Journal article

Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity

Junyun Lai, Sherly Mardiana, Imran G House, Kevin Sek, Melissa A Henderson, Lauren Giuffrida, Amanda XY Chen, Kirsten L Todd, Emma Petley, Jack D Chan, Emma M Carrington, Andrew M Lew, Benjamin J Solomon, Joseph A Trapani, Katherine Kedzierska, Maximilien Evrard, Stephin J Vervoort, Jason Waithman, Phillip K Darcy, Paul A Beavis

Nature Immunology | NATURE PUBLISHING GROUP | Published : 2020

Abstract

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 ind..

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Grants

Awarded by National Health and Medical Research Council (NHMRC)


Awarded by Cancer Council Victoria


Awarded by National Breast Cancer Foundation


Awarded by National Breast Cancer Foundation Fellowship


Awarded by NHMRC Research Fellowships


Funding Acknowledgements

We acknowledge assistance from the staff of the Animal Facility, the Centre for Advanced Histology and Microscopy, the Flow Cytometry Facility, the Molecular Genomics Core and the Pathology departments at the Peter MacCallum Cancer Centre. We also acknowledge the contribution of consumer advocates K. Gill, M. Rear and G. Sissing for this study. This work was funded by the National Health and Medical Research Council (NHMRC; grant nos. 1062580, 1143976 and 1150425), the Cancer Council Victoria (grant no. 1156382), the National Breast Cancer Foundation (grant no. IIRS-19-016 19-22), the CLEARbridge Foundation and the Tour de Cure Foundation. P.A.B. is supported by a National Breast Cancer Foundation Fellowship (ID no. ECF-17-005). P.K.D., A.M.L. and K.K. are supported by NHMRC Research Fellowships (grant nos. APP1041828, APP1080321 and APP1102792, respectively).