Generation of Tumor-Specific Cytotoxic T Cells From Blood via In Vitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled Microbeads
For the past decade, adoptive cell therapy including tumor-infiltrating lymphocytes, genetically modified cytotoxic lymphocytes expressing a chimeric antigen receptor, or a novel T-cell receptor has revolutionized the treatment of many cancers. Progress within exome sequencing and neoantigen predict...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.866763/full |
| _version_ | 1811272486750257152 |
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| author | Adela Kiessling Keerthana Ramanathan Ola B. Nilsson Ola B. Nilsson Luigi Notari Luigi Notari Stefanie Renken Rolf Kiessling Rolf Kiessling Hans Grönlund Hans Grönlund Stina L. Wickström Stina L. Wickström Stina L. Wickström Stina L. Wickström |
| author_facet | Adela Kiessling Keerthana Ramanathan Ola B. Nilsson Ola B. Nilsson Luigi Notari Luigi Notari Stefanie Renken Rolf Kiessling Rolf Kiessling Hans Grönlund Hans Grönlund Stina L. Wickström Stina L. Wickström Stina L. Wickström Stina L. Wickström |
| author_sort | Adela Kiessling |
| collection | DOAJ |
| description | For the past decade, adoptive cell therapy including tumor-infiltrating lymphocytes, genetically modified cytotoxic lymphocytes expressing a chimeric antigen receptor, or a novel T-cell receptor has revolutionized the treatment of many cancers. Progress within exome sequencing and neoantigen prediction technologies provides opportunities for further development of personalized immunotherapies. In this study, we present a novel strategy to deliver in silico predicted neoantigens to autologous dendritic cells (DCs) using paramagnetic beads (EpiTCer beads). DCs pulsed with EpiTCer beads are superior in enriching for healthy donor and patient blood-derived tumor-specific CD8+ T cells compared to DC loaded with whole-tumor lysate or 9mer neoantigen peptides. A dose-dependent effect was observed, with higher EpiTCer bead per DC being favorable. We concluded that CD8+ T cells enriched by DC loaded with EpiTCer beads are tumor specific with limited tumor cross-reactivity and low recognition of autologous non-activated monocytes or CD8+ T cells. Furthermore, tumor specificity and recognition were improved and preserved after additional expansion using our Good Manufacturing Process (GMP)-compatible rapid expansion protocol. Phenotypic analysis of patient-derived EpiTCer DC expanded CD8+ T cells revealed efficient maturation, with high frequencies of central memory and effector memory T cells, similar to those observed in autologous expanded tumor-infiltrating lymphocytes. These results indicate that DC pulsed with EpiTCer beads enrich for a T-cell population with high capacity of tumor recognition and elimination, which are features needed for a T-cell product to be used for personalized adoptive cell therapy. |
| first_indexed | 2024-04-12T22:41:10Z |
| format | Article |
| id | doaj.art-180142d7736a41b9b9a4d5ba34bef933 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T22:41:10Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-180142d7736a41b9b9a4d5ba34bef9332022-12-22T03:13:42ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-03-011210.3389/fonc.2022.866763866763Generation of Tumor-Specific Cytotoxic T Cells From Blood via In Vitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled MicrobeadsAdela Kiessling0Keerthana Ramanathan1Ola B. Nilsson2Ola B. Nilsson3Luigi Notari4Luigi Notari5Stefanie Renken6Rolf Kiessling7Rolf Kiessling8Hans Grönlund9Hans Grönlund10Stina L. Wickström11Stina L. Wickström12Stina L. Wickström13Stina L. Wickström14Department of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenNEOGAP Therapeutics AB, Stockholm, SwedenDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenNEOGAP Therapeutics AB, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenTheme Cancer, Patient Area Head and Neck, Lung and Skin, Karolinska University Hospital, Stockholm, SwedenDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenNEOGAP Therapeutics AB, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenNEOGAP Therapeutics AB, Stockholm, SwedenTheme Cancer, Patient Area Head and Neck, Lung and Skin, Karolinska University Hospital, Stockholm, SwedenFor the past decade, adoptive cell therapy including tumor-infiltrating lymphocytes, genetically modified cytotoxic lymphocytes expressing a chimeric antigen receptor, or a novel T-cell receptor has revolutionized the treatment of many cancers. Progress within exome sequencing and neoantigen prediction technologies provides opportunities for further development of personalized immunotherapies. In this study, we present a novel strategy to deliver in silico predicted neoantigens to autologous dendritic cells (DCs) using paramagnetic beads (EpiTCer beads). DCs pulsed with EpiTCer beads are superior in enriching for healthy donor and patient blood-derived tumor-specific CD8+ T cells compared to DC loaded with whole-tumor lysate or 9mer neoantigen peptides. A dose-dependent effect was observed, with higher EpiTCer bead per DC being favorable. We concluded that CD8+ T cells enriched by DC loaded with EpiTCer beads are tumor specific with limited tumor cross-reactivity and low recognition of autologous non-activated monocytes or CD8+ T cells. Furthermore, tumor specificity and recognition were improved and preserved after additional expansion using our Good Manufacturing Process (GMP)-compatible rapid expansion protocol. Phenotypic analysis of patient-derived EpiTCer DC expanded CD8+ T cells revealed efficient maturation, with high frequencies of central memory and effector memory T cells, similar to those observed in autologous expanded tumor-infiltrating lymphocytes. These results indicate that DC pulsed with EpiTCer beads enrich for a T-cell population with high capacity of tumor recognition and elimination, which are features needed for a T-cell product to be used for personalized adoptive cell therapy.https://www.frontiersin.org/articles/10.3389/fonc.2022.866763/fullneoantigentumor-specific antigensautologous tumor recognitiondendritic cell-mediated activationpersonalized cancer immunotherapy |
| spellingShingle | Adela Kiessling Keerthana Ramanathan Ola B. Nilsson Ola B. Nilsson Luigi Notari Luigi Notari Stefanie Renken Rolf Kiessling Rolf Kiessling Hans Grönlund Hans Grönlund Stina L. Wickström Stina L. Wickström Stina L. Wickström Stina L. Wickström Generation of Tumor-Specific Cytotoxic T Cells From Blood via In Vitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled Microbeads Frontiers in Oncology neoantigen tumor-specific antigens autologous tumor recognition dendritic cell-mediated activation personalized cancer immunotherapy |
| title | Generation of Tumor-Specific Cytotoxic T Cells From Blood via In Vitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled Microbeads |
| title_full | Generation of Tumor-Specific Cytotoxic T Cells From Blood via In Vitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled Microbeads |
| title_fullStr | Generation of Tumor-Specific Cytotoxic T Cells From Blood via In Vitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled Microbeads |
| title_full_unstemmed | Generation of Tumor-Specific Cytotoxic T Cells From Blood via In Vitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled Microbeads |
| title_short | Generation of Tumor-Specific Cytotoxic T Cells From Blood via In Vitro Expansion Using Autologous Dendritic Cells Pulsed With Neoantigen-Coupled Microbeads |
| title_sort | generation of tumor specific cytotoxic t cells from blood via in vitro expansion using autologous dendritic cells pulsed with neoantigen coupled microbeads |
| topic | neoantigen tumor-specific antigens autologous tumor recognition dendritic cell-mediated activation personalized cancer immunotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.866763/full |
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