Oligoclonality of TRBC1 and TRBC2 in T cell lymphomas as mechanism of primary resistance to TRBC-directed CAR T cell therapies
Ferrari and Righi et al.'s recent Nature Communications publication highlights the precise engineering of immunotherapies targeting the T cell receptor ß-chain constant domain 2 (TRBC2) in T cell lymphomas. A key challenge in treating these lymphomas is the lack of a distinct marker to differentiate healthy and malignant T cells, which is critical to prevent CAR T cell fratricide and life-threatening T cell depletion. The ability to distinguish TRBC1 and TRBC2—differing by just two amino acids in an accessible epitope—is a significant technological breakthrough, building on the group's earlier success with TRBC1-targeting CAR T cell therapy, currently under clinical evaluation (NCT03590574). While promising, preliminary phase 1 data presented at ICML 2023 revealed early disease progression in 2 of 4 patients treated at the target dose level. Expanding this research to target TRBC2 offers the potential to treat all patients with TCR ß-chain-expressing lymphomas. However, the observed early progression suggests mechanisms of primary resistance, beyond limited CAR T cell expansion and persistence, that require further investigation.