Matt Furlow co-authored this post with Pranav Srivastava.
In the novel A Wind in the Door by Madeleine L’Engle, the main character’s younger brother gets sick when fictional symbiotic entities within his mitochondria called farandolae fail to work together to prevent illness. My co-author and I were reminded of that story as we looked for parallels for the symbiotic nature of gut flora and the notion that the gut microbiome can have significant implications on health—a promising area of research that should be on the radar of oncology companies looking to expand their portfolios.
The role of the gut microbiome in gastrointestinal disorders is becoming better understood, resulting in therapeutic implications like the use of fecal transplant to treat clostridium difficile infection. However, the gut microbiome’s impact on cancer is a nascent area of study. While most oncology therapies have focused on killing cancer cells through different mechanisms, research into the role of the gut microbiome has only recently started showing some results. There’s pre-clinical evidence that gut flora can impact a patient’s response to CTLA-4 blockade and potentiate PD-L1 blockade. Gut flora could even have anti-tumor properties of its own. Additionally, research presented at the 2017 American Society of Clinical Oncology Annual Meeting noted that the gut flora of metastatic melanoma patients who were responsive to anti-PD-1 therapy was different than the gut flora of patients who weren’t responsive.
These results are exciting, and they indicate a need for oncology companies to explore the clinical implications of the intersection of the gut microbiome, immunotherapy and cancer. We see a few promising routes that this research could lead to:
- Enabling more therapeutic options with gut flora enhancement: As the oncology industry’s understanding of the mechanisms of response to immunotherapy evolve, there’s increasing interest in how to transform non-responsive “immune cold” tumors into responsive “immune hot” tumors. Certain gut flora can contribute to a more immune-responsive tumor microenvironment, so clinical trials investigating combinations of immunotherapy agents and bacterial transplantation are merited. In these trials, it will be critical to characterize not only which particular gut flora synergize most effectively with various immunotherapy modalities, but also the most effective route of transplantation and role of other elements of the gut microbiome. For example, previous research has shown that bacterial isolates taken orally aren’t necessarily effective at treating clostridium difficile infection.
- Helping patients stay on therapy by mitigating immunotherapy side effects through gut flora modification: On the other side of the coin, immunotherapies come with side effects, some of which reside in the gastrointestinal system, like colitis. Fecal transplant has been shown to be effective in treating inflammatory bowel disease and colitis, so in addition to augmenting immunotherapy efficacy, gut flora may also be able to mitigate side effects related to immunotherapy. Again, further study is needed to better understand these linkages, and to take these findings from the lab bench to the clinic.
- Functioning as a prognostic risk-marker: There’s a growing body of evidence that diet and gut microbiome each impact cancer risk, likely in a collaborative way. There’s a mind-boggling number of factors behind these interactions, but nonetheless, research must be undertaken to incrementally build an understanding of how gut flora mediate dietary stimuli and to identify intervention points. This is a grand aim that may not immediately translate into therapeutic options, but as the old axiom says, an ounce of prevention is worth a pound of cure.
The intersection of gut microbiome and cancer therapy may boost our ability to fight cancer in the future. Thinking again about the story from A Wind in the Door, when the symbiosis of the character’s farandolae is reestablished, his illness begins to subside. Investment in microbiome research and its applications is happening already at academic centers like the University of Chicago and at private companies like Bristol-Myers Squibb, which is expecting to initiate human trials investigating gut flora and cancer next year.
In our continued fight against cancer, the next frontier may be in the gut, so if you’re looking to extend your oncology portfolio, it’s certainly worth a look inside.
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