Treatment with metronidazole improves response and reduces toxicity to immune checkpoint blockade therapy
Introduction
Immune checkpoint blockade (ICB) therapy transformed clinical oncology by inducing durable responses in many types of cancers. However, only a subset of patients benefit from ICB. Recent studies suggest that the gut microbiome may act as a therapeutic target for ICB response, and that treatment with broad spectrum antibiotics abrogates response. However, targeted antibiotic approaches have not been well-studied, and could represent a tangible near-term treatment to improve outcomes to treatment with ICB for cancer.
Methods
We hypothesized that treatment with a targeted antibiotic would improve outcomes to ICB by selectively rebalancing deleterious and beneficial microbial taxa within the gut microbiome. To study this, we assessed the impact of metronidazole on ICB treatment response in pre-clinical models. Mice were treated with oral gavage of metronidazole prior to MC38 tumor cells injection, with metronidazole maintained in the drinking water. Mice were then treated with ICB and tumor growth, immune responses and microbiome profiles were analyzed. Importantly, we also assessed survival in patients with solid tumors who received targeted (metronidazole) or beta lactam-based antibiotics within 60 days of treatment with ICB (aCTLA-4).
Results
In our pre-clinical studies, treatment with metronidazole in combination with ICB was associated with suppressed tumor growth compared to treatment with ICB alone (p=0.0013). Whole genome sequencing analysis of fecal samples revealed mice treated with metronidazole have increased abundance of bacterial taxa previously associated with positive ICB response, including Bifidobacterium (log2 fold-change 4.1, p=0.00001). To complement these studies, we assessed a cohort of patients at MD Anderson treated with metronidazole versus beta lactam-based antibiotics prior to ICB treatment. We found that patients who received metronidazole prior to ICB had improved survival compared to patients treated with ICB alone (median overall survival [OS] undefined vs. 20 months, p=0.01), whereas patients who received beta lactam-based antibiotics had worse outcomes (9.7 months, p=0.0567).
Conclusion
Treatment with metronidazole prior to ICB is associated with improved survival in pre-clinical models and in an exploratory cohort of patients treated at MD Anderson. Further studies are underway to elucidate the mechanism behind these findings, with opportunities to translate these findings in clinical trials.