tumor peptides via the endogenous antigen presentation pathway to activate CD4+ and CD8+ T cells. Because of their efficacy in mice, we are translating this vaccine strategy for clinical use. To obtain MHC class II+CD80+Ii- human tumor cells we have developed retroviruses encoding HLA-DR1 and CD80. The HLA-DR1 virus encodes the DRα and DRβ0101 chains using an internal ribosomal entry site to coordinate expression. SUM159PT mammary carcinoma and Mel 202 ocular melanoma cells transduced with retroviruses (HLA-DR1/CD80) express high levels of DRB0101 and CD80 on the cell surface in the absence of Ii. Irradiated SUM159PT/DR1/CD80 vaccines stimulate proliferation of non-HLA-DRB0101 peripheral blood mononuclear cells (PBMC) and present an exogenous DR1-restricted tetanus toxoid (TT) peptide, indicating the transduced DRB0101 is functional. SUM159PT/DR1/CD80 vaccines were further transduced with a retrovirus encoding the TT fragment C gene, as a model tumor antigen. These cells stimulate IFNγ release from TT-primed PBMC, demonstrating their ability to present “endogenous” tumor antigen. Depletion and antibody blocking experiments confirm that the vaccine cells present MHC class II-restricted endogenously synthesized epitopes to CD4+ T cells. Cytokine production data also demonstrated that the SUM/DR1/CD80/TT vaccine cells polarized the activated CD4+ T cells towards a Type 1 response. Therefore, these MHC class II and CD80-transduced human tumor cell vaccines are highly efficient antigen presenting cells for the activation of tumor-specific MHC class II-restricted, Type 1 CD4+ T lymphocytes, and they are a novel and potentially useful immunotherapeutic agent for the treatment of metastatic cancers. Supported by R01CA84232, R01CA52527 (NIH) and DAMD-17-01-1-0312 (DOD).
[Proc Amer Assoc Cancer Res, Volume 45, 2004]