Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer

Our plain-English summary of Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer, by G. Reid, S.C. Kao, N. Pavlakis, et al (Epigenomics, 2016).

The study

• Authors: G. Reid, S.C. Kao, N. Pavlakis, H. Brahmbhatt, J. MacDiarmid, S. Clarke, M. Boyer, N. van Zandwijk
• Journal: Epigenomics
• Published: 2016;8(8):1079-85
• Type of article: Review
• Cited by: 187 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

miRNAs are responsible for post-transcriptional control of gene expression, and are frequently downregulated in cancer. It has become well established that restoring miRNA levels can inhibit tumor growth, and many studies have demonstrated this in preclinical models. This in turn has led to the first clinical trials of miRNA replacement therapy. This special report focuses on the development of TargomiRs - miRNA mimics delivered by targeted bacterial minicells - and the very first clinical experience of a miRNA replacement therapy in thoracic cancer patients in the Phase I MesomiR-1 trial.

In plain English

This special report described TargomiRs, an experimental treatment for malignant pleural mesothelioma (MPM) and advanced non-small-cell lung cancer. TargomiRs are synthetic miRNA mimics with novel sequences based on a miR-15/107 consensus sequence, packaged in bacterially derived particles called EDVs targeted with an anti-EGFR antibody. The report reviewed laboratory and animal studies and gave interim results from the Phase I MesomiR-1 trial: 18 patients treated, all with MPM, with detailed data for the first six. In most patients, infusions were followed by brief inflammatory symptoms (shivering, rigor, raised temperature) and a short period of lymphopenia (low lymphocyte count) and neutrophilia. Among the first six, lymphopenia reached grade 4 in four and grade 3 in two. Half had transient pain in the area of disease. After 8 weeks, one had a confirmed partial response, four had stable disease, and one had progressive disease plus a second primary cancer; disease was controlled in five of six. The authors concluded the treatment had been well tolerated and shown to be safe, noting that initial results suggest these therapies will not work in all patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Special report: a narrative review of preclinical studies of miRNA mimics in lung cancer and mesothelioma, plus interim results from the authors' Phase I MesomiR-1 trial (3 + 3 dose escalation design)
• Who was studied: MesomiR-1 trial, started December 2014 (the authors' affiliations are in Sydney, Australia): 18 patients, all with malignant pleural mesothelioma, treated to date. Detailed data were reported for the first six (four men and two women, aged 52 to 78), all previously treated with chemotherapy.
• Exposure: The exposure studied was a treatment, not asbestos: TargomiRs, which are synthetic miRNA mimics with novel sequences based on a consensus sequence derived from the miR-15/107 group, packaged in EDVs targeted with an anti-EGFR antibody. They were given as a 20-minute intravenous infusion once a week. Asbestos is mentioned only as background, as associated with MPM.
• Main results:
  • Among the first six patients, disease control was achieved in five of six after 8 weeks of protocol treatment.
  • Among the first six patients, one had a partial response and four had stable disease after 8 weeks.
  • One of the first six patients (patient 4) had progressive disease, with a second primary cancer noted in Table 2.
  • In most patients, infusion was followed by rapidly transient inflammatory symptoms (shivering, rigor, temperature elevation) and a short period of lymphopenia/neutrophilia. Table 2 lists lymphopenia of grade 4 in four of the first six patients and grade 3 in two.
  • Half of the first six patients had transient discomfort (pain) in the area of disease. The authors suggested this meant TargomiRs reached their target.
  • The patient with the partial response started on an adapted, lower starting dose because of an elevated IL-6 blood level at baseline. The partial response was seen on chest CT at 8 weeks and confirmed 4 weeks later, and this patient continued treatment for more than 40 weeks.
• The authors' conclusion: The authors concluded that TargomiR treatment had been well tolerated and shown to be safe in patients. They called the partial responses very promising given that Phase I patients are mostly late-stage, and said the results support plans for Phase II studies, possibly a randomized trial against second- or third-line chemotherapy.
• Limitations the authors state:
  • The authors stated that initial results suggest these miRNA-based therapies will not be effective in all patients, and that selecting those most likely to respond will be a major challenge.
  • The authors noted that the treatment causes a marked inflammatory response. They said it is not yet known how much of this comes from the carrier versus the miRNA mimics, or whether it is related to response; future biomarker studies are planned.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Clinical Trial.

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