T cell exhaustion in bi- and trispecific T cell engager therapy in hematologic malignancies: Mechanisms and implications

T cell engagers (TCEs) have revolutionized the treatment of hematologic malignancies, with eight approved bispecific constructs and numerous bi- and trispecific TCEs currently in clinical trials. However, despite their clinical success, lack of response and high relapse rates remain major challenges. T cell exhaustion has emerged as an important mechanism of resistance to TCE therapy. Characterizing the T cell pool in patients prior to and during TCE therapy is warranted (1) to identify patients who will benefit most from TCE therapy and (2) to develop strategies to circumvent exhaustion during treatment to improve patient outcomes. We here review the current evidence of pre-existing and acquired T cell exhaustion during TCE therapy in patients with hematologic malignancies. We furthermore review state-of-the-art (pre)clinical strategies aimed at ameliorating exhaustion and reinvigorating T cell function.