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Inhibition of ITK differentiates GVT and GVHD in allo-HSCT

By Mahinbanu Mammadli, Weishan Huang, Rebecca Harris, Aisha Sultana, Ying Cheng, Wei Tong, Jeffery Pu, Teresa Gentile, Jessica Henty-Ridilla, Shanti Dsouza, Qi Yang, Avery August, Alaji Bah, Mobin Karimi

Posted 15 Jul 2020
bioRxiv DOI: 10.1101/2020.07.15.204693

Donor T cells contained within the graft prevent tumor recurrence via graft-versus-tumor (GVT) effects, however, also cause graft-versus-host disease (GVHD). Novel treatment strategies are therefore needed to allow maintenance of GVT while suppressing GVHD. Here we show using murine models, that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving the beneficial GVT effects. Donor T cells from Itk-/- mice exhibit significantly reduced production of inflammatory cytokines and migration to GVHD target organs such as liver and small intestine, while maintaining GVT efficacy against primary B-ALL tumors. Itk-/- T cells exhibited reduced expression of IRF4 and decreased JAK/STAT signaling activity, but preserved cytotoxicity, which was accompanied by upregulation of Eomesodermin (Eomes), which was necessary for GVT function. A novel peptide inhibitor ITK signaling is also able to prevent GVHD. This novel peptide inhibitor also reduced cytokine production in mice and human T cells. Altogether, our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVT effects following allo-HSCT treatment.

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