MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

Cancer growth and progression are associated with immune suppression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. Monoclonal antibodies that target immune checkpoints provided an immense breakthrough in cancer therapeutics. Among the immune checkpoint inhibitors, PD-1/PD-L1 and CTLA-4 inhibitors showed promising therapeutic outcomes, and some have been approved for certain cancer treatments, while others are under clinical trials. Recent reports have shown that patients with various malignancies benefit from immune checkpoint inhibitor treatment. However, mainstream initiation of immune checkpoint therapy to treat cancers is obstructed by the low response rate and immune-related adverse events in some cancer patients. This has given rise to the need for developing sets of biomarkers that predict the response to immune checkpoint blockade and immune-related adverse events. In this review, we discuss different predictive biomarkers for anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors, including immune cells, PD-L1 overexpression, neoantigens, and genetic and epigenetic signatures. Potential approaches for further developing highly reliable predictive biomarkers should facilitate patient selection for and decision-making related to immune checkpoint inhibitor-based therapies.

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Immune checkpoint inhibitors: recent progress and potential biomarkers.

Putting p53 in Context

Regulation and Function of the PD-L1 Checkpoint

Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.

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Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape.

TP53, also known as p53, is one of the most commonly mutated genes in cancer (1). It is critical in regulating cell division, apoptosis, senescence, and DNA damage and repair (2–4). p53 is also important for modulating the immune response (5–9). However, whether p53 is involved in tumor immune evasion is poorly understood. This topic is particularly relevant for several reasons, among them evidence linking microRNAs (miRNAs), p53, and adaptive and innate immunity (6,10). For instance, several p53-regulated miRNAs have been implicated in adaptive and innate immunity, including the miR-17~92 cluster (11), miR-145 (12), and let-7 (13). Importantly, p53 can regulate tumor cell recognition by natural killer (NK) cells via the p53-regulated miRNA miR-34a (10). We recently showed that the miR-200 family, another miRNA family regulated by p53 (14), directly regulates PDL1 (programmed death 1 ligand 1; also known as B7-H1 or CD274) (15). PDL1 is overexpressed in many human cancers, including non–small cell lung cancer (NSCLC) (16–18), promoting T-cell tolerance and escape host immunity (19). Early clinical trials using monoclonal antibodies that block the PD1/PDL1 interaction have shown promise in some patients with advanced cancer (20,21).

Here, we investigated the potential role of p53 in regulating PDL1 expression in NSCLC. We found that p53 regulates PDL1 via miR-34 by using a series of experiments involving lung cancer cell lines, miRNA target-predicting databases, and tissue samples from patients with NSCLC. Using a syngeneic mouse model of lung cancer, we demonstrated that MRX34, a liposomal formulation complexed with miR-34a mimics that is currently the subject of a phase I clinical cancer trial (22–24), alone or in combination with radiotherapy (XRT), reduced PDL1 expression in the tumor and antagonized T-cell exhaustion.

PDL1 Regulation by p53 via miR-34

In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11–55). MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. NCT01829971.

Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.

e14074Background: Each microRNA (miRNA) modulates the expression of hundreds of genes across distinct cellular pathways. This broad activity gives miRNA-based therapy the potential to simultaneousl...

In vivo localization of miR-34 delivered via liposomal MRX34: chromogenic in situ hybridization (CISH) results in a preclinical model and liver biopsies from phase I patients.

Desiree Martin

Papers

PDL1 Regulation by p53 via miR-34

Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.

In vivo localization of miR-34 delivered via liposomal MRX34: chromogenic in situ hybridization (CISH) results in a preclinical model and liver biopsies from phase I patients.