Current treatments of
high-grade lymphoma often have curative potential, but unfortunately many patients relapse and develop therapeutic resistance. Thus, there remains a need for novel
therapeutics that can target the
residual cancer cells whose phenotypes are distinct from the bulk
tumor and that are capable of reforming
tumors from very few cells. Oncolytic viruses offer an approach to destroy
tumors by multiple mechanisms, but they cannot effectively reach residual disease or
micrometastases, especially within the lymphatic system. To address these limitations, we have generated immune cells infected with oncolytic viruses as a therapeutic strategy that can combine effective cellular delivery with synergistic
tumor killing. In this study, we tested this approach against minimal disease states of
lymphomas characterized by the persistence of
cancer cells that display stem cell-like properties and resistance to conventional
therapies. We found that the immune cells were capable of trafficking to and targeting
residual cancer cells. The combination
biotherapy used prevented relapse by creating a long-term, disease-free state, with acquired immunity to the
tumor functioning as an essential mediator of this effect. Immune components necessary for this acquired immunity were identified. We further demonstrated that the dual
biotherapy could be applied before or after conventional
therapy. Our approach offers a potentially powerful new way to clear
residual cancer cells, showing how restoring immune surveillance is critical for maintenance of a disease-free state.