Microenvironment and Immunology Intracellular Tumor-AssociatedAntigensRepresentEffective Targets for Passive Immunotherapy

Monoclonal antibody (mAb) therapy against tumor antigens expressed on the tumor surface is associated with clinical benefit. However,many tumor antigens are intracellularmolecules that generallywould not be considered suitable targets formAb therapy. In this study, we provide evidence challenging this view through an investigation of the efficacy of mAb directed against NY-ESO-1, a widely expressed immunogen in human tumors that is expressed intracellularly rather than on the surface of cells. On their own, NY-ESO-1 mAb could neither augment antigen-specific CD8þ T-cell induction nor cause tumor eradication. To facilitate mAb access to intracellular target molecules, we combined anti-NY-ESO-1 mAb with anticancer drugs to accentuate the release of intracellular NY-ESO-1 from dying tumor cells. Strikingly, combination therapy induced a strong antitumor effect that was accompanied by the development of NY-ESO-1–specific effector/memory CD8þ T cells that were not elicited by single treatments alone. The combinatorial effect was also associated with upregulation of maturationmarkers on dendritic cells, consistent with the organization of an effective antitumor T-cell response. Administration of Fc-depleted F(ab) mAb or combination treatment in Fcg receptor–deficient host mice abolished the therapeutic effect. Together, our findings show that intracellular tumor antigens can be captured by mAbs and engaged in an efficient induction of CD8þ T-cell responses, greatly expanding the possible use of mAb for passive cancer immunotherapy. Cancer Res; 72(7); 1–11. 2012. AACR.