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

Mol Ther. 2021 Mar 3;29(3):1199-1213. doi: 10.1016/j.ymthe.2020.11.019. Epub 2020 Nov 17.


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.

Keywords: CD4 T cell; MHC class II; T cell receptor; immunotherapy; in vivo model; solid tumor; telomerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Histocompatibility Antigens Class II / immunology*
  • Humans
  • Immunotherapy / methods*
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / pathology
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Receptors, Antigen, T-Cell / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Telomerase / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Histocompatibility Antigens Class II
  • Receptors, Antigen, T-Cell
  • Telomerase