The Negative Impact of Antibiotics on Outcomes in Cancer Patients Treated With Immunotherapy

A New Independent Prognostic Factor?

A. Elkrief; L. Derosa; G. Kroemer; L. Zitvogel; B. Routy

Disclosures

Ann Oncol. 2019;30(10):1572-1579. 

In This Article

Abstract and Introduction

Abstract

Immune-checkpoint inhibitors (ICI) now represent the standard of care for several cancer types. In pre-clinical models, absence of an intact gut microbiome negatively impacted ICI efficacy and these findings permitted to unravel the importance of the commensal microbiota in immuno-oncology. Recently, multiple clinical studies including more than 1800 patients in aggregate demonstrated the negative predictive impact of treatments with broad-spectrum antibiotics (ATB) on cancer patients receiving ICI. Altogether, these results have led to the hypothesis that ATB-induced dysbiosis might influence the clinical response through the modulation of the gut microbiome. Controversy still remains, as ATB treatment might simply constitute a surrogate marker of unfit or immunodeficient patients. In this review, we summarize recent publications addressing the impact of the gut microbiome on ICI efficacy, discuss currently available data on the effect of ATB administered in different time-frames respect to ICI initiation, and finally, evoke the therapeutic implications of these findings.

Introduction

The development of novel cancer treatments, including immune-checkpoint inhibitors (ICI), has revolutionized the therapeutic landscape in patients with melanoma and a variety of distinct epithelial cancers. ICI now represent the backbone treatment of several advanced carcinomas. Moreover, positive trials were recently published in neo-adjuvant and adjuvant settings, further expanding the clinical utility of ICI.[1,2]

Despite these advances, durable responses to ICI still remain exceptional. For example, in renal cell cancer (RCC)[3,4] and non-small-cell lung cancer (NSCLC),[5] primary resistance rates range from 35% to 44% while secondary resistance rates approach 100%. In advanced melanoma, 40%–65% and >40% of patients progress with anti-PD-1 alone[6] and in combination with anti-CTLA-4 therapy, respectively.[7] As a result, there is an unmet clinical need to develop biomarkers that predict response to ICI.

Factors contributing to the primary or acquired resistance to ICI are manifold and include cancer cell-centric markers such as PD-L1 expression and tumor mutational load,[8] the tumor immune infiltrate [local interferon-gamma gene expression, presence of CD8+, regulatory T cells and myeloid-derived suppressor cells (MDSC)], as well as environmental factors.[9] An unexpected paradigm shift occurred when the composition of gut commensal microbes (the microbiota) including bacteria, fungi, archaea and viruses was associated with the therapeutic response of cancer-bearing patients to ICI.[10–13] Completely neglected in oncology, the influence of the gut microbiota on cancer development and response to immunotherapy emerged from the development of next generation sequencing (NGS) technologies such as 16S rRNA and shotgun metagenomics. Furthermore, development of different culturomics methods coupled to mass spectrometric microbial identification techniques accelerated the identification of beneficial and fastidious bacterial strains and species.[14]

When dysregulated, the gut microbiota contributes to alter systemic immune responses, potentially favoring the development of chronic inflammatory disorders such as obesity, Crohn's disease and type II diabetes.[15] Experiments in germ-free (GF) and broad-spectrum antibiotic (ATB)-treated mice indicated that the tumor growth-reducing activity of ICI requires the presence of a specific set of bacteria in the gut. In these settings, using mice with similar sex, age and genetic background, the immune anticancer activity of anti-CTLA-4, anti-PD-1/PD-L1 or the combination of both antibodies was lost in the absence of immunogenic gut bacteria.[10–13] Building on the hypothesis that the composition of the gut microbiota determines resistance to ICI, microbiome profiling was carried out in patients with advanced melanoma, NSCLC and RCC. This approach revealed that the intestinal microbiota from patients who failed to benefit from ICI differed in its composition from those who responded.[11,12,16]

These initial results spurred further studies designed to determine whether ATB prescription to cancer patients at the time of ICI initiation would influence the clinical response in the same way as in the pre-clinical models. Despite the life-saving potential of ATBs to treat common and severe bacterial infections, the inventor of penicillin, Alexander Fleming, already warned the scientific community during his Nobel prize acceptance speech in 1943 about the risk of ATB resistance. However, the impact of ATB use on recolonization and subsequent changes in microbiota composition, which ultimately lead to a decrease in the commensal diversity, has only recently been appreciated.[17] ATB-induced dysbiosis seems especially deleterious for children's health, causing durable shifts of the developing microbiota with the potential for long-lasting health effects that extend into adulthood.[18,19] Antibiotics can induce intestinal dysbiosis through the diminution of the abundance of critical species or through the complete eradication of important commensals, therefore altering normal gut homeostasis with effects on local and whole-body metabolism as well as major consequences on the immune system.[10]

The majority of papers or abstracts published on the effects of ATB on the clinical outcome of ICI-based anticancer immunotherapy mirror the murine data, demonstrating that the efficacy of antibodies against CTLA-4 and PD-1/PD-L1 is reduced in patients who received ATB shortly before or after the initiation of immunotherapy. However, these important results as well as their impact on the clinical routine practice of oncologists remain controversial. Indeed, it is challenging to know if ATB use reflects a state of poor physical conditions (and in particular deficient immune function) rendering it a surrogate marker of dismal outcome, without any relationship to its effects on the gut microbiome. In this review, we will examine currently available data on the impact of ATB on ICI response in cancer patients and discuss their clinical implications.

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