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

• Published in: Molecular therapy Vol. 29; no. 3; pp. 1199 - 1213
• Main Authors: Dillard, Pierre, Köksal, Hakan, Maggadottir, Solrun Melkorka, Winge-Main, Anna, Pollmann, Sylvie, Menard, Mathilde, Myhre, Marit Renée, Mælandsmo, Gunhild M., Flørenes, Vivi Ann, Gaudernack, Gustav, Kvalheim, Gunnar, Wälchli, Sébastien, Inderberg, Else Marit
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2021; American Society of Gene & Cell Therapy
• Subjects: Animals; Apoptosis; CD4 T cell; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Histocompatibility Antigens Class II - immunology; Humans; immunotherapy; Immunotherapy - methods; in vivo model; Melanoma - immunology; Melanoma - metabolism; Melanoma - pathology; Melanoma - therapy; MHC class II; Mice; Mice, Inbred NOD; Mice, SCID; Original; Receptors, Antigen, T-Cell - immunology; solid tumor; T cell receptor; T-Lymphocytes, Cytotoxic - immunology; telomerase; Telomerase - antagonists & inhibitors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; T cell receptor; telomerase; immunotherapy; solid tumor; CD4 T cell; in vivo model; MHC class II
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2020.11.019

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. [Display omitted] CD4 T cells are major players in the antitumor response. Dillard et al. target a universal cancer antigen, telomerase, with a TCR recognizing its presentation on a frequently expressed HLA class II allele. Such TCR-redirected T cells provide both helper and direct cytotoxic functions and destroy telomerase-expressing tumors in vitro and in vivo, thus offering an alternative solution for solid tumor treatment.