A second chance for telomerase reverse transcriptase in anticancer immunotherapy

Abstract

Telomerase reverse transcriptase (TERT) is a self-antigen that is expressed constitutively in many tumours, and is, therefore, an important target for anticancer immunotherapy. In the past 10 years, trials of immunotherapy with TERT-based vaccines have demonstrated only modest benefits. In this Perspectives, I discuss the possible immunological reasons for this limited antitumour efficacy, and propose that advances in our understanding of the genetics and biology of the involvement of TERT in cancer provides the basis for renewed interest in TERT- based immunotherapy. Telomerase and TERT are expressed in cancer cells at every stage of tumour evolution, from the cancer stem cell to circulating tumour cells and tumour metastases. Many cancer types also harbour cells with mutations in the TERT promoter region, which increase transcriptional activation of this gene. These new findings should spur new interest in the development of TERT-based immunotherapies that are redesigned in line with established immunological considerations and working principles, and are tailored to patients stratified on the basis of TERT-promoter mutations and other underlying tumour characteristics. Thus, despite the disappointment of previous clinical trials, TERT offers the potential for personalized immunotherapy, perhaps in combination with immune-checkpoint inhibition.

TERT promoter mutation subtypes and survival in stage I and II melanoma patients

“…If validated, the TERT promoter mutations can eventually enter clinical practice for at‐risk patient identification. TERT itself represents near ubiquitous self‐antigen that has been subject of trials in immunotherapy and its increased expression in tumors with the promoter mutations with generation of additional peptides would likely make tumor cells further vulnerable to T‐cell killing . In particular, the observation of the synergistic effect due to combination of the TERT promoter and BRAF / NRAS mutations could have implication for patients treated with MAP kinase inhibitors.…”

Genomic Alterations in Fatal Forms of Non-Anaplastic Thyroid Cancer: Identification of MED12 and RBM10 as Novel Thyroid Cancer Genes Associated with Tumor Virulence

“…There is a great interest to specifically target mutated TERT promoter and our findings suggest aggressive thyroid cancer with these mutations would be an ideal cancer to treat. In addition, new insights into TERT genetics and biology may also offer a potential for personalized immunotherapy (43). The rare STRN-ALK rearrangement can be targeted with ALK inhibitors, crizotinib and TAE864, as previously mentioned.…”

Telomeres and Telomere Length: A General Overview

“…The use of G-quadruplex stabilizers as treatment for progressive and malignant cancers gradually shortens the 3 single-stranded ends of the telomeres, without reducing the overall length of the telomeres, thereby indirectly inhibiting telomerase activity [250,266]. Although the TERT-based therapeutic vaccination have limited anti-proliferation efficiency, the focus has shifted to personalized interventions specifically for patients with TERT promoter mutations and TERT genomic rearrangements, in combination with immune-checkpoint inhibitors [267]. Individuals with short telomeres are more prone to damage by irradiation compared to those with long telomeres.…”