Turning tumor cells in situ into T-helper cell-stimulating, MHC class II tumor epitope-presenters: immuno-curing and...

Immunological control or cure of tumors depends on initiating a robust T helper cell response to MHC class II epitopes of tumor-associated antigens. T helper cells regulate the potency of cytotoxic T lymphocyte and antibody responses. We have developed a novel approach to stimulate T helper cells by converting tumor cells into MHC class II molecule-positive, antigen presenting cells. Furthermore, using antisense methods, we suppress expression of the Ii protein, that normally blocks the antigenic peptide binding site of MHC class II molecules during synthesis in the endoplasmic reticulum. In such gene-engineered tumor cells, the MHC class II molecules pick up antigenic peptides, which have been transported into the endoplasmic reticulum for binding to MHC class I molecules. All nucleated cells create such "surveys of self" to detect viral or malignant transformation. Our method extends that survey of self to MHC class II endogenous tumor-associated antigens. Simultaneous presentation of tumor antigens by both MHC class I and II generates a robust and long-lasting antitumor immune response. Injecting murine tumors with genes, which induce MHC class II molecules and suppress Ii protein, cures a significant number of animals with renal and prostate tumors. We have developed analogous human gene vectors that are suitable for most patients and cancers, because they are monomorphic and active in all HLA-DR alleles. We review our findings, and analyze remaining issues for preclinical study and the design of clinical trials.