No patient left behind: The promise of immune priming with epigenetic agents

Abstract

Checkpoint inhibitors, monoclonal antibodies that inhibit PD-1 or CTLA-4, have revolutionized the treatment of multiple cancers. Despite the enthusiasm for the clinical successes of checkpoint inhibitors, and immunotherapy, in general, only a minority of patients with specific tumor types actually benefit from treatment. Emerging evidence implicates epigenetic alterations as a mechanism of clinical resistance to immunotherapy. This review presents evidence for that association, summarizes the epi-based mechanisms by which tumors evade immunogenic cell death, discusses epigenetic modulation as a component of an integrated strategy to boost anticancer T cell effector function in relation to a tumor immunosuppression cycle and, finally, makes the case that the success of this no-patient-left-behind strategy critically depends on the toxicity profile of the epigenetic agent(s).

CCDC6 and USP7 expression levels suggest novel treatment options in high-grade urothelial bladder cancer

“…Several genomics studies have highlighted the importance of epigenetic changes and genomic instability in the development and progression of bladder cancer, suggesting, as a novel treatment option, the use of epigenetic drugs in association with immune checkpoint therapies [24, 25].…”

“…Therefore, it is possible to hypothesize the use of the RRx-001 agent in combination with the immune checkpoint inhibitors, in the treatment of urothelial carcinomas, as for different tumors [3, 6]. Nevertheless, RRx-001 has been already reported to enhance tumor response to antitumor immune checkpoint therapies and inserted in several clinical trials, also reducing the side effects (NCT02452970, NCT020966354, NCT02489903) [6, 24, 40]. Indeed, as in 2017 another anti immune checkpoint drug, pembrolizumab, has been FDA approved for bladder cancer patients, the use of RRx-001 might improve the quality of response [41].…”

The transition from primary colorectal cancer to isolated peritoneal malignancy is associated with an increased tumour mutational burden

“…Methylation appeared to be dysregulated in CPM with a bias towards a hypermethylator phenotype caused by somatic mutation of the TET2 tumour suppressor and CDH7 chromatin regulator. Active DNA demethylation by TET enzymes is an important tumour suppressor mechanism in a variety of cancers 67 – 69 . Downregulation of CES2, a gene known to activate the prodrug irinotecan, a chemotherapy used as part of the FOLFIRI regimen in the UK in the adjuvant treatment of primary CRC and CPM was seen in this cohort.…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…8,105,176,261-264 Unfortunately, it has soon become clear that the majority of immunotherapies developed so far is poorly active when employed as standalone therapeutic intervention, largely reflecting (1) natural and treatment-driven immunoediting, resulting in the selection of poorly immunogenic cancer cell populations; 115,265,266 and (2) the robust immunosuppression established by malignant cells, both locally and systemically. 267-269 In line with this notion, the vast majority of peptide-based vaccines tested in the clinic so far mediated limited, if any, therapeutic activity, despite being able to elicit tumor-targeting immune responses, at least to some degree. 118 The field is therefore moving along three non-mutually exclusive directions: (1) combining peptide-based vaccination with additional forms of (immuno)therapy, with the specific aim of reverting immunosuppression and enabling therapeutically relevant immune responses, 270-272 (2) targeting private antigenic epitopes that originate from mutations affecting only malignant cells (or sub-populations thereof), with PPV, 167,272-275 and (3) identifying specific patient populations that may obtain clinical benefit from the use of peptide-based vaccination.…”