Potential Mechanisms

The results of this research suggest that antibiotic use may adversely impact clinical outcomes of NSCLC patients treated with ICIs, Ms Crespin said.

She noted that the cause or causes of this association cannot be ascertained from a meta-analysis but offered 2 potential explanations.


Continue Reading

First, there may be an immunomodulatory effect related to the gut microbiome.5 For example, in mouse lung tumor models, infield and abscopal tumor cell death from radiotherapy was modulated by antibiotics.6

Alternatively, gastrointestinal bacteria and tumor antigens could be cross-reactive for the same antigen-specific T cells. The cross-reactivity could interfere with immunogenic cell death.7

Limitations and Implications

There are limitations to this meta-analysis that call into question the association between antibiotic use and outcomes.

Due to the absence of individual patient data, the researchers could not ascertain whether some patients received prophylactic antibiotics and lacked an underlying severe infection. Also lacking is information on the reason for antibiotic use, duration of use, antibiotic class, and route of administration.

One possibility is that patients requiring antibiotics may have had adverse tumor kinetics and higher tumor burden. The PFS data did not suggest worsened tumor kinetics, but there was no independent central review of that endpoint.

Another limitation is that the studies included in the meta-analysis were highly heterogeneous. Sex, age, tumor histology, stage, and performance status score were unevenly noted. Patients were treated with ICIs in different lines of therapy with highly variable use of subsequent therapies across countries. This could have influenced the OS endpoint.

Furthermore, studies demonstrating a positive or neutral impact of antibiotics on ICI efficacy may go unpublished due to publication bias.

Despite these caveats, the need for identifying good biomarkers of ICI efficacy in NSCLC and other malignancies suggests a need for prospective studies. If a link between intestinal dysbiosis and inferior outcomes from immunotherapy is confirmed, basic research will be needed to define the precise mechanism by which that occurs.

Only with more robust medical data from controlled studies in carefully annotated populations can the medical community be properly guided regarding antibiotic use in patients with cancer who could benefit from ICI therapy. If antibiotic exposure does, in fact, impact the results of immunotherapy, the implications of this association could be profound.

Disclosures: This research was sponsored by Da Volterra. Ms Crespin and colleagues disclosed affiliations with Da Volterra, including employment.

References

  1. Crespin A, Bandinelli PA, Le Bescop C, et al. Systematic review and meta-analysis evaluating the impact of antibiotic use on clinical outcomes of non-small-cell lung cancer patients treated with immune checkpoint inhibitors. SITC 2021; November 10-14, 2021. Abstract 278.
  2. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97-103. doi:10.1126/science.aan4236
  3. Pinato DJ, Howlett S, Ottaviani D, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol. 2019;5(12):1774-1778. doi:10.1001/jamaoncol.2019.2785
  4. Lurienne L, Cervesi J, Duhalde L, et al. NSCLC immunotherapy efficacy and antibiotic use: A systematic review and meta-analysis. J Thorac Oncol. 2020;15(7):1147-1159. doi:10.1016/j.jtho.2020.03.002
  5. Sepich-Poore GD, Zitvogel L, Straussman R, et al. The microbiome and human cancer. Science. 2021;371(6536):eabc4552. doi:10.1126/science.abc4552
  6. Fluckiger A, Daillere R, Sassi M, et al. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science. 2020;369(6506):936-942. doi:10.1126/science.aax0701
  7. Uribe-Herranz M, Rafail S, Beghi S, et al. Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response. J Clin Invest. 2020;130(1):466-479. doi:10.1172/JCI124332