Targeting antigen-loss variant tumors through CD134 plus CD137 dual costimulation-mediated bystander programming (VAC10P.964)

Tumor-specific cytotoxic CD8 T cell-based therapies can be efficacious in cancer patients. Nevertheless, disease progression often resumes due to outgrowth of antigen-loss variants (ALVs) that lack expression of the targeted MHC class I-restricted epitopes. Co-administration of agonists to the TNF/TNFR costimulatory family members CD134 (OX40) and CD137 (4-1BB) can program antigen-stimulated CD4 T cells to differentiate into cytotoxic Th1 cells, which can directly target MHC II+ tumors and provide classical helper function that facilitates effector differentiation in CD8 T cells responding to a linked epitope. Interestingly, these specific cytotoxic CD4 Th1 cells also imprint antigen-non-responding T cells with a similar ability to express IFN-γ and cytotoxic molecules. Because these bystander-programmed effector T cells are polyclonal, we currently hypothesized that they contain specificities capable of targeting ALVs. In both lymphoma and melanoma models, dual costimulation therapy was markedly enhanced when specific CD4 T cells were engaged to differentiate into cytotoxic Th1 effectors. This augmentation occurred not only when the tumor expressed the MHC class II-restricted epitope recognized by the specific cytotoxic CD4 Th1 cells, but importantly also with tumors modeling ALVs that lack the targeted epitope. Taken together, dual-costimulated tumor-non-specific CD4 T cells provide an alternate form of help that facilitates targeting of ALVs.