A preclinical research finding in mice with tumors treated with checkpoint inhibitors that was first reported in 2015 has now been expanded to human clinical trials.
Pending further investigation and confirmation, the results could have far-reaching implications for cancer immunotherapy. Researchers at the Gustave Roussy Cancer Campus in France reported in the November 5, 2015 issue of Science that differences in the gut flora of mice influenced responses to treatment with the checkpoint inhibitor class of immuno-oncology (IO) drugs, and subsequently proceeded to test the concept in the clinic.
The results of the research, led by investigator Laurence Zitvogel, were reported in Science on November 2, and claimed that patients with bladder, renal, or lung cancers who took antibiotics shortly before or during the study relapsed more quickly and had shorter survival times that those patients whose gut microbiome diversity had not been disrupted by antibiotics. Furthermore, the study identified the type of bacteria involved in the increased response as Akkermansia muciniphila, a normal resident species of human gut mucosa. Interestingly, A. muciniphila was previously identified as having a role in protecting against obesity and diabetes.
While these results are intriguing, they will have to be confirmed by other groups in carefully designed and controlled clinical studies to be of major impact. The French study had several design shortcomings that future studies should avoid.
First, the study retrospectively assessed data from 249 patients, of which only 69 had taken antibiotics shortly before or within one month of their first cancer drug treatment during the original study.
Second, in addition to the fact that patients in the non-antibiotic treated group outnumbered the antibiotic-treated group more than twice over, the study was retrospective and certain uncontrolled factors may have confounded the results. However, it is worth noting that related findings in another cancer type have also been released; while that study was prospective, it drew upon patients who were starting treatments in other studies.
In that same issue of Science, a research team at MD Anderson Cancer Center in Houston, Texas, US, led by Jennifer Wargo, prospectively assessed melanoma patients who were undergoing treatment with checkpoint inhibitors. This study found that patients who responded to these drugs had a more diverse complement of bacteria in their microbiomes than those who did not respond. Additionally, the responding patients in the US study possessed a greater number of several types of bacteria, but not A. muciniphila, as reported in the French study. The MD Anderson group also reported that mice receiving fecal transplants from responding melanoma patients had more primed T-cells in their gut and tumors, suggesting a role for particular bacterial species in T-cell priming.
These findings, if confirmed, will offer a great deal of promise for increasing the efficacy of treatment with checkpoint inhibitors, a therapy class that has traditionally suffered from a lack of reliable biomarkers.
While the constitution of the patient’s gut microbiome could prove to be a very good biomarker for predicting their response to checkpoint inhibitors and possibly other IO therapies, it is also a characteristic that can be fairly easily manipulated to increase the likelihood of response to cancer therapy. The current research has shown that the avoidance of antibiotics during treatment with checkpoint inhibitors is associated with increased responses to these drugs.
The same research studies imply that by performing the additional step of manipulating the microbiome, it is possible to further increase the responses to these therapies and perhaps other IO drugs as well.
In 2018, Jennifer Wargo plans to initiate a trial with a group at the Parker Institute for Cancer Immunotherapy in San Francisco, California, US to test whether manipulating the microbiome in patients with either a fecal transplant pill or bacterial treatment could increase responses to treatment with checkpoint inhibitors. Given the fact that the current response rate to checkpoint inhibitors is approximately 25%, successful results in this trial would have major implications for the treatment of a large number of cancers.
The interplay between the gut bacteria of patients and their responses to immune system-enhancing cancer therapies can be compared to the host-pathogen interactions seen in certain infectious disease scenarios. Particular pathogen characteristics interact with factors in the host to determine the overall extent of infection; the same types of interactions could be occurring between the non-pathogenic bacteria comprising the normal gut flora and the immune system to determine the patient’s response to checkpoint inhibitors.
In fact, the researchers at the Gustave Roussy Cancer Campus in France found that in those patients with bladder, renal or lung cancers who responded to checkpoint inhibitors and had increased levels of A. muciniphila in their gut microbiome released the cytokine IL-12, which in turn attracts tumor-fighting T-cells.
These initial studies are promising, but there still remains a need for carefully controlled, large prospective studies in different tumor types to corroborate these results. In addition, significant research will be required in order to identify which bacterial species are influencing the response to the IO drugs and the mechanisms by which they are doing so.
The current results are intriguing, as they point to previously unknown roles for the human microbiome and further highlight the importance of the immune system in cancer.
This research has uncovered opportunities to fine tune treatment paradigms for a variety of cancer types, ultimately benefitting both patients and drug development stakeholders, in a therapeutic area where treatment outcomes have generally been poor.