Targeting the TRBC gene expressed by T-cell malignancies mitigates severe immunosuppression.
Major finding: Targeting the TRBC gene expressed by T-cell malignancies mitigates severe immunosuppression.
Concept: T-cell lymphomas express either TRBC1 or TRBC2, which can then be selectively targeted.
Impact: T-cell receptor β-chain constant region–targeting CAR T cells may be efficacious in patients with lymphoma.
Although there are no antigens that are selectively expressed by B-cell malignancies, CAR T cells targeting pan–B cell antigens have been effective and well tolerated in spite of the resulting B-cell aplasia. The αβ T-cell receptor (TCR) is a pan–T cell antigen that is highly expressed by peripheral T-cell lymphomas (PTCL). However, targeting the αβ TCR would result in severe immunosuppression due to T-cell aplasia, and generating a bespoke reagent for each patient's T-cell clone is impractical. Because T cells mutually exclusively express either TRBC1 and TRBC2, which are the two genes associated with the TCR β-chain constant region, Maciocia and colleagues sought to determine whether targeting either TRBC1 or TRBC2 would be an effective and safe immunotherapeutic approach for patients with PTCL. Screening of Jurkat T cells expressing either TRBC1 or TRBC2 with a panel of anti-TCR antibodies revealed that the JOVI-1 mAb exhibited high specificity for TRBC1, and structural analysis identified the residues comprising the discriminating JOVI-1 epitope in TRBC1 that are targeted by JOVI-1. Flow cytometric analysis of JOVI-1–stained T cells from healthy donors or malignant T cells showed that normal αβ TCR T-cell populations are comprised of both TRBC1+ and TRBC2+ T cells; however, leukemia and lymphoma cell lines and malignant T cells from patients with leukemia were homogenous TRBC1+ or TRBC2+ populations. CAR T cells expressing the JOVI-1 ScFv exhibited selective toxicity against TRBC1+ T cell malignancy–derived cell lines and T cells from patients with TRBC1+ leukemias or PTCL. Further, anti-TRBC1 treatment of mice injected with TRBC1+ Jurkat cells resulted in the depletion of disseminated TRBC1+ malignant and normal T cells and the persistence of normal TRBC2+ T cells. These results provide evidence that patients with T-cell malignancies may benefit from immunotherapies that target the TCR β-chain constant region with acceptable levels of immunosuppression.
Maciocia PM, Wawrzyniecka PA, Philip B, Ricciardelli I, Akarca AU, Onuoha SC, et al. Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Nature Med 2017;23:1416–23.
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