Preclinical model for evaluating human TCRs against chimeric syngeneic tumors
Background The adoptive cell transfer (ACT) of T cell receptor (TCR)-engineered T cells targeting the HLA-A2-restricted epitope NY-ESO-1157-165 (A2/NY) has yielded important clinical responses against several cancers. A variety of approaches are being taken to augment tumor control by ACT including...
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BMJ Publishing Group
2024-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/12/e009504.full |
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| author | Olivier Michielin Philippe Guillaume Melita Irving Patrick Reichenbach Vincent Zoete Elise Gray-Gaillard Evangelos Stefanidis Aikaterini Semilietof Julien Pujol Alessia D'Esposito |
| author_facet | Olivier Michielin Philippe Guillaume Melita Irving Patrick Reichenbach Vincent Zoete Elise Gray-Gaillard Evangelos Stefanidis Aikaterini Semilietof Julien Pujol Alessia D'Esposito |
| author_sort | Olivier Michielin |
| collection | DOAJ |
| description | Background The adoptive cell transfer (ACT) of T cell receptor (TCR)-engineered T cells targeting the HLA-A2-restricted epitope NY-ESO-1157-165 (A2/NY) has yielded important clinical responses against several cancers. A variety of approaches are being taken to augment tumor control by ACT including TCR affinity-optimization and T-cell coengineering strategies to address the suppressive tumor microenvironment (TME). Most TCRs of clinical interest are evaluated in immunocompromised mice to enable human T-cell engraftment and do not recapitulate the dynamic interplay that occurs with endogenous immunity in a treated patient. A variety of humanized mouse models have been described but they have limitations in immune reconstitution and are technically challenging to implement. Here, we have developed a chimeric syngeneic tumor model in which A2Kb transgenic C57BL/6 mice are engrafted with B16 expressing A2Kb:NY as a single chain trimer (SCT) and treated by ACT with murine T cells expressing A2/NY TCRs comprising human variable fused to mouse constant regions.Methods We compared the function of a supraphysiological affinity A2/NY TCR (wtc51m), a computationally designed TCR in an optimal affinity range (DMβ), and a near non-binding TCR (V49I), engineered in both primary human and murine T cells by lentiviral and retroviral transduction, respectively. We evaluated a variety of strategies to stably express A2Kb:NY on the surface of mouse tumor cell lines including B16 melanoma, ultimately achieving success with an SCT comprising human β2m fused by GS linkers to both the NY-peptide and to α1 of the HLA complex. ACT studies were performed in B16-A2Kb:NY tumor-bearing, non-preconditioned immune-competent HLA-A*0201/H-2Kb (A2Kb) transgenic C57BL/6 mice and tumors characterized post-transfer.Results We observed significantly improved function of DMβ-T cells as well as superior infiltration and tumor control upon ACT as compared to the control TCR-T cells. Moreover, with our chimeric syngeneic tumor model, we were able to track dynamic and favorable changes in the TME upon DMβ-T cell transfer.Conclusions We have developed a robust, simple, and inexpensive preclinical strategy for evaluating human TCRs in the context of a fully competent murine immune system that can aid in the development of coengineered TCR-T cells and combination treatments translated to the clinic. |
| format | Article |
| id | doaj-art-10ce8d6b6ab94b46998c5d1a07647b08 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-10ce8d6b6ab94b46998c5d1a07647b082025-01-14T20:45:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-12-01121210.1136/jitc-2024-009504Preclinical model for evaluating human TCRs against chimeric syngeneic tumorsOlivier Michielin0Philippe Guillaume1Melita Irving2Patrick Reichenbach3Vincent Zoete4Elise Gray-Gaillard5Evangelos Stefanidis6Aikaterini Semilietof7Julien Pujol8Alessia D'Esposito9Precision Oncology, University Hospital of Geneva, Geneva, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges, SwitzerlandSwiss Institute of Bioinformatics, Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges, SwitzerlandSwiss Institute of Bioinformatics, Lausanne, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges, SwitzerlandDepartment of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges, SwitzerlandBackground The adoptive cell transfer (ACT) of T cell receptor (TCR)-engineered T cells targeting the HLA-A2-restricted epitope NY-ESO-1157-165 (A2/NY) has yielded important clinical responses against several cancers. A variety of approaches are being taken to augment tumor control by ACT including TCR affinity-optimization and T-cell coengineering strategies to address the suppressive tumor microenvironment (TME). Most TCRs of clinical interest are evaluated in immunocompromised mice to enable human T-cell engraftment and do not recapitulate the dynamic interplay that occurs with endogenous immunity in a treated patient. A variety of humanized mouse models have been described but they have limitations in immune reconstitution and are technically challenging to implement. Here, we have developed a chimeric syngeneic tumor model in which A2Kb transgenic C57BL/6 mice are engrafted with B16 expressing A2Kb:NY as a single chain trimer (SCT) and treated by ACT with murine T cells expressing A2/NY TCRs comprising human variable fused to mouse constant regions.Methods We compared the function of a supraphysiological affinity A2/NY TCR (wtc51m), a computationally designed TCR in an optimal affinity range (DMβ), and a near non-binding TCR (V49I), engineered in both primary human and murine T cells by lentiviral and retroviral transduction, respectively. We evaluated a variety of strategies to stably express A2Kb:NY on the surface of mouse tumor cell lines including B16 melanoma, ultimately achieving success with an SCT comprising human β2m fused by GS linkers to both the NY-peptide and to α1 of the HLA complex. ACT studies were performed in B16-A2Kb:NY tumor-bearing, non-preconditioned immune-competent HLA-A*0201/H-2Kb (A2Kb) transgenic C57BL/6 mice and tumors characterized post-transfer.Results We observed significantly improved function of DMβ-T cells as well as superior infiltration and tumor control upon ACT as compared to the control TCR-T cells. Moreover, with our chimeric syngeneic tumor model, we were able to track dynamic and favorable changes in the TME upon DMβ-T cell transfer.Conclusions We have developed a robust, simple, and inexpensive preclinical strategy for evaluating human TCRs in the context of a fully competent murine immune system that can aid in the development of coengineered TCR-T cells and combination treatments translated to the clinic.https://jitc.bmj.com/content/12/12/e009504.full |
| spellingShingle | Olivier Michielin Philippe Guillaume Melita Irving Patrick Reichenbach Vincent Zoete Elise Gray-Gaillard Evangelos Stefanidis Aikaterini Semilietof Julien Pujol Alessia D'Esposito Preclinical model for evaluating human TCRs against chimeric syngeneic tumors Journal for ImmunoTherapy of Cancer |
| title | Preclinical model for evaluating human TCRs against chimeric syngeneic tumors |
| title_full | Preclinical model for evaluating human TCRs against chimeric syngeneic tumors |
| title_fullStr | Preclinical model for evaluating human TCRs against chimeric syngeneic tumors |
| title_full_unstemmed | Preclinical model for evaluating human TCRs against chimeric syngeneic tumors |
| title_short | Preclinical model for evaluating human TCRs against chimeric syngeneic tumors |
| title_sort | preclinical model for evaluating human tcrs against chimeric syngeneic tumors |
| url | https://jitc.bmj.com/content/12/12/e009504.full |
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