A Significant Metabolic and Radiological Response after a Novel Targeted MicroRNA-based Treatment Approach in Malignant Pleural Mesothelioma

Our plain-English summary of A Significant Metabolic and Radiological Response after a Novel Targeted MicroRNA-based Treatment Approach in Malignant Pleural Mesothelioma, by S.C. Kao, M. Fulham, K. Wong, et al (American Journal of Respiratory and Critical Care Medicine, 2015).

The study

• Authors: S.C. Kao, M. Fulham, K. Wong, W. Cooper, H. Brahmbhatt, J. MacDiarmid, S. Pattison, J.O. Sagong, Y. Huynh, F. Leslie, N. Pavlakis, S. Clarke, M. Boyer, G. Reid, N. van Zandwijk
• Journal: American Journal of Respiratory and Critical Care Medicine
• Published: 2015;191(12):1467-9
• Type of article: Case report, Letter
• Cited by: 57 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Summary of the article

This letter reported one patient with malignant pleural mesothelioma (MPM) treated in MesomiR 1, an ongoing phase 1 trial in Sydney, Australia. The trial was testing intravenous, epidermal growth factor receptor (EGFR)-targeted EnGeneIC Delivery Vehicle (EDV) nanocells carrying miR-16-based mimics (TargomiRs) in patients with MPM and advanced non-small-cell lung cancer. The approach was based on the authors' earlier findings that the miR-15/16 family was down-regulated in MPM and that restoring miR-16 inhibited tumor growth in cell lines and in mice. Six patients had completed 8 weeks of weekly treatment at the first dose level. The patient described was a 51-year-old plumber with right-sided epithelial MPM diagnosed in May 2013. His disease had progressed after two courses of platinum/pemetrexed chemotherapy. Weak EGFR staining was found in 5% of his tumor cells. After 8 weeks of TargomiRs he had grade 1 toxicities and reported less chest pain. PET-CT showed a "complete" metabolic response, with peak standard uptake value falling from 17.1 to 2.7, an 84% reduction. Chest CT showed a partial response, confirmed 4 weeks later. His lung function improved, with FEV1 rising from 2.9 to 3.7 L and FVC from 3.84 to 5.22 L. Of the other five patients, four had stable disease and one had progressive disease. Most patients had shivering or rigors after infusion and transient rises in inflammatory cytokines. The authors described the results as very preliminary but called this the first report of an objective treatment response using a microRNA-based therapy.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This letter to the editor described one patient from MesomiR 1, an ongoing phase 1 trial of an experimental treatment called TargomiRs in malignant pleural mesothelioma and advanced non-small-cell lung cancer. TargomiRs are tiny particles, aimed at the EGFR protein on cancer cells, carrying copies of miR-16, a molecule the authors had earlier found reduced in mesothelioma. The patient, a 51-year-old plumber with right-sided epithelial pleural mesothelioma, had disease that progressed after second-line chemotherapy. The letter did not describe his asbestos exposure. After eight weekly infusions, a PET-CT scan showed what the authors called a "complete" metabolic response, with an 84% fall in peak tracer uptake. A CT scan showed a partial response, confirmed 4 weeks later. Breathing test results also improved. Side effects were mild: chills, low-grade fever, fatigue and headache. Of the other five patients in the first group, four had stable disease and one had progressive disease. The authors called the results very preliminary. They concluded that the case illustrated the promise of the approach, which still needs further testing.

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: Letter to the editor reporting a single patient (case report) from an ongoing phase 1 dose-finding trial (MesomiR 1), with a brief summary of the other five patients in the first trial cohort
• Who was studied: One 51-year-old plumber in Sydney, Australia, diagnosed in May 2013 with right-sided malignant pleural mesothelioma of the epithelial subtype. His disease progressed after first-line and second-line platinum/pemetrexed chemotherapy. He was one of six patients recruited to cohort 1 of a trial enrolling patients with malignant pleural mesothelioma and advanced non-small-cell lung cancer. His asbestos exposure is not described.
• Exposure: Not an asbestos exposure study. The treatment studied was intravenous EGFR-targeted EDV nanocells carrying miR-16-based mimics (TargomiRs), given weekly for 8 weeks. Because his baseline IL-6 level was raised, this patient received two lower adapted doses in weeks 1 and 2, then the phase 1 dose for the following 6 weeks. The scanned text prints the doses as '1 3 109', '2 3 109' and '5 3 109', apparently 1, 2 and 5 × 10^9 TargomiRs.
• Main results:
  • In this patient, at the end of the 8 weeks, PET-CT showed what the authors termed a "complete" metabolic response.
  • In this patient, peak standard uptake value on PET-CT was 17.1 before starting the trial and 2.7 after 8 weeks of treatment, an 84% reduction in tracer uptake.
  • In this patient, chest CT showed a partial response by modified RECIST criteria, confirmed 4 weeks later.
  • In this patient, breathing test results improved from baseline to 8 weeks after treatment (Table 1): FEV1 2.9 to 3.7 L, FVC 3.84 to 5.22 L, corrected DLCO 25.7 to 31.06 ml/min/mm Hg, and total lung capacity 6.04 to 7.88 L.
  • This patient had minor (grade 1) side effects: transient chills, low-grade fever, fatigue and headache.
  • Among the other five patients in cohort 1, response assessment showed four with stable disease and one with progressive disease.
  • Across cohort 1, the majority of patients had shivering or rigors 80 to 90 minutes after the infusion started. Laboratory tests showed a brief rise in inflammatory cytokines, neutrophilia and lymphopenia, sometimes with mild elevation of liver enzymes.
• The authors' conclusion: The authors concluded that this proof-of-concept case illustrates the promise of using targeted EDV nanocells to restore down-regulated miRs in malignant pleural mesothelioma. They noted that further evaluation and phase 2 studies are needed to confirm efficacy.
• Limitations the authors state:
  • The authors stated that the results are very preliminary.
  • The maximum tolerated dose and the full extent of possible off-target effects had not yet been determined.
  • Responses varied between patients, and factors that predict response had not yet been identified. The authors also noted that, with only 5% of this patient's cancer cells EGFR-positive, other mechanisms must be involved.

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: Pleural Mesothelioma, EGFR, Lung Cancer, Pemetrexed (Alimta), Chemotherapy, PET-CT, FEV1, Cytokine.

Related studies

• 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 — N. van Zandwijk, N. Pavlakis, et al. (2017)
• MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma — M.B. Kirschner, Y.Y. Cheng, et al. (2015)
• Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma — G. Reid, M.E. Pel, et al. (2013)
• The analysis of novel microRNA mimic sequences in cancer cells reveals lack of specificity in stem-loop RT-qPCR-based microRNA detection — P. Winata, M. Williams, et al. (2017)
• The role of microRNAs in the diagnosis and treatment of malignant pleural mesothelioma--a short review — K.W. Sheff, M.A. Hoda, et al. (2012)
• Response to "An innovative mesothelioma treatment based on mir-16 mimic loaded EGFR targeted minicells (TargomiRs)" — N. van Zandwijk, J. McDiarmid, et al. (2018)

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