TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy
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 curr...
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BMJ Publishing Group
2023-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/8/e006847.full |
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| author | Marco Donia Özcan Met Julie Westerlin Kjeldsen Sine Reker Hadrup Inge Marie Svane Arianna Draghi Anders Handrup Kverneland Christina Heeke Siri Amanda Tvingsholm Marcus Svensson Frej Vibeke Mindahl Rafa Ulla Kring Hansen Maria Ormhøj Alexander Tyron Agnete W P Jensen Mohammad Kadivar Amalie Kai Bentzen Kamilla K Munk Gitte N Aasbjerg Jeppe S H Ternander Tripti Tamhane Christian Schmess Samuel A. Funt Søren Nyboe Jakobsen |
| author_facet | Marco Donia Özcan Met Julie Westerlin Kjeldsen Sine Reker Hadrup Inge Marie Svane Arianna Draghi Anders Handrup Kverneland Christina Heeke Siri Amanda Tvingsholm Marcus Svensson Frej Vibeke Mindahl Rafa Ulla Kring Hansen Maria Ormhøj Alexander Tyron Agnete W P Jensen Mohammad Kadivar Amalie Kai Bentzen Kamilla K Munk Gitte N Aasbjerg Jeppe S H Ternander Tripti Tamhane Christian Schmess Samuel A. Funt Søren Nyboe Jakobsen |
| author_sort | Marco Donia |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a25dad34aae2492e8875e883c1894921 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-a25dad34aae2492e8875e883c18949212025-02-03T22:10:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-08-0111810.1136/jitc-2023-006847TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapyMarco DoniaÖzcan Met0Julie Westerlin Kjeldsen1Sine Reker Hadrup2Inge Marie Svane3Arianna Draghi4Anders Handrup Kverneland5Christina Heeke6Siri Amanda Tvingsholm7Marcus Svensson Frej8Vibeke Mindahl Rafa9Ulla Kring Hansen10Maria Ormhøj11Alexander Tyron12Agnete W P Jensen13Mohammad Kadivar14Amalie Kai Bentzen15Kamilla K Munk16Gitte N Aasbjerg17Jeppe S H Ternander18Tripti Tamhane19Christian Schmess20Samuel A. Funt21Søren Nyboe Jakobsen22National Center for Cancer Immune Therapy (CCIT-DK), Herlev, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, Denmark4Section for Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, DenmarkDepartment of Oncology, National Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, DenmarkDepartment of Oncology, Copenhagen University Hospital, National Center for Cancer Immune Therapy (CCIT-DK), Herlev, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkDepartment of Health Technology, Technical University of Denmark, Lyngby, DenmarkDepartment of Health Technology, Technical University of Denmark, Lyngby, DenmarkPokeAcell Aps, BioInnovation Institute, Copenhagen, DenmarkDepartment of Health Technology, Technical University of Denmark, Lyngby, DenmarkPokeAcell Aps, BioInnovation Institute, Copenhagen, DenmarkDepartment of Health Technology, Technical University of Denmark, Lyngby, DenmarkDepartment of Health Technology, Technical University of Denmark, Lyngby, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkDepartment of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark1UCL Cancer Institute, Pre-Cancer Immunology Laboratory, London, UKDepartment of Health Technology, Technical University of Denmark, Lyngby, DenmarkDepartment of Health Technology, Technical University of Denmark, Lyngby, DenmarkPokeAcell Aps, BioInnovation Institute, Copenhagen, DenmarkDepartment of Health Technology, Technical University of Denmark, Lyngby, DenmarkNMI Natural and Medical Science Institute, University of Tübingen, Tubingen, GermanyDeptartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USADepartment of Health Technology, Technical University of Denmark, Lyngby, DenmarkBackground 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.https://jitc.bmj.com/content/11/8/e006847.full |
| spellingShingle | Marco Donia Özcan Met Julie Westerlin Kjeldsen Sine Reker Hadrup Inge Marie Svane Arianna Draghi Anders Handrup Kverneland Christina Heeke Siri Amanda Tvingsholm Marcus Svensson Frej Vibeke Mindahl Rafa Ulla Kring Hansen Maria Ormhøj Alexander Tyron Agnete W P Jensen Mohammad Kadivar Amalie Kai Bentzen Kamilla K Munk Gitte N Aasbjerg Jeppe S H Ternander Tripti Tamhane Christian Schmess Samuel A. Funt Søren Nyboe Jakobsen TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy Journal for ImmunoTherapy of Cancer |
| title | TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy |
| title_full | TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy |
| title_fullStr | TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy |
| title_full_unstemmed | TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy |
| title_short | TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy |
| title_sort | tcr engaging scaffolds selectively expand antigen specific t cells with a favorable phenotype for adoptive cell therapy |
| url | https://jitc.bmj.com/content/11/8/e006847.full |
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