HLA-independent T-cell receptors (HIT receptors) exhibit greater antigen sensitivity than CD28-based CARs.

  • Major Finding: HIT receptors exhibit greater antigen sensitivity than CD28-based CARs.

  • Concept:TRAC locus editing established TCR–CD3 complexes incorporating CAR-matched heavy and light chains.

  • Impact: This HIT design allows for the targeting of low-density antigens, leading to improved tumor rejection.

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Antigen escape, either through loss of target antigen expression or reduction in expression below the antigen threshold, is one of the major mechanisms behind relapse using chimeric antigen receptor (CAR) T-cell therapy. CD28-based CARs represent the current most sensitive CAR, but, in an effort to increase antigen sensitivity, Mansilla-Soto, Eyquem, and colleagues used editing of the TRAC locus in human peripheral blood T cells to allow engagement of cell-surface targets through their T-cell receptor (TCR)–CD3 complex with the same immunoglobulin heavy and light chains as a matched CAR. These new HLA-independent TCRs (HIT receptors) provide T cells with single specificity and exhibit greater antigen sensitivity than canonical CARs. This phenotype is further supported by the release of critical cytokines such as interferon-γ, interleukin-2, and tumor necrosis factor α at low antigen densities (generally defined as ∼20 CD19 molecules/cell). Furthermore, these HIT receptor T cells demonstrate greater phosphorylation of CDζ, ZAP70, and ERK1/2 at lower antigen densities as well as more frequent and rapid degranulation contributing to more effective killing of cells at low antigen density. In in vivo models using NALM6, a common pre–B acute lymphoblastic leukemia, these CD19-specific HIT T cells showed greater elimination of tumors with low antigen levels. To improve persistence of these HIT T cells, costimulatory support was provided through coexpression of CD28 and 4-1BB ligands (HIT + CD80/4-1BBL) and was found to yield greater T-cell survival and to outperform the CD28-based CAR T cells in two models targeting either CD19 or BCMA, which is abundant in myeloma. Additionally, targeting of CD70, a clinically relevant low abundance target in acute myeloid leukemia, also demonstrated a similar phenotype, with these CD70-targeting HIT + CD80/4-1BBL T cells showing markedly improved antitumor efficacy. This study provides the HIT design to improve response to antigens expressed below the CAR threshold, making these T cells more sensitive, and allows for expansion in the number of tumors that can be targeted by engineered T cells. ■

Mansilla-Soto J, Eyquem J, Haubner S, Hamieh M, Feucht J, Paillon N, et al. HLA-independent T cell receptors for targeting tumors with low antigen density. Nat Med 2022 Jan 13 [Epub ahead of print].

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©2022 American Association for Cancer Research.
2022
American Association for Cancer Research.