One of the challenges of developing effective therapies for T cell lymphomas and leukemias—for which few treatments exist—is that patients are extremely sensitive to the loss of these versatile immune cells. Enough T cells must be left alive following therapy to ensure patients can still battle infections. In pursuit of that goal, researchers led by Ludwig Johns Hopkins’ Jiaxin Ge, Kenneth Kinzler, Bert Vogelstein and Suman Paul reported in Nature Cancer in December the second iteration of a therapeutic strategy for selectively killing T cells recently developed at the Johns Hopkins Center that could enable the development of an off-the-shelf therapy for these cancers. Their strategy exploits the fact that healthy T cell pools in people express a mix of two T cell receptor alleles: TRBC1 (about 40%) and TRBC2 (60%). Cancerous T cell pools, being descendants of a single transformed clone, express only one of those alleles. The researchers described the design and preclinical evaluation of an antibody-drug conjugate (ADC) that selectively targets TRBC2-expressing T cells, following up on one reported in 2024 that similarly eliminates T cells expressing TRBC1. The high-affinity anti-TRBC2 ADC specifically targeted TRBC2+ cancers in vitro and in mouse models, opening a new approach to treating T cell malignancies that targets one clonotype that characterizes a T cell cancer while sparing the other to sustain T cell-mediated immune responses.
TRBC2-targeting antibody–drug conjugates for the treatment of T cell cancers
Nature Cancer, 2025 December 22