Challenges and solutions for therapeutic TCR-based agents

Recent development of methods to discover and engineer therapeutic T-cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that TCR-based agents will be similarly important contributors to the treatment of a variety of medical conditions, especially cancers. TCR engineered cells, soluble TCRs and their derivatives, TCR-mimic antibodies, and TCR-based CAR T cells promise the possibility of highly specific drugs that can expand the scope of immunologic agents to recognize intracellular targets, including mutated proteins and undruggable transcription factors, not accessible by traditional antibodies. Hurdles exist regarding discovery, specificity, pharmacokinetics, and best modality of use that will need to be overcome before the full potential of TCR-based agents is achieved. HLA restriction may limit each agent to patient subpopulations and off-target reactivities remain important barriers to widespread development and use of these new agents. In this review we discuss the unique opportunities for these new classes of drugs, describe their unique antigenic targets, compare them to traditional antibody therapeutics and CAR T cells, and review the various obstacles that must be overcome before full application of these drugs can be realized.

Automated summary

Recent advances in discovering and engineering therapeutic T-cell receptors (TCRs) or TCR antibody mimics lag behind therapeutic antibodies, but hold great promise for treating various medical conditions, particularly cancers. TCR-based agents, including engineered cells, soluble TCRs, TCR-mimic antibodies, and TCR-based CAR T cells, offer the potential for highly specific drugs that can target intracellular antigens inaccessible to traditional antibodies. However, there are challenges to overcome in terms of discovery, specificity, pharmacokinetics, and optimal modality of use. HLA restriction and off-target reactivities also present barriers to widespread development and use of TCR-based agents.