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T cell engagers are a class of bispecific molecules that induce highly potent T cell-dependent cytotoxicity by bringing T cell activating receptors into proximity with cancer-associated cell surface antigens. However, because of their high potency, there is a greater risk of on-target/off-tumor toxicity owing to normal tissues having tumor antigen expression even at low levels. To reduce these adverse events, the dysregulated activity of proteases within the tumor microenvironment has recently been explored to create inert prodrugs that become conditionally active engagers after their cleavage by these enzymes. T-cell engagers that have been introduced for clinical use, and their respective successes and failures are reviewed. The unique challenges of these bispecific molecules for treating solid tumors and prior technologies used to exploit the proteolytic tumor microenvironment to create better-tolerated prodrugs and how that experience has led to the current series of conditionally active T-cell engagers are discussed. Methods for modulating the serum half-life of both inert and activated T cell engagers could have important ramifications in how they infiltrate tumors and prevent toxicity. Alternative features of the tumor microenvironment can also be leveraged in the development of conditional T cell engagers.

Conditionally active T cell engagers for the treatment of solid tumors: rationale and clinical development