The emergence of a new paradigm with signal 1 and signal 2 T-cell engagers in hematology.

First-generation T-cell engagers have demonstrated significant efficacy in treating hematological malignancies by providing a potent T-cell receptor Signal 1. However, their efficacy is limited by the absence of a TCR co-stimulatory Signal 2, which results in T-cell exhaustion and resistance. A new strategy that addresses this issue is the use of bispecific antibodies (bsAbs) that target co-stimulatory Signal 2. These bispecific antibodies (bsAbs) co-engage a cancer-associated antigen (CAA) with a T-cell co-stimulatory receptor, such as CD28 or 4-1BB. Recent clinical strategies have combined Signal 1 and Signal 2 engagers in dual-bispecific regimens for lymphoma and multiple myeloma treatment. Therefore, the "Signal 1 + Signal 2" approach represents a significant advancement in immunotherapy, offering the potential to achieve deeper responses, overcome drug resistance and establish a robust 'off-the-shelf' therapeutic platform.