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Targeting Telomerase with an HLA Class II-Restricted TCR for Cancer Immunotherapy.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2021 Mar 03; Vol. 29 (3), pp. 1199-1213. Date of Electronic Publication: 2020 Nov 17. - Publication Year :
- 2021
-
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 <superscript>+</superscript> and CD8 <superscript>+</superscript> T cells demonstrated in vitro efficacy, producing inflammatory cytokines and killing hTERT <superscript>+</superscript> 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 <superscript>+</superscript> 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.<br /> (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Apoptosis
Cell Proliferation
Humans
Melanoma immunology
Melanoma metabolism
Melanoma pathology
Mice
Mice, Inbred NOD
Mice, SCID
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
CD8-Positive T-Lymphocytes immunology
Histocompatibility Antigens Class II immunology
Immunotherapy methods
Melanoma therapy
Receptors, Antigen, T-Cell immunology
T-Lymphocytes, Cytotoxic immunology
Telomerase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 33212301
- Full Text :
- https://doi.org/10.1016/j.ymthe.2020.11.019