Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies

Abstract

Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor β-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1 and TRBC2 compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1, but not TRBC2, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Lately, using a very elegant approach to treat T-cell malignancies, Pule and colleagues isolated an antibody specific for the TCRβ1 constant region. A CAR based on this TCRβ1 specific antibody was efficient in mediating cytotoxicity against leukemic and healthy TCRβ1 cells while preserving the TCRβ2 population and thus potentially, full immunity [151].…”

Can one target T-cell ALL?

“…In this context, allele specific CAR T cells targeting the monoallelically expressed TCRB constant chain may deliver effective antileukemic effects with preservation of T-cell immune function [54,55]. During T cell receptor β (TCRB) rearrangement, developing T cells can engage two different modules in the TCR locus both encoding the constant region of this receptor chain.…”

Novel Immunotherapies for T Cell Lymphoma and Leukemia

“…A possible drawback of these approaches is that in clinical trials, if effective, these CART products will cause profound T cell aplasia could put the patient at serious risk of potentially fatal infections. To overcome this issue, an interesting approach was proposed by Maciocia et al(118). The authors developed CART cells that can specifically target one of the 2 variants of the constant regions of the TCR: C1 or C2.…”