Journal article
39P TCR engaging antigen-scaffolds for targeted expansion of functionally improved T cells for adoptive cell therapy
DTU HealthTech, Technical University of Denmark, Kongens Lyngby, Denmark1
DTU HealthTech, Technical University of Denmark, Copenhagen, Denmark2
Nationalt Center for Cancer Immunterapi, CCIT-DK, Herlev Hospital, Herlev, Denmark3
Department of Dermatology, Universitaets-Hautklinik Tübingen, Tübingen, Germany4
Natural and Medical Sciences Institute, Universitätsklinikum Tübingen, Tübingen, Germany5
Precise targeting of patient’s tumor can be facilitated through T cells recognizing specific pMHC complexes on these tumors. Once such antigen landscape is defined, an additional challenge relates to the ability to mount a functional T cell response specific to such antigens. Current T Cell expansion techniques provide no efficient strategy for antigen-specific stimulation and results largely in exhausted T cells.
Here we present a new technology for ex-vivo peptide-MHC directed expansion and functional enhancement of T cells, using artificial antigen-presenting scaffolds (Ag-scaffolds). Dextran backbone conjugated with streptavidin was used for Ag-scaffold assembly. Such backbone was incubated together with biotinylated MHC class I molecules holding a given peptide (pMHC) and biotinylated human cytokines in various ratios.
PBMCs from healthy donors with known virus epitopes and from melanoma patients with known epitopes were expanded for 2 weeks with Ag-scaffold, added when the cell cultures were initiated and twice per week for two weeks. The expansion of antigen-specific CD8 T cells was monitored and analyzed by flow cytometry.
Here we demonstrate the value of the antigen-scaffold based expansion, by the expansion of virus-CD8 T cells from peripheral blood, and tumor-specific T cells from both peripheral blood and tumor site. We can favorably expand both neo- and shared antigen specific T cell populations. The resulting T cell product exhibit a multifunctional cytokine profile upon antigen challenge, high levels of CD28 expression, and reduced levels of PD-1 expression.
Importantly, numerous different pMHC-specific T-cell populations can be stimulated in a single culture, and we can obtain better tumor killing properties than conventional TIL-ACT products. This study presents a new technology for expanding functionally enhanced antigen-specific CD8 T cells suited for implementation to ACT strategies.
T cell phenotype and functionality are known to be important parameters in successful adoptive T cell transfer, and hence it´s plausible that antigen scaffold based expanded T cell product may improve treatment outcome compared to conventional expansion strategies. The authors. Innovation Fund Denmark.
All authors have declared no conflicts of interest.
Language: | English |
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Publisher: | Oxford University Press |
Year: | 2019 |
Pages: | xi13 |
ISSN: | 15698041 and 09237534 |
Types: | Journal article |
DOI: | 10.1093/annonc/mdz448.004 |