Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial
In their groundbreaking paper, Bertrand Routy, John G. Lenehan, and team explore the potential of Fecal Microbiota Transplantation (FMT) in enhancing the efficacy of immune checkpoint inhibitors for refractory melanoma patients. By combining FMT with PD-1 inhibitors, they provide insights into first-line treatment avenues.
In the quest to treat advanced melanoma, a significant number of patients fail to respond to single-agent anti-PD-1, an immune checkpoint inhibitor. This highlights an urgent need for novel therapeutic strategies. A ray of hope emerges from the realm of our guts: the microbiome. Several studies have suggested that specific gut bacteria can influence both the response to and side effects from immune checkpoint inhibitors (ICIs). Some bacteria, like Ruminococcus, Faecalibacterium, and Eubacterium, correlate with favorable outcomes in melanoma treatment. Building on this knowledge, a phase I trial combined fecal microbiota transplantation (FMT) from healthy donors with anti-PD-1 in melanoma patients.
Safety and Clinical Efficacy
The trial’s paramount objective was to evaluate safety. Thankfully, severe adverse effects (grade 3) stemming directly from FMT were absent. However, 25% of the patients did experience significant immune-related side effects from the combined treatment. Importantly, the objective response rate stood at an encouraging 65%, with 20% achieving a complete response.
As expected, patients’ gut microbiomes began to resemble that of their donors post-transplantation. Interestingly, this resemblance only grew over time in patients who responded positively to the treatment. Furthermore, these responding patients experienced a growth in beneficial bacteria and a reduction in harmful ones post-FMT.
Benefits of Healthy Donor Stool
The trial utilized FMT capsules prepared from healthy donor stool, a divergence from previous trials that used stool from patient donors. This offers a scalable alternative, bypassing the challenges of patient donor recruitment.
Gut Microbiome’s Influence on Treatment
One exciting revelation was the shift in the composition of responders’ microbiomes towards certain bacterial taxa, a change not evident pre-treatment. Some of these bacteria, like Ruminococcus and Faecalibacterium, have previously been associated with favorable outcomes.
The Mouse Model Insights: Experiments using murine avatar models showcased that the gut microbiota composition could influence the efficacy of anti-PD-1 treatments. When mice were treated with FMT from donors or responding patients post-FMT, there was a marked improvement in the anti-PD-1’s performance.
This phase I trial breaks new ground by spotlighting the potential of combining FMT from healthy donors with anti-PD-1 treatment in the frontline setting for advanced melanoma patients. The results are promising, illustrating the safety of the approach and its potential benefits. Notably, FMT did not seem to increase the incidence of adverse effects compared to anti-PD-1 alone. However, while these findings are an exciting stride forward, several questions loom. We need to unravel the optimal bacterial mix for transplantation and ascertain the best means to prepare the patient’s gut for transplantation. Future research will undoubtedly delve deeper into these aspects, further refining our understanding and application of this promising therapeutic avenue.
Routy, B., Lenehan, J.G., Miller, W.H. et al. “Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial.” Nat Med (2023). https://doi.org/10.1038/s41591-023-02453-x
Bertrand Routy, John G. Lenehan, Wilson H. Miller Jr, Rahima Jamal, Meriem Messaoudene, Brendan A. Daisley, Cecilia Hes, Kait F. Al, Laura Martinez-Gili, Michal Punčochář, Scott Ernst, Diane Logan, Karl Belanger, Khashayar Esfahani, Corentin Richard, Marina Ninkov, Gianmarco Piccinno, Federica Armanini, Federica Pinto, Mithunah Krishnamoorthy, Rene Figueredo, Pamela Thebault, Panteleimon Takis, Jamie Magrill, LeeAnn Ramsay, Lisa Derosa, Julian R. Marchesi, Seema Nair Parvathy, Arielle Elkrief, Ian R. Watson, Rejean Lapointe, Nicola Segata, S.M. Mansour Haeryfar, Benjamin H. Mullish, Michael S. Silverman, Jeremy P. Burton & Saman Maleki Vareki.