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Clinical Studies

Prospective manipulation of the gut microbiome with microbial ecosystem therapeutic 4 (MET4) in HPV-related locoregionally-advanced oropharyngeal cancer squamous cell carcinoma (LA-OPSCC) undergoing primary chemoradiation: ROMA2 study

Abstract

Background

Gut microbiome modulation to boost antitumor immune responses is under investigation.

Methods

ROMA-2 evaluated the microbial ecosystem therapeutic (MET)-4 oral consortia, a mixture of cultured human stool-derived immune-responsiveness associated bacteria, given with chemoradiation (CRT) in HPV-related oropharyngeal cancer patients. Co-primary endpoints were safety and changes in stool cumulative MET-4 taxa relative abundance (RA) by 16SRNA sequencing. Stools and plasma were collected pre/post-MET-4 intervention for microbiome and metabolome analysis.

Results

Twenty-nine patients received ≥1 dose of MET-4 and were evaluable for safety: drug-related adverse events (AEs) occurred in 13/29 patients: all grade 1–2 except one grade 3 (diarrhea). MET-4 was discontinued early in 7/29 patients due to CRT-induced toxicity, and in 1/29 due to MET-4 AEs. Twenty patients were evaluable for ecological endpoints: there was no increase in stool MET-4 RA post-intervention but trended to increase in stage III patients (p = 0.06). MET-4 RA was higher in stage III vs I-II patients at week 4 (p = 0.03) and 2-month follow-up (p = 0.01), which correlated with changes in plasma and stool targeted metabolomics.

Conclusions

ROMA-2 did not meet its primary ecologic endpoint, as no engraftment was observed in the overall cohort. Exploratory findings of engraftment in stage III patients warrants further investigation of microbiome interventions in this subgroup.

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Fig. 1: Ecological primary endpoints.
Fig. 2: Exploratory stage subgroup analysis.
Fig. 3: Plasma and stool short chain fatty acids exploratory analysis in stage subgroups.

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Data availability

The datasets generated and analyzed during the current study will be made available in public repository. OTU tables are provided in the Supplementary Material.

References

  1. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7.

    Article  CAS  PubMed  Google Scholar 

  2. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103.

    Article  CAS  PubMed  Google Scholar 

  3. Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371:595–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;371:602–9.

    Article  CAS  PubMed  Google Scholar 

  5. Marcella C, Cui B, Kelly CR, Ianiro G, Cammarota G, Zhang F. Systematic review: the global incidence of faecal microbiota transplantation-related adverse events from 2000 to 2020. Aliment Pharm Ther. 2021;53:33–42.

    Article  Google Scholar 

  6. Araujo DV, Watson GA, Oliva M, Heirali A, Coburn B, Spreafico A, et al. Bugs as drugs: the role of microbiome in cancer focusing on immunotherapeutics. Cancer Treat Rev. 2020;92:102125.

    Article  PubMed  Google Scholar 

  7. Louie T, Golan Y, Khanna S, Bobilev D, Erpelding N, Fratazzi C, et al. VE303, a defined bacterial consortium, for prevention of recurrent clostridioides difficile infection: a randomized clinical trial. JAMA. 2023;329:1356–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. van der Lelie D, Oka A, Taghavi S, Umeno J, Fan TJ, Merrell KE, et al. Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis. Nat Commun. 2021;12:3105.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Spreafico A, Heirali AA, Araujo DV, Tan TJ, Oliva M, Schneeberger PHH, et al. First-in-class microbial ecosystem therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial). Ann Oncol. 2023;34:520–30.

    Article  CAS  PubMed  Google Scholar 

  10. Oliva M, Spreafico A, Taberna M, Alemany L, Coburn B, Mesia R, et al. Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma. Ann Oncol. 2019;30:57–67.

    Article  CAS  PubMed  Google Scholar 

  11. Orlandi E, Iacovelli NA, Tombolini V, Rancati T, Polimeni A, De Cecco L, et al. Potential role of microbiome in oncogenesis, outcome prediction and therapeutic targeting for head and neck cancer. Oral Oncol. 2019;99:104453.

    Article  PubMed  Google Scholar 

  12. Oliva M, Schneeberger PHH, Rey V, Cho M, Taylor R, Hansen AR. Transitions in oral and gut microbiome of HPV+ oropharyngeal squamous cell carcinoma following definitive chemoradiotherapy (ROMA LA-OPSCC study). Br J Cancer. 2021;124:1543–1551.

  13. Oliva Bernal M, Schneeberger PHH, Taylor R, Rey V, Hansen AR, Taylor K, et al. Role of the oral and gut microbiota as a biomarker in locoregionally advanced oropharyngeal squamous cell carcinoma (ROMA LA-OPSCC). J Clin Oncol. 2019;37:6045.

    Article  Google Scholar 

  14. Wong KCW, Johnson D, Hui EP, Lam RCT, Ma BBY, Chan ATC. Opportunities and challenges in combining immunotherapy and radiotherapy in head and neck cancers. Cancer Treat Rev. 2022;105:102361.

    Article  CAS  PubMed  Google Scholar 

  15. Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13:581–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol. 2019;37:852–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021;374:1632–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dizman N, Meza L, Bergerot P, Alcantara M, Dorff T, Lyou Y, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022;28:704–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Eng L, Sutradhar R, Niu Y, Liu N, Liu Y, Kaliwal Y, et al. Impact of antibiotic exposure before immune checkpoint inhibitor treatment on overall survival in older adults with cancer: a population-based study. J Clin Oncol. 2023;41:3122–34.

