Immunosuppressant therapy averts rejection of allogeneic FKBP1A-disrupted CAR-T cells
2024; Elsevier BV; Volume: 32; Issue: 10 Linguagem: Inglês
10.1016/j.ymthe.2024.06.022
ISSN1525-0024
AutoresColby R. Maldini, Angelica Messana, Paula B. Bendet, Adam J. Camblin, Faith Musenge, Moriah White, Joseph J. Rocha, Lindsey Coholan, Cisem Karaca, Frederick W. B. Li, Bo Yan, Vladimir Vrbanac, Emily Marte, Daniel T. Claiborne, Christian L. Boutwell, Todd M. Allen,
Tópico(s)Silicon Carbide Semiconductor Technologies
ResumoChimeric antigen receptor (CAR) T cells from allogeneic donors promise "off-the-shelf" availability by overcoming challenges associated with autologous cell manufacturing. However, recipient immunologic rejection of allogeneic CAR-T cells may decrease their in vivo lifespan and limit treatment efficacy. Here, we demonstrate that the immunosuppressants rapamycin and tacrolimus effectively mitigate allorejection of HLA-mismatched CAR-T cells in immunocompetent humanized mice, extending their in vivo persistence to that of syngeneic humanized mouse-derived CAR-T cells. In turn, genetic knockout (KO) of FKBP prolyl isomerase 1A (FKBP1A), which encodes a protein targeted by both drugs, was necessary to confer CD19-specific CAR-T cells (19CAR) robust functional resistance to these immunosuppressants. FKBP1A
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