These microbiome insights are brought to you by Dr. Vancheswaran Gopalakrishnan and Dr. Jennifer Wargo of The University of Texas MD Anderson Cancer Center, and Arrowhead Publishers. Dr. Gopalakrishnan will be presenting MD Anderson’s work at Arrowhead’s 4th Annual Translational Microbiome Conference, 18th-20th April, 2018.
Pioneering research performed at the MD Anderson Cancer Center1 suggests that the gut microbiome influences how cancer responds to immunotherapy; potentially creating new opportunities to improve treatment.
Cancer patients who saw no benefit from anti-PD1 checkpoint blockade immunotherapy lacked certain beneficial gut bacteria. On the other hand, cancer patients who responded to anti -PD1 immunotherapy possessed gut bacteria whose abundance in the gut correlated with the presence of cancer-killing T-cells. When the researchers transferred gut bacteria from human cancer patients into germ-free mice using fecal matter transplantation (FMT), the rodents mirrored the patient’s fates.
Anti-PD1 immunotherapy “unleashes the brakes on the immune system” by preventing programmed-death-1 (PD-1) binding to programmed-death ligand-1 (PD-L1) on cancer cells, allowing T-cells to attack. However, anti-PD1 immunotherapy is not effective for all cancer patients and responses are not always durable.
The Answer’s in the Poop!
To assess the impact of the microbiome, the MD Anderson team analysed oral and fecal samples of 112 metastatic melanoma patients undergoing anti-PD1 immunotherapy1. 16rRNA and whole genome sequencing was performed to determine diversity, composition and functional potential of the oral and fecal microbiomes. Baseline tumor and blood samples were also analysed.
While no differences in response or progression were found in connection with the oral samples; the 43 fecal samples told another story. Analysis of the fecal microbiome samples (30 of which were responders and 13 non-responders) found that patients with a greater diversity of bacteria in their gut microbiome at baseline had a longer median progression-free survival (PFS). While the high diversity group had not reached median PFS, intermediate and low diversity groups had median PFS of 232 and 188 days, respectively.
Additional analysis showed that responding patients with high levels of beneficial Clostridiales/Ruminococcaceae had greater presence of anti-tumor T-cells in their tumors, and higher levels of circulating T cells that kill abnormal cells. On the other hand, patients abundant with Bacteriodales had higher levels of circulating regulatory T cells, myeloid derived suppressor cells and a blunted cytokine response, resulting in diminished anti-tumor immunity.
To investigate causal mechanisms, the team transplanted fecal microbiomes from responding patients and non-responding patients into germ-free mice. Those receiving transplants from responding patients had significantly reduced tumor growth as well as higher densities of beneficial T cells in their gut and tumor sites and lower levels of immune suppressive cells. They also had better outcomes when treated with PD-1 axis blockade
Antibiotics May also Affect Anti-PD1 Immunotherapy
Interestingly, the MD Anderson’s findings complement those of the Gustave Roussy Cancer Campus, France2. Lung, kidney or bladder cancer patients who received antibiotics to treat infection shortly before or after starting anti-PD1 immunotherapy, did not respond as well to treatment. The presence of Akkermansia muciniphila bacteria in both humans and mice was linked to improved responses to anti- PD1 immunotherapy.
Modulation of the Gut Microbiome Could Improve Cancer Prognosis
Although these findings are early, they suggest the connection between the gut microbiome and immune system could have major implications for cancer treatment and prognosis. Further work is needed to analyse the diversity and composition of the gut microbiome to predict response to anti-PD1 immunotherapy; and to modulate the gut microbiome to enhance treatment.
Research has shown that the human microbiome may be modulated by diet, exercise, probiotic or antibiotic use or FMT – however these need to be carefully studied in clinical trials.
On that note, the MD Anderson team is now planning a clinical trial using strategies to modulate the gut microbiome in patients with metastatic melanoma going onto anti-PD1 (in collaboration with the Parker Institute for Cancer Immunotherapy and Seres Therapeutics). The primary hypothesis of this trial will be that we can safely modulate the gut microbiome in metastatic melanoma patients going on to anti-PD1 therapy.
Tremendous promise but challenges ahead
These findings have important potential implications, though challenges are also evident. Several issues have been raised by Dr Jennifer Wargo and Dr Vancehswaran Gopalakrishnan given these results. “These findings have important implications, but we don’t know all the answers yet. Should we be profiling the gut microbiome of patients going onto immunotherapy? And should we tightly monitor antibiotic use in these patients? Furthermore, what other factors – including diet – may be influencing the microbiome? Should we also be profiling the gut microbiome in pre-clinical models where we are testing therapeutic strategies to fight cancer and other diseases? And finally, can we manipulate the microbiome to improve overall health and to facilitate cancer immunosurveillance?”
In addition to this, strategies such as FMT have their own inherent challenges. Although first documented in 4th century China as ‘yellow soup’; FMT has slowly gained popularity over the past years in the US for the treatment of inflammatory gastrointestinal disorders
FMT as a novel adjuvant cancer therapy could bring many rewards, though poses tough challenges. As a cutting-edge forefront therapy, FMT follows unique regulatory oversight. In May 2013, the FDA announced it would regulate FMT as an Investigational New Drug (IND) and Biologics. This classification restricted physicians to file an IND application to use FMT in a clinical trial. However, both patients and physicians raised concerns this would restrict patient access to FMT.
In June 2013, the FDA responded to these concerns and issued its Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies (http://fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm361379.htm).
Under this ruling, qualified physicians can perform FMT for recurrent C. dfficile not responding to standard treatment outside clinical trials without filing for an IND application.
FMT also has other challenges, given variation between preparations. Ultimately, the MD Anderson team and their collaborators hope to identify a live bacterial product incorporating consortia of bacteria implicated in enhancing immunity and therapeutic responses. Though challenges exist, given the potential far-reaching rewards, these efforts are clearly worth pursuing.
- Gopalakrishnan V. et al., Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 2017 Nov http://dx.doi.org/10.1126/science.aan4236
- Routy B. et al., Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 2017 Nov http://dx.doi.org/10.1126/science.aan3706
- Matson V. et al., The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science, 2018 Jan http://doi1126/science.aao3290
#microbiome #Arrowhead #cancer #melanoma #PD-1 inhibitors #Gopalakrishnan #Wargo #MD Anderson Cancer Center #FMT #FDA #Seres Therapeutics #Parker Institute for Cancer Immunotherapy