miR-16 miRNA Vector Therapy May Be Feasible For Malignant Pleural Mesothelioma Patients

TargomiRs containing microRNAs lost in patients with malignant pleural mesothelioma are well tolerated and may have antitumour activity

medwireNews: Phase I trial findings suggest that minicells loaded with micro (mi)RNA tumour suppressors downregulated in malignant pleural mesothelioma may have treatment potential for patients with recurrent disease.

The first-in-human study assessed the feasibility of TargomiRs – vectors filled with a miR-16-based miRNA mimic – targeted against epidermal growth factor receptor (EGFR) expressed on the surface of mesothelioma cells.

The author of a comment linked to the study published in The Lancet Oncology says the research shows for the first time “the potential of nanotechnology to clinically restore the tumour-suppressive function of a [miRNA], in an exemplar of bench-to-bedside translational research.”

Describing the findings as “exciting”, Dean Fennell, from the University of Leicester in the UK, highlights the disease control rate of 73% in 22 patients given TargomiRs, writing: “In the context of previous studies in relapsed mesothelioma, this finding was a respectable signal that warrants further investigation.”

In all, 26 patients with tumours positive for EGFR expression received at least one 20-minute infusion of TargomiRs once or twice a week. Findings from the first eight patients resulted in the use of an initial 1 x 109 dose in the remaining patients, explain Nico van Zandwijk, from the University of Sydney in New South Wales, Australia, and co-authors.

Dose-limiting toxicities of infusion-related inflammation and coronary ischaemia were reported in two patients who began treatment at the 5 x 109 dose twice weekly, while anaphylaxis and cardiomyopathy were reported in two patients using a 5 x 109 once weekly treatment alongside dexamethasone, and one patient given this weekly dose only had noncardiac pain.

“Stepwise increases in dose and continued treatment seemed to confer a degree of tolerance to the effects of TargomiR infusions”, the investigators say, setting the maximum tolerated dose at 5 x 109 per week.

Infusions were also associated with transient lymphopenia (96%), temporal hypophosphataemia (65%), and elevated blood aspartate aminotransferase or alanine aminotransferase (23%) and alkaline phosphatase (8%).

Computed tomography in 22 patients revealed there was one (5%) partial response to treatment and this objective response lasted 32 weeks. A further 15 (68%) of patients had stable disease and six (27%) had progressive disease; median overall survival was 200 days.

Acknowledging the need for confirmation of their findings in larger studies, the researchers cite translational research indicating that miR-16 may sensitise tumours to pemetrexed and gemcitabine, opening the possibility of a trial investigating the addition of TargomiRs to standard cisplatin–pemetrexed chemotherapy.

The team also notes the discovery of an inverse relationship between miR-16 and PD-L1 expression in malignant pleural mesothelioma.

“This interaction, which has also been reported for miR-34a, provides a rationale for combination of immune checkpoint inhibitors with TargomiRs and investigation of whether the somewhat poor efficacy of checkpoint inhibitors in malignant pleural mesothelioma can be boosted by combination with miRNA mimic”, write Nico van Zandwijk et al.

References

van Zandwijk N, Pavlakis N, Kao SC, et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol; Advance online publication 1 September 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30621-6

Fennell D. miR-16: expanding the range of molecular targets in mesothelioma. Lancet Oncol; Advance online publication 1 September 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30596-X

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