Gut instinct

It's what's inside that counts- microbiome research is 

starting to pin down how gut bacteria contribute

to a variety of disease states.

It's estimated that the number of Intestinal bacteria is roughly equal to the number of cells in our bodies and, intuitively, one would expect such a substantial and active biomass (around 200g in a 70kg adult) to have some influence on health and disease.

Increasingly sophisticated means of profiling the multitude of bacterial species found in the gut microbiome and the metabolites they produce are beginning to identify factors that contribute to inflammatory bowel disease, cardiovascular disease, metabolic diseases and how individuals respond to cancer immunotherapy. 

The role of the microbiome in gut conditions has, as might be expected, received particular attention. Inflammatory bowel disease (IBD) falls largely into two distinct types: ulcerative colitis (UC), which is confined to the large intestine; and Crohn's disease (CD), which may affect any part of the digestive tract. Both are chronic conditions characterised by periods of remission and flare, and are treatable but not curable. IBD is immune-mediated, although the trigger(s) remain largely undefined: genetics; the integrity of the gut surface, and environmental factors (diet, stress, antibiotic use) which may change the gut flora all play a part. 

Analysis of the gut microbiome in IBD sufferers suggests that both UC and CD are associated with different "microbial signatures", with certain bacterial species being present in abundance, and other species being absent or present only in low numbers. Bacterial degradation of mucin, a protective glycoprotein which lines and protects the gut is one possible contributory mechanism, as are changes in microbial fatty acid and amino acid biosynthesis. Association is by no means proof of causation- changes in the microbiome- “dysbiosis”- might result in chronic inflammation, but the reverse may also be the case.

Alteration of the microbiome through antibiotic treatment is associated with better clinical outcomes in IBD, but also appears to be a risk factor for the development of CD. There is no compelling evidence that probiotics- the "good bacteria" of marketing campaigns- are of benefit in IBD. While understandably unappealing, re-balancing the gut flora through "faecal microbial transplantation" (FMT) has been shown to be of benefit in small studies involving IBD patients. 

A recent study throws light on the relationship between one particular bacterial metabolite, ascorbate (vitamin C) and IBD. Microbially produced vitamin C does not contribute to our nutritional requirement but its presence in the gut may be significant. University of California researchers investigated 139 different microbial metabolites associated with CD for their effects on human T cells which mediate inflammatory processes. Fifteen metabolites were identified as having an effect on T cells, of which only ascorbate served as an inhibitor of T cell activation, possibly through altering glycolysis, a key energy-producing pathway.

That certain bacterial species associated with CD are capable of ascorbate production adds a little more circumstantial weight to the hypothesis, but further elucidation of the relationship between disease and gut ascorabate levels and the presence or absence of ascorbate-producing species is required before practical use can be made of this observation. 

The enzyme indoleamine-2,3-dioxygenase (IDO) has featured in a couple of my blog pieces as a target of great interest in cancer immunotherapy. IDO is an important regulator of tryptophan levels and increased IDO activity contributes to unwanted immunosuppression within the tumour microenvironment. The clinical performance of IDO inhibiting drugs in combination with established immuno-oncology agents has been less than stellar, leading to the large scale abandonment of further development [IDO a no-go: what’s up next in immuno-oncology combination therapy?]

Intriguingly and unexpectedly, IDO, or more accurately, the lack of it, has been found to have a beneficial effect on gut microbes in an animal model of obesity. IDO activity is increased in obesity and French researchers have shown that IDO action in the gut results in a "rewiring" of tryptophan metabolism which in turn impacts on insulin sensitivity, lipid metabolism in the liver, the integrity of the gut surface and levels of chronic inflammation. 

These effects are mediated through production of IL-22, a signalling protein involved in immune regulation and liver and gut epithelial cell survival. Knocking out IDO activity allows gut bacteria to direct tryptophan metabolism in a benign manner. The composition of the gut microbiome was found to be different between mice with active and inactive IDO. 

It's a leap to suppose that IDO inhibitors might eventually be repurposed as treatments for obesity, but better understanding of the interplay between "immunometabolic" mediators such as IDO and the microbiome could open up paths to better therapies or means of either preventing metabolic disease or identifying individuals at higher risk of obesity.

Photo credit: Darryl Leja, National Human Genome Research Institute, National Institutes of Health.

IDO a no-go: what’s up next in immuno-oncology combination therapy?

IDO inhibitors: only stalled or
now off-road?

Earlier this year, I mused on the prospects for inhibitors of IDO (indoleamine-2,3-dioxygenase-1),then considered among the most promising of small molecule drugs that might safely enhance the effectiveness of immune checkpoint inhibitors [Are IDO inhibitors still the next big thing in immuno-oncology? ]. 

While attracting big pharma interest (and partnering dollars), IDO inhibitor clinical development progress has been mixed, with both Roche and Pfizer abandoning early-stage clinical collaborations, leaving Incyte Pharma’s epacadostat in the spotlight and all eyes on the outcome of ECHO-301, a Phase III clinical study designed to establish whether combination treatment with epacadostat and Merck’s anti-PD-1 immune checkpoint inhibitor, pembrolizumab (Keytruda®), first approved as a melanoma treatment in 2014 might further benefit patients with advanced melanoma. 

According to a joint release from Merck and Incyte, data analysis indicates that, in contrast to Phase II study findings, combination treatment did not result in an improvement in progression-free survival over Keytruda® alone, nor is a meaningful increase in overall survival anticipated. 

The ECHO-301 study is to be halted and it’s likely that that a raft of other studies involving epacadostat- pembrolizumab combination treatment in colorectal, gastric, non-small cell lung, bladder cancer and other solid tumours will be put on hold or terminated. AstraZeneca may be having second thoughts over planned combination studies with their anti-PD-L1 inhibitor.

