Journal article
Enhancing Adoptive Cell Therapy by T Cell Loading of SHP2 Inhibitor Nanocrystals before Infusion
Biotherapeutic Engineering and Drug Targeting, Department of Health Technology, Technical University of Denmark1
Department of Health Technology, Technical University of Denmark2
T-Cells and Cancer, Experimental & Translational Immunology, Department of Health Technology, Technical University of Denmark3
Experimental & Translational Immunology, Department of Health Technology, Technical University of Denmark4
Colloids & Biological Interfaces, Biotherapeutic Engineering and Drug Targeting, Department of Health Technology, Technical University of Denmark5
Materials at the Interface of Biology, Nanocharacterization, National Centre for Nano Fabrication and Characterization, Technical University of Denmark6
Nanocharacterization, National Centre for Nano Fabrication and Characterization, Technical University of Denmark7
National Centre for Nano Fabrication and Characterization, Technical University of Denmark8
Whereas adoptive T cell therapy has been extensively studied for cancer treatment, the response is still limited primarily due to immune dysfunction related to poor cell engraftment, tumor infiltration and engagement, and lack of a target. In addition, the modification of therapeutic T cells often suffers from being complex and expensive.
Here, we present a strategy to load T cells with SHP099, an allosteric SHP2 inhibitor, to enhance the therapeutic efficacy of the T cells. Remote-loading of SHP099 into lipid nanoparticles decorated with triarginine motifs resulted in nanocrystal formation of SHP099 inside the lipid vesicles and allowed high loading efficiency and prolonged retention of SHP099 nanocrystals within T cells.
Cell-loaded SHP099 enabled sustained inhibition of the PD-1/PD-L1 signaling and increased cytolytic activity of the T cells. We show in a mouse model that tumor-homing T cells can circulate with the cargos, improving their tumor accumulation compared to systemically administered lipid nanoparticles.
On an established solid tumor model, adoptively transferred SHP099 loaded T cells induced complete tumor eradication and durable immune memory against tumor rechallenging on all treated mice by effectively inhibiting the PD-1/PD-L1 checkpoint signal. We demonstrate that the combination of T cell therapy with SHP2 inhibition is a promising therapeutic strategy, and the lipid nanocrystal platform could be generalized as a promising approach for T cell loading of immunomodulatory drugs.
Language: | English |
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Publisher: | American Chemical Society |
Year: | 2022 |
Pages: | 10918-10930 |
ISSN: | 1936086x and 19360851 |
Types: | Journal article |
DOI: | 10.1021/acsnano.2c03311 |
ORCIDs: | Li, Xin , Halldórsdóttir, Hólmfridur R. , Weller, Sven , Bak, Martin , Kempen, Paul , Clergeaud, Gael and Andresen, Thomas L. |