Anti-Cancer Immunotherapies Targeting Telomerase

Abstract

Telomerase is a reverse transcriptase that maintains telomeres length, compensating for the attrition of chromosomal ends that occurs during each replication cycle. Telomerase is expressed in germ cells and stem cells, whereas it is virtually undetectable in adult somatic cells. On the other hand, telomerase is broadly expressed in the majority of human tumors playing a crucial role in the replicative behavior and immortality of cancer cells. Several studies have demonstrated that telomerase-derived peptides are able to bind to HLA (human leukocyte antigen) class I and class II molecules and effectively activate both CD8+ and CD4+ T cells subsets. Due to its broad and selective expression in cancer cells and its significant immunogenicity, telomerase is considered an ideal universal tumor-associated antigen, and consequently, a very attractive target for anti-cancer immunotherapy. To date, different telomerase targeting immunotherapies have been studied in pre-clinical and clinical settings, these approaches include peptide vaccination and cell-based vaccination. The objective of this review paper is to discuss the role of human telomerase in cancer immunotherapy analyzing recent developments and future perspectives in this field.

TERT Promoter Alterations in Glioblastoma: A Systematic Review

“…An ideal tumor-associated antigen should have the following characteristics: a selective and broad expression in cancer cells, within all phases of tumor progression and the capacity to induce strong and effective immune responses. hTERT has been identified as such a tumor-associated antigen [ 118 , 119 ]. Dendritic cells (DC) represent a heterogeneous family of immune cells that link innate and adaptive immunity.…”

Reciprocal Inhibition of Immunogenic Performance in Mice of Two Potent DNA Immunogens Targeting HCV-Related Liver Cancer

“…Different telomerase-targeting immunotherapies have been studied in preclinical and clinical settings [ 64 ]. DNA vaccines appear especially promising [ 65 , 66 , 67 ].…”

Telomerase as a Target for Therapeutic Cancer Vaccines and Considerations for Optimizing Their Clinical Potential

“…TCVs aim to induce T cells that target a tumor antigen leading to improved anti-tumor immune responses and, ultimately, cancer cell death. As recently reviewed, telomerase vaccination has been evaluated across 34 clinical trials spanning almost two decades ( 39 ). However, there have been no positive late-phase studies, and as such, there is an obvious need for improvement, either in vaccine design (including sequence choice, formulation, and delivery), selection of indications, or treatment combination strategies.…”

“…Recently, however, synthetic long peptides (SLPs) have been in focus since they have the potential to provide cross-presentation by APCs leading to both class I and II presentation, and hence CD8+ and CD4+ immune responses, respectively ( 58 , 59 ). The use of epitope dense SLPs also allows enrollment of patients independently of their HLA types (such as with GV1001 and UV1), whereas many short peptide vaccines have been tailored to fit single HLA class I molecules, thus limiting inclusion to patients harboring this HLA type ( 39 ) ( Table 1 ).…”

“…The most reported side effect with telomerase-targeting cancer vaccines is injection site reactions, including local erythema and pruritus, and flu-like symptoms such as fever, muscle and joint pain, and fatigue. Generally, telomerase vaccination appears to be well tolerated, with only a few cases of serious adverse events reported ( 39 ). As an endogenous self-antigen, an immune response against hTERT is associated with a theoretical risk for off-tumor on-target toxicity.…”