Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimen to prevent antagonistic effects. Thus, this work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

The authors have declared no competing interest.

This research work was supported in part by the National Institutes of Health (NIH) Grants 1R01CA222007 (VC, BO, GAC, ZW), 1R01CA253865 (VC, BO, ZW), 1R01CA226537 (VC, ZW), 1R01AI165372 (ZW), R01DK132104 (ZW), 1R03EB033576 (PD), and P50CA217674 (KA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study used ONLY openly available preclinical and human data that were originally located at: 1) Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, et al. Atezolizumab for First Line Treatment of PD L1 Selected Patients with NSCLC. New England Journal of Medicine 2020;383(14):1328-39 doi 10.1056/NEJMoa1917346. 2) Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD L1 Positive Non Small Cell Lung Cancer. New England Journal of Medicine 2016;375(19):1823-33 doi 10.1056/NEJMoa1606774. 3) Pawel Jv, Roemeling Rv, Gatzemeier U, Boyer M, Elisson LO, Clark P, et al. Tirapazamine Plus Cisplatin Versus Cisplatin in Advanced Non Small Cell Lung Cancer: A Report of the International CATAPULT I Study Group. Journal of Clinical Oncology 2000;18(6):1351-9 doi 10.1200/jco.2000.18.6.1351. 4) Van Roosbroeck K, Fanini F, Setoyama T, Ivan C, Rodriguez Aguayo C, Fuentes-Mattei E, et al. Combining Anti Mir 155 with Chemotherapy for the Treatment of Lung Cancers. Clin Cancer Res 2017;23(11):2891-904 doi 10.1158/1078-0432.Ccr-16-1025. 5) Chen X, Gao A, Zhang F, Yang Z, Wang S, Fang Y, et al. ILT4 inhibition prevents TAM- and dysfunctional T cell mediated immunosuppression and enhances the efficacy of anti PD L1 therapy in NSCLC with EGFR activation. Theranostics 2021;11(7):3392-416 doi 10.7150/thno.52435. 6) Wang M, Yao LC, Cheng M, Cai D, Martinek J, Pan CX, et al. Humanized mice in studying efficacy and mechanisms of PD 1 targeted cancer immunotherapy. Faseb j 2018;32(3):1537-49 doi 10.1096/fj.201700740R.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Model code is available upon reasonable request to the authors.