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Constant attack on T cell lymphomas

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Science Immunology  01 Dec 2017:
Vol. 2, Issue 18, eaar5171
DOI: 10.1126/sciimmunol.aar5171

Abstract

A proof-of-principle study generates CAR-T cells against T cell lymphoma by selectively targeting the T cell receptor β-chain constant region 1.

Chimeric antigen receptor T cell (CAR-T) therapy is a promising strategy for cancer treatment that is based on genetically engineering T cells to target antigens present on the surface of tumor cells. As such, the clinical utility of CAR-T cells is predicated on the identification of suitable target proteins that are either tumor-specific or non-essential for host viability. For example, strategies that utilize anti-CD19 CAR-T cells have been highly effective for the treatment of B cell malignancies, including B lymphoblastic leukemia and mature B cell lymphomas. Although treatment with anti-CD19 CAR-T cells leads to the on-target toxicity of B cell aplasia and hypogammaglobulinemia, these side effects can usually be managed with intravenous immunoglobulin replacement.

The adaptation of CAR-T cell therapy to T cell malignancies, however, has been more problematic because targeting of pan–T cell antigens (e.g., CD3) runs the risk of severe or unmanageable immunosuppression. Maciocia and colleagues report a proof-of-principle study for the application of CAR-T therapy to T cell malignancies by demonstrating selective targeting of the T cell receptor β-chain constant region 1. Polyclonal αβ T cell populations comprise a mixture of β-chain constant region 1 and constant region 2 expressing cells. Neoplastic T cell populations, however, express a clonal T cell receptor and show exclusive expression of either β-chain constant region 1 or constant region 2. Although these regions are highly similar with regard to amino acid sequence, Maciocia et al. identified a monoclonal antibody (JOVI-1) that selectively targets the T cell receptor β-chain constant region 1 but not constant region 2. Accordingly, this approach would be anticipated to preserve a substantial portion of the normal T cell repertoire (including all β-chain constant region 2 and γ-chain expressing T cells).

After validating the specificity of the JOVI-1 antibody for β-chain constant region 1, the authors show that JOVI-1 reliably identifies a subset of polyclonal αβ T cells in normal individuals (about 35% of the total αβ population) as well as a subset of primary human T cell malignancies. Using a single chain variable fragment based on the JOVI-1 antigen binding site, the authors then generated CAR-T cells targeting the human T cell receptor β-chain constant region 1 and successfully used these cells to selectively eradicate β-chain constant region 1-expressing T cells in vitro and in a mouse xenograft model of human T cell leukemia.

As the authors demonstrate, however, only 25 to 45% of T cell malignancies express β-chain constant region 1, and the expansion of this strategy to encompass all clinically relevant T cell malignancies would require the identification of equally specific antibodies targeting T cell receptor β-chain constant region 2 as well as each T cell receptor γ-chain constant region. Last, although this approach would be expected to leave a substantial portion of the T cell repertoire intact, the actual impact of constant region-based depletion on host defense was not explored in the present study and warrants further evaluation. In addition, the risk of cytokine release syndrome with anti–T cell receptor–based CAR-T therapies is an additional serious and potentially fatal toxicity that warrants further exploration.

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