Mechanisms of Resistance to Monoclonal Antibodies (mAbs) in Lymphoid Malignancies

Pallawi Torka, Mathew Barth, Robert Ferdman, Francisco J. Hernandez-Ilizaliturri

Passive immunotherapy with therapeutic monoclonal antibodies (mAbs) has revolutionized the treatment of cancer, especially hematological malignancies over the last 20 years. While use of mAbs has improved outcomes, development of resistance is inevitable in most cases, hindering the long-term survival of cancer patients. This review focuses on the available data on mechanisms of resistance to rituximab and includes some additional information for other mAbs currently in use in hematological malignancies. Mechanisms of resistance have been identified that target all described mechanisms of mAb activity including altered antigen expression or binding, impaired complement-mediated cytotoxicity (CMC) or antibody-dependent cellular cytotoxicity (ADCC), altered intracellular signaling effects, and inhibition of direct induction of cell death. Numerous approaches to circumvent identified mechanisms of resistance continue to be investigated, but a thorough understanding of which resistance mechanisms are most clinically relevant is still elusive. In recent years, a deeper understanding of the tumor microenvironment and targeting the apoptotic pathway has led to promising breakthroughs. Resistance may be driven by unique patient-, disease-, and antibody-related factors. Understanding the mechanisms of resistance to mAbs will guide the development of strategies to overcome resistance and re-sensitize cancer cells to these biological agents.