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.
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. ■
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