Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity
- Lai, J; Mardiana, S; House, IG; Sek, K; Henderson, MA; Giuffrida, L; Chen, AXY; Todd, KL; Petley, EV; Chan, JD; Carrington, EM; Lew, AM; Solomon, BJ; Trapani, JA; Kedzierska, K; Evrard, M; Vervoort, SJ; Waithman, J; Darcy, PK; Beavis, PA;
- Journal Title
- Nature Immunology
- Publication Type
- Journal epub ahead of print
- 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.
- WEHI Research Division(s)
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-05-25 01:54:59Last Modified: 2020-05-25 02:02:33