Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors

Elkrief, Arielle; Raichani, Layal El; Richard, Corentin; Messaoudene, Meriem; Belkaïd, Wiam; Malo, Julie; Bélanger, Karl; Miller, Wilson H.; Jamal, Rahima; Letarte, Nathalie; Wong, Philip; Routy, Bertrand

doi:10.1080/2162402x.2019.1568812

Cited by 159 publications

(120 citation statements)

References 28 publications

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“…When examining the timing of ATB treatment, it appeared that patients treated with ATB before ICI initiation had a shorter PFS and OS compared with those who were treated with ATB after the first administration of ICI. These findings were corroborated another study of melanoma patients, where the multivariate showed that ATB administration was associated with worse PFS [55]. Focusing on an even shorter time frame of 14 days between ATB-use and first injection of ICI, Ahmed et al conducted a retrospective study on 60 patients with a variety of cancer types receiving pembrolizumab, nivolumab, atezolizumab or a combination of ICI with chemotherapy.…”

Section: Atb-related Dysbiosis and Impact Of Atb On Efficacy Of Immunmentioning

confidence: 61%

The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

Elkrief

Derosa

Kroemer³

et al. 2019

Annals of Oncology

165

136

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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.

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Section: Atb-related Dysbiosis and Impact Of Atb On Efficacy Of Immunmentioning

confidence: 61%

The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

Elkrief

Derosa

Kroemer³

et al. 2019

Annals of Oncology

165

136

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“…Soft tissue infections or deep neck infection in the head and neck region can occur in patients with locally advanced HNSCC. Antibiotic usage around the time of ICI treatment could dampen the effects of PD-1/PD-L1 blockade (36)(37)(38)(39), as antibiotics usage for head and neck soft tissue infection will disrupt the integrity of the gut microbiome. A recent study demonstrates that disruptions in the gut microbiome composition, also known as dysbiosis, is one of the mechanisms of primary resistance to ICI therapy (36).…”

Section: Primary Resistance To Icis In Hnsccmentioning

confidence: 99%

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Kok

2020

Front. Oncol.

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Starting in 2014, large phase III clinical trials began to disclose the study results of using programmed death (PD)-1 immune checkpoint inhibitors (ICIs) (pembrolizumab, nivolumab) and PD-ligand (L)1 (atezolizumab, durvalumab, avelumab) ICIs immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). In the recurrent and metastatic (R/M), cisplatin-refractory setting, nivolumab achieved a 2.2-fold increase of the median 1-year overall survival as compared with investigators' choice of salvage chemotherapy (36.0 vs. 16.6%). A paradigm shift to the winning regimen, pembrolizumab combined with platinum and infusional fluorouracil, has outperformed the past gold standard of cetuximab-based platinum and fluorouracil combination in terms of overall survival (median, 13.6 vs. 10.1 mo) when administered as the first-line treatment for R/M HNSCC. Nevertheless, many patients still did not respond to the PD-1/PD-L1 checkpoint inhibitor treatment, indicating innate, adapted, or quickly acquired resistance to the immunotherapy. The mechanisms of resistance to ICIs targeting the PD-1/PD-L1 signaling pathway in the context of HNSCC are the focus of this review. The past 5 years have seen improved understanding of the mechanisms underlying checkpoint inhibition resistance in tumor cells, such as: tumor cell adaption with malfunction of the antigen-presenting machinery via class I human leukocyte antigen (HLA), reintroduction of cyclin D-cyclin-dependent kinase (CDK) 4 complex to cell cycles, enrichment of CD44+ cancer stem-like cells, or development of inactivating mutation in IKZF1 gene; impairment of T-cell functions and proliferation through mutations in the interferon-γ-regulating genes, suppression of the stimulator of interferon genes (STING) pathway, or resulted from constitutional nutritional iron deficiency state; metabolic reprogramming by cancer cells with changes in metabolites such as GTP cyclohydrolase 1, tetrahydrobiopterin, kynurenine, indoleamine 2,3-dioxygenase, and arginase 1; defective dendritic cells, CD-69 sufficient state; and the upregulation or activation of the alternative immune checkpoints, including lymphocyte activation gene-3 (LAG3), T-cell Kok Immune Evasion From PD-1/PD-L1 Immunotherapy immunoglobulin and ITIM domain (TIGIT)/CD155 pathway, T-cell immunoglobulin mucin-3 (TIM-3), and V domain-containing Ig suppressor of T-cell activation (VISTA). Several potential biomarkers or biosignatures, which could predict the response or resistance to the PD-1/PD-L1 checkpoint immunotherapy, are also discussed.

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“…The effect of the gut microbiome on immune response is further illustrated by clinical studies showing the influence of pretreatment antibiotic use on the outcomes of immune checkpoint blockade. Pretreatment antibiotic use was associated with significantly decreased PFS in patients with advanced melanoma treated with immune checkpoint inhibitors (2.4 vs. 7.3 months; HR, 0.28 [95% CI, 0.10–0.76], p = .01; Elkrief et al, ). Thus, there is a reasonable probability that both gut microbiome‐based predictive biomarkers and therapeutic interventions could be developed.…”

Section: Biomarkers Of Response and Resistance To Immunotherapymentioning

confidence: 99%

Targeted therapy and immunotherapy: Emerging biomarkers in metastatic melanoma

LoRusso

Schalper

Sosman

2020

Pigment Cell Melanoma Res

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Targeted therapy directed against oncogenic BRAF mutations and immune checkpoint inhibitors have transformed melanoma therapy over the past decade and prominently improved patient outcomes. However, not all patients will respond to targeted therapy or immunotherapy and many relapse after initially responding to treatment. This unmet need presents two major challenges. First, can we elucidate novel oncogenic drivers to provide new therapeutic targets? Second, can we identify patients who are most likely to respond to current therapeutic strategies in order to both more accurately select populations and avoid undue drug exposure in patients unlikely to respond? In an effort to evaluate the current state of the field with respect to these questions, we provide an overview of some common oncogenic mutations in patients with metastatic melanoma and ongoing efforts to therapeutically target these populations, as well as a discussion of biomarkers for response to immune checkpoint inhibitors—including tumor programmed death ligand 1 expression and the future use of neoantigens as a means of truly personalized therapy. This information is becoming important in treatment decision making and provides the framework for a treatment algorithm based on the current landscape in metastatic melanoma.

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Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors

Abstract: Routy (2019) Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors, OncoImmunology, 8:4, e1568812,

Cited by 159 publications

References 28 publications

The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Targeted therapy and immunotherapy: Emerging biomarkers in metastatic melanoma

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