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Targeting Telomerase with an HLA Class II-Restricted TCR for Cancer Immunotherapy

Targeting Telomerase with an HLA Class II-Restricted TCR for Cancer Immunotherapy


Title: Targeting Telomerase with an HLA Class II-Restricted TCR for Cancer Immunotherapy
Author: Dillard, Pierre
Köksal, Hakan
Maggadóttir, Sólrún Melkorka
Winge-Main, Anna
Pollmann, Sylvie
Menard, Mathilde
Myhre, Marit Renée
Mælandsmo, Gunhild M.
Flørenes, Vivi Ann
Gaudernack, Gustav
... 3 more authors Show all authors
Date: 2021-03-03
Language: English
Scope: 15
Department: Faculty of Medicine
Series: Molecular Therapy; 29(3)
ISSN: 1525-0016
DOI: https://doi.org/10.1016/j.ymthe.2020.11.019
Subject: Meðferð; Krabbamein; T-frumur; CD4 T cell; immunotherapy; in vivo model; MHC class II; solid tumor; T cell receptor; telomerase; Cell Proliferation; Immunotherapy/methods; Humans; Histocompatibility Antigens Class II/immunology; Melanoma/immunology; Mice, SCID; Xenograft Model Antitumor Assays; CD8-Positive T-Lymphocytes/immunology; Telomerase/antagonists & inhibitors; Animals; Receptors, Antigen, T-Cell/immunology; Mice, Inbred NOD; Mice; Tumor Cells, Cultured; T-Lymphocytes, Cytotoxic/immunology; Apoptosis; Drug Discovery; Genetics; Molecular Medicine; Molecular Biology; Pharmacology
URI: https://hdl.handle.net/20.500.11815/2893

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Citation:

Dillard , P , Köksal , H , Maggadóttir , S M , Winge-Main , A , Pollmann , S , Menard , M , Myhre , M R , Mælandsmo , G M , Flørenes , V A , Gaudernack , G , Kvalheim , G , Wälchli , S & Inderberg , E M 2021 , ' Targeting Telomerase with an HLA Class II-Restricted TCR for Cancer Immunotherapy ' , Molecular Therapy , vol. 29 , no. 3 , pp. 1199-1213 . https://doi.org/10.1016/j.ymthe.2020.11.019

Abstract:

T cell receptor (TCR)-engineered T cell therapy is a promising cancer treatment approach. Human telomerase reverse transcriptase (hTERT) is overexpressed in the majority of tumors and a potential target for adoptive cell therapy. We isolated a novel hTERT-specific TCR sequence, named Radium-4, from a clinically responding pancreatic cancer patient vaccinated with a long hTERT peptide. Radium-4 TCR-redirected primary CD4 + and CD8 + T cells demonstrated in vitro efficacy, producing inflammatory cytokines and killing hTERT + melanoma cells in both 2D and 3D settings, as well as malignant, patient-derived ascites cells. Importantly, T cells expressing Radium-4 TCR displayed no toxicity against bone marrow stem cells or mature hematopoietic cells. Notably, Radium-4 TCR + T cells also significantly reduced tumor growth and improved survival in a xenograft mouse model. Since hTERT is a universal cancer antigen, and the very frequently expressed HLA class II molecules presenting the hTERT peptide to this TCR provide a very high (>75%) population coverage, this TCR represents an attractive candidate for immunotherapy of solid tumors.

Description:

Funding Information: The authors would like to thank our colleagues from the Department of Cellular Therapy; in particular, Ms. Hedvig Vidarsdotter Juul for expert technical assistance and Dr. Stein S?b?e-Larssen for providing the pCIp102 expression vector. We thank Dr. Rainer L?w (EUFETS AG, Germany) for providing the luciferase-reporter vector and Gibco and Life Technologies AS for supplying CTS Dynabeads CD3/CD28. The J76 cells were a kind gift from Dr. Miriam Hemskeerk (Leiden University Medical Center, the Netherlands) and the ESTDAB-039 cell line generously provided by Dr. Graham Pawelec (University of T?bingen, Germany). We would like to thank the Department of Immunology and Transfusion Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway, for its kind help with HLA typing. We also thank the Flow Cytometry Core Facility of OUS for providing technical assistance. This study was supported by The Research Council of Norway (grant numbers 244388 and 254817) and the Norwegian Health Region South East (grant numbers 2017075 and 2016006). Conceptualization, S.W. and E.M.I.; Methodology, P.D. G.M.M. V.A.F. G.K. G.G. S.W. and E.M.I.; Investigation, P.D. H.K. S.M.M. A.W.-M. S.P. M.M. and M.R.M.; Resources, G.M.M. V.A.F. G.K. G.G. S.W. and E.M.I.; Writing ? Original Draft, P.D. S.M.M. S.W. and E.M.I.; Writing ? Review & Editing, all authors; Visualization, P.D. S.M.M. M.R.M. S.W. and E.M.I.; Supervision, S.W. and E.M.I.; Project Administration, E.M.I.; Funding Acquisition, G.K. G.G. S.W. and E.M.I. G.G. G.K. S.W. and E.M.I. are inventors on the patent WO2019166463. G.G. and G.K. are shareholders in Zelluna Immunotherapy AS. S.P. is currently employed by Zelluna Immunotherapy AS. All other authors declare no competing interests. Funding Information: The authors would like to thank our colleagues from the Department of Cellular Therapy; in particular, Ms. Hedvig Vidarsdotter Juul for expert technical assistance and Dr. Stein Sæbøe-Larssen for providing the pCIp 102 expression vector. We thank Dr. Rainer Löw (EUFETS AG, Germany) for providing the luciferase-reporter vector and Gibco and Life Technologies AS for supplying CTS Dynabeads CD3/CD28. The J76 cells were a kind gift from Dr. Miriam Hemskeerk (Leiden University Medical Center, the Netherlands) and the ESTDAB-039 cell line generously provided by Dr. Graham Pawelec (University of Tübingen, Germany). We would like to thank the Department of Immunology and Transfusion Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway, for its kind help with HLA typing. We also thank the Flow Cytometry Core Facility of OUS for providing technical assistance. This study was supported by The Research Council of Norway (grant numbers 244388 and 254817 ) and the Norwegian Health Region South East (grant numbers 2017075 and 2016006 ). Publisher Copyright: © 2020 The Authors

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