Advancements in TRBC1 and TRBC2-Targeted Therapies for T Cell Lymphomas

Mature T cell lymphomas are aggressive malignancies that are difficult to treat and often have poor outcomes. Traditional immunotherapies have struggled to differentiate between cancerous and healthy T cells. However, the distinct expression of TCR β chains (TRBC) 1 or 2 presents a potential target for therapy. The challenge lies in the development of antibodies that can differentiate between the two isoforms, which differ by only a two-amino acid inversion.

The study reports the development of a TRBC2-specific binder and CAR T cell, expanding on previous work with a TRBC1-specific antibody. The TRBC2 binders were identified through a combination of crystallography and structural engineering of the TRBC1-specific antibody, using a targeted library screening approach. These binders were then optimized for use in CAR T cells, which were evaluated for both in vitro and in vivo anti-tumor activity and selectivity.

The TRBC2 CARs demonstrated similar efficacy to the TRBC1 CARs in vitro, with the ability to selectively target and kill TRBC2-expressing cells while sparing TRBC1-expressing cells. In mouse models, both TRBC1- and TRBC2-directed CARs showed high specificity for their respective antigens. Additionally, the antibodies were adapted for use as Antibody Drug Conjugates (ADCs), showing effective internalization and cytotoxic potential.

The research concludes that the TRBC2-specific CAR T cells have been successfully characterized and show promise for use in treating T cell lymphomas. Furthermore, the TRBC1 and TRBC2 antibodies, now engineered with an optimal affinity for improved uptake, also show potential as targeting agents for ADCs. This dual approach offers new avenues for the treatment of peripheral T cell lymphomas, including those associated with HTLV-1, where traditional CAR T cell therapy may not be suitable.