NewLink Genetics, a pioneer of IDO inhibitor development which has also experienced development setbacks, has been hit by the fallout, suffering a hefty dent in share price and prompting a review of its planned clinical programmes. Bristol Myers Squibb may face the same dilemma with respect to continuing patient recruitment for a Phase III study of its own IDO inhibitor, BMS-986205, in combination with its anti-PD1 drug, nivolumab (Opdivo®). 

Tryptophan metabolism plays a key role in tumour immunosuppression and while epacadostat’s failure will prompt a major rethink of drug development strategy, the door may remain open for those developers focused on different targets within the IDO pathway. Success with epacdostat would have handed Merck a significant advantage over its rivals in the immune checkpoint inhibitor field, but with hundreds of pembrolizumab clinical studies ongoing or in the process of recruiting subjects, Merck remains a strong player in the long game.

The demise of IDO inhibitors (at least for the time being) will move expectation to other “second wave” immuno-oncology drugs, although all are in relatively early stage clinical development. Those catching the interest of oncologists and industry analysts include BMS’s relatlimab, which targets LAG3 (Lymphocyte activation gene 3), a promising immune checkpoint inhibitor expressed on tumour-infiltrating T cells: early studies in melanoma patients have hinted at responses in patients failing to benefit from Opdivo® alone. Recruitment is underway for studies in patients with renal, gastric, lung or colorectal cancers. 

BMS is also evaluating combination with NKTR-214 (Nektar Therapeutics), a protein drug which targets a receptor (CD122) expressed by tumour-infiltrating T cells, in patients with a variety of advanced solid cancers. Pfizer has hopes that utomilumab, an antibody directed against CD137 (4-1BB), a receptor present on a variety of immune cells and also expressed by some tumours, will synergise with anti-PD1 and other immuno-oncology treatments.

There are a variety of possible permutations of established immune checkpoint inhibitors and investigational agents waiting to be explored. Combination therapy has its drawbacks with respect to balancing efficacy and safety and of course cost. In the longer term, it can only be hoped that the current generation of IO drugs will be replaced by next-generation agents able to safely achieve meaningful clinical responses in their own right. 

Photo credit: Pujanak from Wikimedia Commons

Are IDO inhibitors still the next big thing in immuno-oncology?

Metastatic melanoma cells

It's a safe prediction that immuno-oncology (IO) drug development activity is unlikely to diminish in 2018, with a major objective being the validation and approval of agents that synergise with the established anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors.

Much has been written on the broad utility of inhibitors of indoleamine-2,3-dioxygenase-1 (IDO), an intracellular enzyme present in both immune cells and cancer cells and  which regulates tryptophan levels in the tumour microenvironment (TME). 

Depletion of tryptophan by upregulated IDO expression starves cancer-antigen specific T cells, while a rise in the concentration of tryptophan metabolites triggers the development of immunosuppressive Treg cells.

This central role in local immunosuppresion and the prospect of synergy with immune checkpoint inhibitor treatment and other immunotherapies has made IDO (along with a similar enzyme, tryptophan-2,3-dioxygenase 2- TDO)  an attractive target for IO drug development, and a variety of  orally available small molecule inhibitors have entered clinical evaluation as both monotherapy and in combination with immunotherapies or cytotoxic cancer drugs.

Big pharma interest in  IDO and TDO inhibitors has fuelled several “big headline” partnering deals, including  BMS and Flexus Biosciences ($1.25 billon); Roche and CuraDev Pharma ($555m); Roche and NewLink Genetics ($1 billion), and Incyte Pharma and Roche, AstraZeneca, Merck and BMS (undisclosed terms).

 

IDO inhibitor progress has been mixed. In June last year, Roche returned the rights to NewLink's navoximod (GDC-0919), the latter failing to meet any of the primary study objectives (overall survival, progression-free survival or objective response rate) when combined with taxane chemotherapy in breast cancer patients.  Combination with Roche's ant-PD-L1 immune checkpoint inhibitor, Tecentriq® did not achieve an overall response rate better than Tecentriq® alone in patients with advanced solid tumours. Absence of efficacy was cited by iTeos Therapeutics today as the reason for termination of an IDO development partnership with Pfizer following analysis of interim trial data from a Phase I monotherapy study in patients with malignant glioma.

Failure in cancer drug development is, unfortunately, the norm rather than the exception, and it's possible that other IDO inhibitors with different chemistries and better bioavailability may prove capable of either upping the response to immune checkpoint inhibitors or being valuable treatments in their own right. Phase II data from a study of Incyte's epacadostat in combination with anti-PD-1 (Keytruda®) hinted that the combination might prove superior to, and safer than, combined anti-CTLA-4 (Yervoy®) and anti-PD-1 therapy in patients with advanced melanoma. A Phase III study (NCT02752074) is underway in collaboration with Merck, with primary data anticipated around the middle of 2018.

AstraZeneca, a company which could stand some good IO related news, recently expanded its collaboration with  Incyte to include lung cancer studies in combination with the anti-PD-L1 checkpoint inhibitor, Imfinzi®; other companies, including Kyowa Kirin, Jubilant Biosys, Kyn Therapeutics and e-Therapeutics have recently entered the IDO/TDO inhibitor game.

The apparent failure of ITeos's  candidate might not give immediate cause for concern (glioma is a very hard target), but it's reasonable to suppose that there are many fingers crossed in pharma management meetings in the hope that Incyte's Phase III study leads to registration and paves the way for the first small molecule IO treatments.

Photo credit: National Cancer Institute