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Lai, Junyun; Mardiana, Sherly; House, Imran G; Sek, Kevin; Henderson, Melissa A; Giuffrida, Lauren; Chen, Amanda X Y; Todd, Kirsten L; Petley, Emma V; Chan, Jack D; Carrington, Emma M; Lew, Andrew M; Solomon, Benjamin J; Trapani, Joseph A; Kedzierska, Katherine; Evrard, Maximilien; Vervoort, Stephin J; Waithman, Jason; Darcy, Phillip K; Beavis, Paul A
Nature immunology, 08/2020, Letnik: 21, Številka: 8Journal Article
Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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