DUBLIN – The still-tentative dalliance between immuno-oncology and gut microbiome research could blossom into a full-on romance, as Bristol-Myers Squibb Co. (BMS) and Enterome Bioscience SA entered a broadly based pact focused on biomarker, target and drug discovery, which involves $15 million up front plus undisclosed milestones.

The collaboration will build on internal research conducted at Paris-based Enterome, which indicates that elements derived from gut-resident bacteria enter the circulation and play a role in modulating host immune responses to cancer. "It's still a scientific and clinical hypothesis – [that] we have some factors provided by the gut microbiome that are protecting us from tumorigenesis," Enterome CEO Pierre Belichard told BioWorld Today.

Further exploring – and exploiting – that basic idea, as it applies to defined immuno-oncology targets, is at the core of the alliance. New York-based BMS will gain exclusive rights to whatever intellectual property and therapies flow from the initiative. Enterome would receive preclinical and clinical milestones, plus sales royalties, on new drugs discovered under the alliance, plus additional milestones for new diagnostic products.

"There is a lot of background science that is now really ripe for application," Carl Decicco, head of discovery at BMS, told BioWorld Today. "I consider Enterome one of the pioneers in taking a molecular approach." The alliance will give BMS access to Enterome's extensive metagenomic and bioinformatics platforms – it will be able to run patient stool samples from across its portfolio of programs through the Enterome analytic engine in order to identify microbiome signatures associated with safety and efficacy signals, which could improve patient stratification and patient outcomes. "We've taken this area of research very seriously," Decicco said.

Several research groups, on either side of the Atlantic, have already published evidence indicating that patient responses to cancer immunotherapy are mediated by residents of the gut microbiome. Most recently, Laurence Zitvogel, of Institut Gustave Roussy, in Paris, and colleagues reported that two bacterial species, Enterococcus hirae and Barnesiella intestinihominis, facilitate the immuno-therapeutic effects of the alkylating agent cyclophosphamide (CTX).

In mice treated with antibiotics, oral gavage (dosing) of E. hirae restored the efficacy of CTX. Also in mice, treatment with CTX causes E. hirae to migrate from the small intestine to secondary lymphoid organs, resulting in an increase of the ratio between CD8+ cytotoxic T lymphocytes and regulatory T-cells within tumors. B. intestinihominis accumulated in the colon, and led to an influx of interferon-gamma-product gamma-delta T-cells into cancer lesions, which are associated with improved survival. Their activities are limited by the pattern recognition receptor nucleotide-binding oligomerization domain-containing 2 (NOD2), however. The group also found that Th1 memory cells directed against the two species were predictive of improved progression-free survival in end-stage cancer patients.

The data appeared in the Oct. 18, 2016, issue of Immunity. The report follows a previous study from the same group – published in the Nov. 27, 2015, edition of Science – which found that another gut microbe, Bacteroides fragilis, mediates the anti-tumor activity of the CTLA-4 inhibitor Yervoy (ipilimumab). In the same issue, Thomas Gajewski and colleagues at the University of Chicago reported that a Bifidobacterium species both enhanced the activity of a PD-L1 inhibitor in a mouse model of cancer and promoted anti-tumor activity itself.

Enterome is keeping the details of its own findings under wraps for now, but its therapeutic approach does not entail the use of probiotic bacteria.

The host immune system and the existing gut microbiome make it difficult for probiotic strains to establish themselves in new hosts, Belichard said. That's why clinical trials of probiotics have failed consistently to demonstrate efficacy over the last 20 years, he added. It distinguishes the company from most other firms focused on the gut microbiome, including, he said, Evelo Biosciences Inc., the Cambridge, Mass.-based firm founded and funded last year by Flagship Ventures. (See BioWorld Today, Nov. 4, 2015.)

It took less than a year to complete the deal. Enterome met with "most of the usual suspects" in immuno-oncology at the JP Morgan Healthcare Conference in January 2016. "BMS were the most reactive," Belichard said. "It is by far the largest deal we have signed since the formation of Enterome," he said. Though undisclosed, the biobucks attached to the alliance "are in the ballpark of existing immuno-oncology deals," he said. The deal is also significant in being the first with a therapeutic dimension to take Enterome beyond inflammatory bowel disease (IBD). It has existing relationships in IBD with Johnson & Johnson, of New Brunswick, N.J.; Abbvie Inc., of North Chicago; and Osaka, Japan-based Takeda Pharmaceutical Co. Ltd.