Bringing Together the Power of T Cell Receptor Mimic and Bispecific Antibodies for Cancer Immunotherapy: Still a Long Way to Go

Abstract

Antibody-based cancer immunotherapy has revolutionized oncology. The first successful therapeutic antibodies relied on eliciting immune-mediated cytotoxicity (rituximab) or modulation of intracellular signaling (trastuzumab). Further attempts to enhance the antitumor effects led to the development of immunoconjugates with radioactive or cytotoxic compounds (tositumomab, brentuximab vedotin). Another line of research led to the bispecific antibodies that can enhance the formation of immunological synapse between cancer and cytotoxic T cells (blinatumomab). Despite the constant advances in design and production, the application of monoclonal antibodies in cancer treatment remains limited by the presence of specific cell surface markers. A rational approach to target intracellular cancer antigens was proposed almost two decades ago by the development of anti-peptide human leukocyte antigen (HLA) complex (T cell receptor-like/mimic) antibodies. They could recognize specifically cancer neoantigens expressed in the context of specific HLA molecules theoretically providing unprecedented specificity. Furthermore, they can be developed in a semigeneric format, that is, to target common neoantigens expressed in the context of common HLA molecules. It is rationale to expect that the development of such antibodies in the format of bispecific antibody constructs can bring together the power of specific antibody-based recognition and that of T cell-mediated lysis. There are already some preliminary reports that suggest such constructs would be an achievable goal. In this brief review, we discuss some of the successful preclinical developments in the field and the major challenges that are yet to be addressed.