Abstract
Oncologists are testing fecal transplants and other microbiome-based products in combination with checkpoint inhibitors in an effort to increase and enhance responses. However, questions remain about how the microbes affect host immunity and which preparations of bacteria are optimal.
More than 1,700 studies are testing drugs targeting the PD-1 pathway in tandem with chemotherapy, radiation, or other anticancer therapies. Of these combination strategies, however, only a handful have garnered FDA approvals.
Now, clinicians are trying a less conventional approach to boost the therapeutic value of immunotherapy: administering fecal transplants and other microbiome-based products—combined with infusions of pembrolizumab (Keytruda; Merck), nivolumab (Opdivo; Bristol-Myers Squibb), or other checkpoint inhibitors—to their patients.
Early clinical data suggest the bacterial therapies hold promise. Reporting at the American Association for Cancer Research Annual Meeting 2019 in Atlanta, GA, independent teams led by researchers from the Sheba Medical Center in Ramat Gan, Israel, and the University of Pittsburgh Medical Center in Pennsylvania described patients with melanoma who initially did not benefit from PD-1 blockade but experienced tumor shrinkage after receiving a stool sample from someone for whom the checkpoint inhibitor yielded a durable complete response (ClincialTrials.gov Identifiers NCT03353402 and NCT03341143).
The Israeli investigators also presented a detailed analysis of stool and tissue biopsies taken pre- and posttransplant (Proceedings of the 110th Annual Meeting of the AACR, 2019, abstract CT042). Genetic testing showed that the recipients' microbiomes closely matched those of their stool donors', confirming successful engraftment of the new bacterial community. Immunohistochemical stains revealed an increase in the number of CD68-expressing antigen-presenting cells infiltrating the gut and tumor tissue after the fecal transplant. The tumor biopsies also contained more CD8+ T cells, indicating that the therapeutic stool swap had helped turn previously “cold” tumors into immunologically “hot” ones.
Although the two studies have collectively enrolled only a limited number of patients, others who study the human microbiome's relation to cancer are buoyed by the findings. “To see responses in PD-1–refractory disease—the only variable being a change of the microbiome—is really impressive,” says Jennifer Wargo, MD, of The University of Texas MD Anderson Cancer Center in Houston, who was not involved in either study. However, researchers caution against jumping to conclusions. “We need more follow-up before we can say these responses are real and durable,” says Diwakar Davar, MBBS, of the University of Pittsburgh.
Many questions also remain about what the transplanted microbes are doing to host immunity and how best to administer the bacteria to patients. “This is a scientific frontier,” says Joao Xavier, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY. “We still lack some basic understanding of how the microbes are benefiting the outcomes of patients.”
A more complete picture should emerge as researchers amass clinical data—and methodologic differences between ongoing studies should help fill in biological details about the optimal source and delivery routes of transplanted microbes.
Fecal microbial transplant capsules are being studied at the Lawson Health Research Institute in London, Ontario, Canada.
In many studies, for example, donor stool is delivered during a colonoscopy, as is standard with fecal transplants for superbug infections. Yet most patients with cancer do not otherwise need the invasive medical procedure—one that Lillian Siu, MD, of Princess Margaret Cancer Centre in Toronto, Canada, describes as “not the most tolerable.” That's why she and others have begun testing bacteria-stuffed pills in patients at the time of immunotherapy infusions.
John Lenehan, MD, of the University of Western Ontario in London, Canada, is leading one such trial of fecal capsules—and unlike the Israeli group, Lenehan's team is delivering the therapy as a complement to front-line checkpoint blockade rather than as a rechallenge for nonresponders.
In addition, researchers are evaluating defined formulations of microbes selected based on observational clinical studies and mouse experiments defining which ones influence response to immunotherapy. For example, Siu and her colleague Anna Spreafico, MD, PhD, are testing a cocktail of more than 30 species in a pill dubbed MET-4 (NuBiyota), and Vedanta Biosciences will soon begin human testing of VE800, an 11-strain mixture shown to elicit anticancer immunity in mice (Nature 2019:565;600–5).
The Parker Institute for Cancer Immunotherapy, in collaboration with Seres Therapeutics and Wargo's team at MD Anderson, is also testing oral encapsulated stool from immunotherapy responders against SER-401, which contains spores from dozens of bacterial species. According to the Parker's head of translational medicine, Theresa LaVallee, PhD, that study includes “deep immune profiling to really understand the links between the microbiome, immune tone, and outcome.”
Paring down the microbiome even further, two companies—Evelo Biosciences and 4D Pharma—are betting that single bacterial strains will sufficiently boost the efficacy of PD-1 inhibitors. Dismissing complete fecal transplants as a “sledgehammer approach,” 4D's chief scientific officer, Alex Stevenson, PhD, says that the company's proprietary strain of Enterococcus gallinarum, MRx0518, has induced proinflammatory responses in cell culture and elicited antitumor effects in mouse models (Sci Rep 2019;9:801; J Clin Oncol 2018;36: no.15_suppl e15006).
Researchers studying gut microbial aids for patients with cancer generally welcome the multitude of therapeutic strategies under investigation. “It's very, very early, and we don't know which approach is going to succeed,” Davar says. –Elie Dolgin
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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