TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy
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TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy. / Tvingsholm, Siri Amanda; Frej, Marcus Svensson; Rafa, Vibeke Mindahl; Hansen, Ulla Kring; Ormhøj, Maria; Tyron, Alexander; Jensen, Agnete W.P.; Kadivar, Mohammad; Bentzen, Amalie Kai; Munk, Kamilla K.; Aasbjerg, Gitte N.; Ternander, Jeppe S.H.; Heeke, Christina; Tamhane, Tripti; Schmess, Christian; Funt, Samuel A.; Kjeldsen, Julie Westerlin; Kverneland, Anders Handrup; Met, Özcan; Draghi, Arianna; Jakobsen, Søren Nyboe; Donia, Marco; Marie Svane, Inge; Hadrup, Sine Reker.
I: Journal for ImmunoTherapy of Cancer, Bind 11, Nr. 8, e006847, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy
AU - Tvingsholm, Siri Amanda
AU - Frej, Marcus Svensson
AU - Rafa, Vibeke Mindahl
AU - Hansen, Ulla Kring
AU - Ormhøj, Maria
AU - Tyron, Alexander
AU - Jensen, Agnete W.P.
AU - Kadivar, Mohammad
AU - Bentzen, Amalie Kai
AU - Munk, Kamilla K.
AU - Aasbjerg, Gitte N.
AU - Ternander, Jeppe S.H.
AU - Heeke, Christina
AU - Tamhane, Tripti
AU - Schmess, Christian
AU - Funt, Samuel A.
AU - Kjeldsen, Julie Westerlin
AU - Kverneland, Anders Handrup
AU - Met, Özcan
AU - Draghi, Arianna
AU - Jakobsen, Søren Nyboe
AU - Donia, Marco
AU - Marie Svane, Inge
AU - Hadrup, Sine Reker
N1 - Publisher Copyright: © 2023 Author(s). Published by BMJ.
PY - 2023
Y1 - 2023
N2 - Background Adoptive cell therapy (ACT) has shown promising results for the treatment of cancer and viral infections. Successful ACT relies on ex vivo expansion of large numbers of desired T-cells with strong cytotoxic capacity and in vivo persistence, which constitutes the greatest challenge to current ACT strategies. Here, in this study, we present a novel technology for ex vivo expansion of antigen-specific T-cells; artificial antigen-presenting scaffolds (Ag-scaffolds) consisting of a dextran-polysaccharide backbone, decorated with combinations of peptide-Major Histocompatibility Complex (pMHC), cytokines and co-stimulatory molecules, enabling coordinated stimulation of antigen-specific T-cells. Methods The capacity of Ag-scaffolds to expand antigen-specific T-cells was explored in ex vivo cultures with peripheral blood mononuclear cells from healthy donors and patients with metastatic melanoma. The resulting T-cell products were assessed for phenotypic and functional characteristics. Results We identified an optimal Ag-scaffold for expansion of T-cells for ACT, carrying pMHC and interleukin-2 (IL-2) and IL-21, with which we efficiently expanded both virus-specific and tumor-specific CD8+ T cells from peripheral blood of healthy donors and patients, respectively. The resulting T-cell products were characterized by a high frequency of antigen-specific cells with high self-renewal capacity, low exhaustion, a multifunctional cytokine profile upon antigen-challenge and superior tumor killing capacity. This demonstrates that the coordinated stimuli provided by an optimized stoichiometry of TCR engaging (pMHC) and stimulatory (cytokine) moieties is essential to obtain desired T-cell characteristics. To generate an 'off-the-shelf' multitargeting Ag-scaffold product of relevance to patients with metastatic melanoma, we identified the 30 most frequently recognized shared HLA-A0201-restricted melanoma epitopes in a cohort of 87 patients. By combining these in an Ag-scaffold product, we were able to expand tumor-specific T-cells from 60-70% of patients with melanoma, yielding a multitargeted T-cell product with up to 25% specific and phenotypically and functionally improved T cells. Conclusions Taken together, the Ag-scaffold represents a promising new technology for selective expansion of antigen-specific CD8+ T cells directly from blood, yielding a highly specific and functionally enhanced T-cell product for ACT.
AB - Background Adoptive cell therapy (ACT) has shown promising results for the treatment of cancer and viral infections. Successful ACT relies on ex vivo expansion of large numbers of desired T-cells with strong cytotoxic capacity and in vivo persistence, which constitutes the greatest challenge to current ACT strategies. Here, in this study, we present a novel technology for ex vivo expansion of antigen-specific T-cells; artificial antigen-presenting scaffolds (Ag-scaffolds) consisting of a dextran-polysaccharide backbone, decorated with combinations of peptide-Major Histocompatibility Complex (pMHC), cytokines and co-stimulatory molecules, enabling coordinated stimulation of antigen-specific T-cells. Methods The capacity of Ag-scaffolds to expand antigen-specific T-cells was explored in ex vivo cultures with peripheral blood mononuclear cells from healthy donors and patients with metastatic melanoma. The resulting T-cell products were assessed for phenotypic and functional characteristics. Results We identified an optimal Ag-scaffold for expansion of T-cells for ACT, carrying pMHC and interleukin-2 (IL-2) and IL-21, with which we efficiently expanded both virus-specific and tumor-specific CD8+ T cells from peripheral blood of healthy donors and patients, respectively. The resulting T-cell products were characterized by a high frequency of antigen-specific cells with high self-renewal capacity, low exhaustion, a multifunctional cytokine profile upon antigen-challenge and superior tumor killing capacity. This demonstrates that the coordinated stimuli provided by an optimized stoichiometry of TCR engaging (pMHC) and stimulatory (cytokine) moieties is essential to obtain desired T-cell characteristics. To generate an 'off-the-shelf' multitargeting Ag-scaffold product of relevance to patients with metastatic melanoma, we identified the 30 most frequently recognized shared HLA-A0201-restricted melanoma epitopes in a cohort of 87 patients. By combining these in an Ag-scaffold product, we were able to expand tumor-specific T-cells from 60-70% of patients with melanoma, yielding a multitargeted T-cell product with up to 25% specific and phenotypically and functionally improved T cells. Conclusions Taken together, the Ag-scaffold represents a promising new technology for selective expansion of antigen-specific CD8+ T cells directly from blood, yielding a highly specific and functionally enhanced T-cell product for ACT.
KW - antigen presentation
KW - antigens, tumor-associated, carbohydrate
KW - clonal selection, antigen-mediated
KW - immunotherapy
KW - immunotherapy, adoptive
U2 - 10.1136/jitc-2023-006847
DO - 10.1136/jitc-2023-006847
M3 - Journal article
C2 - 37586765
AN - SCOPUS:85168235375
VL - 11
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
SN - 2051-1426
IS - 8
M1 - e006847
ER -
ID: 371195901