    Article  CAS  PubMed  Google Scholar 

  20. Huang C, Feng S, Huo F, Liu H. Effects of four antibiotics on the diversity of the intestinal microbiota. Microbiol Spectr. 2022;10:e0190421.

    Article  PubMed  Google Scholar 

  21. Rooney AM, Cochrane K, Fedsin S, Yao S, Anwer S, Dehmiwal S, et al. A microbial consortium alters intestinal Pseudomonadota and antimicrobial resistance genes in individuals with recurrent Clostridioides difficile infection. mBio. 2023;14:e0348222.

    Article  PubMed  Google Scholar 

  22. Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017;19:29–41.

    Article  CAS  PubMed  Google Scholar 

  23. Mirzaei R, Afaghi A, Babakhani S, Sohrabi MR, Hosseini-Fard SR, Babolhavaeji K, et al. Role of microbiota-derived short-chain fatty acids in cancer development and prevention. Biomed Pharmacother. 2021;139:111619.

    Article  CAS  PubMed  Google Scholar 

  24. Nomura M, Nagatomo R, Doi K, Shimizu J, Baba K, Saito T, et al. Association of short-chain fatty acids in the gut microbiome with clinical response to treatment with nivolumab or pembrolizumab in patients with solid cancer tumors. JAMA Netw Open. 2020;3:e202895.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank all patients and their families for their participation. We acknowledge and are grateful for the support of the Head and Neck Discovery Program, the Tomcyzk AI and Microbiome Working Group, the Bartley-Smith/Wharton, the Gordon Tozer, the Wharton Head and Neck Translational, Dr. Mariano Elia, Petersen-Turofsky Funds and the ‘The Joe & Cara Finley Center for Head & Neck Cancer Research’ at the Princess Margaret Cancer Foundation. MO would like to acknowledge the SEOM Foundation and Cris Contra el Cancer Foundation for their financial-grant support of his fellowship at Princess Margaret Cancer Center; and the Conquer Cancer Foundation 2019 Young Investigator Award, Instituto de Salud Carlos III (ICIII) Rio Hortega Pre-Doctoral Program and M-AES research support grants and Dr. Spreafico Research Funding to the ROMA Project.

Funding

This study was partly supported by MO ASCO Conquer Cancer Foundation Young Investigator Award (YIA) 2019, by the Princess Margaret Hospital DMOH 2019 Grant and by AS Division of Medical Oncology, Department of Medicine, University of Toronto Strategic Planning Innovation Grant.

Author information

Authors and Affiliations

Authors

Contributions

MO, LLS, BC and AS developed the concept and design of the ROMA LA-OPSCC-002 study. Patient recruitment and sample collection was performed by MO, GW, AS, LLS, RT and AH. Clinical data collection, analysis and curation was performed by MO, GW and AS. KC performed 16 S qPCR quantification, sequencing library preparation and taxonomic profiling (with CAGEF). MO, AH and AR conducted microbiome statistical analyses and figure generation under supervision of BC.

Corresponding authors

Correspondence to Bryan Coburn or Anna Spreafico.

Ethics declarations

Competing interests

MO has consulting/advisory arrangements with Merck, MSD and Transgene. Research support from Merck and Roche. The institution receives clinical trial support from Abbvie, Ayala Pharmaceutical, MSD, ALX Oncology, Debiopharm International, Merck, ISA Pharmaceuticals, Roche Pharmaceuticals, Boehringer Ingelheim, Seagen, Gilead. Travel accommodations expenses: BMS, MSD, Merck. AS has consulting/advisory arrangements with Merck, Bristol-Myers Squibb, Novartis, Oncorus, Janssen, Medison & Immunocore. The institution receives clinical trial support from: Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma/Pfizer, GSK, Treadwell, ALX Oncology, Amgen, Servier. RMN has consulting/advisory arrangements with Merck, Bristol-Myers Squibb, Roche, Seattle Genetics, Astra Zeneca, Pfizer, Boehringer Ingelheim. Speaker Bureau honoraria from Merck, MSD and Boehringer Ingelheim. GW has consulting/advisory arrangements with Gilead, Novartis, Pfizer, AstraZeneca, Boehringer-Ingelheim. Research support from Pfizer. Travel grants from BMS, Abbvie.

Ethics approval and consent to participate

ROMA LA-OPSCC-002 was a prospective interventional trial that involved MET-4 drug administration and the collection and analysis of oropharyngeal swabs, stool and plasma samples. The study did not determine the eligibility to receive standard-of-care treatment with definitive chemoradiotherapy. The study was approved by the Princess Margaret Cancer Center Institutional Research Ethics Board (Study ID 19-5079.10) and was conducted in accordance with the Declaration of Helsinki. All patients provided written, signed, informed consent to participate.

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Oliva, M., Heirali, A., Watson, G. et al. Prospective manipulation of the gut microbiome with microbial ecosystem therapeutic 4 (MET4) in HPV-related locoregionally-advanced oropharyngeal cancer squamous cell carcinoma (LA-OPSCC) undergoing primary chemoradiation: ROMA2 study. Br J Cancer 130, 1936–1942 (2024). https://doi.org/10.1038/s41416-024-02701-y

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