Inducing adaptive immunity as a way to improve anti-tumor monoclonal antibody therapy

Abstract

In the past 15 years, eleven monoclonal antibodies (mAbs) have been approved for cancer therapy by the Food and Drug Administration. It is an additional therapeutic option besides the conventional treatments of surgery, chemotherapy and radiation. However, cancer is still one of the most common causes of death, causing 13% of all deaths in the world. At present, mAbs function as a direct hit therapy for cancer, either by inhibiting tumor growth or by killing the malignant cells. However, often therapy is heterogeneous or relapses occur. The holy grail for immunotherapy for cancer is to induce a memory response. Memory T cells can recognize a tumor after re-encountering and induce anti-tumor immune responses up till years after treatment of the primary tumor. Improving mAbs to enhance the induction of adaptive immunity and generation of memory T cells is very promising. One suggested mAb therapy improvement is a combination with cytotoxic therapies. They induce apoptosis of tumor cells and the release of some molecules, in addition to their immunosuppressive action. These molecules promote phagocytosis of the apoptotic cells and antigen presentation in dendritic cells (DCs) to T cells. If timing of administration is correct, 24 hours before mAb treatment, the immunosuppressive function will be minimal and the induction of anti-tumor adaptive immune responses will be enhanced. Antigen presentation in DCs and T cell activation can also be promoted by combining mAb therapy with immunomodulatory molecules or vaccination strategies. Protein engineering of mAbs to increase affinity for their receptors (FcγRs), which are thought to influence for example antigen processing and presentation in DCs, may be an option too. While mAb therapy does not work optimally in all patients, I will describe in this thesis several suggested improvements which enhance the induction of adaptive immunity.