Biopharmaceutical Report IV
Early-phase melanoma trials testing microbiome approaches that leverage a broad- spectrum antibiotic or microbiome monotherapy before coupling with a checkpoint inhibitor have some advantages over a straight combination approach, experts said. Nevertheless, it is not fully clear which approach will have the edge, with patient diversity likely the ultimate obstacle in demonstrating clinical value, they added.
Several companies have ongoing trials in melanoma with microbiome-focused therapeutics designed to enhance checkpoint inhibitor efficacy. While giving the microbiome therapy and immunotherapy at the same time would make efficacy evaluation cleaner, the approach to either use an antibiotic or the microbiome treatment first are designed to boost proliferation of the introduced bacteria, which may be needed for efficacy, experts explained.
While preclinical data provide theoretical rationale for manipulating gut flora to systemically help the immune system recognise tumours, gut flora differences make it challenging to prove that in a clinical trial setting, experts said. It can be different among patients owing to regional variations and even within each person’s gut, they noted.
Some of the microbiome therapeutics being tested introduce one bacteria type versus a combination of bacterial strains. While the first approach may make it easier to pinpoint what caused any efficacy signals, the combination and ratios of multiple bacterial types may be more critical for efficacy, experts added.
The Phase II (NCT03595683) data on Evelo Biosciences’ (NASDAQ:EVLO) EDP1503 are expected in 2H20, while Phase Ib (NCT03817125) results for Seres Therapeutics (NASDAQ:MCRB) SER-401 are anticipated in 2H20 and Cambridge, Massachusetts- based Vedanta Biosciences’ Phase I/II (NCT04208958) in 2021. 4D Pharma’s (LON:DDDD) Phase I/II trial (NCT03637803) is ongoing and timelines have yet to be disclosed.
Seres’ SER-401 is the only therapeutic under clinical investigation in melanoma only, while the other trials are solid tumour basket studies. It is unclear if melanoma is most susceptible to a microbiome approach, owing to other indications sharing the same neoantigen features that make melanoma ideal for checkpoint inhibition, an expert noted.
Time to allow for bacteria proliferation could be crucial
There is no precedence regarding how microbiome approaches should be administered to improve checkpoint inhibitor efficacy, experts said. One strategy—employed by Seres and Vedanta—involves using an antibiotic prior to treatment with the experimental microbiome therapy combined with an approved checkpoint inhibitor.
Administering vancomycin before the microbiome therapeutic may be necessary, as the antibiotic acts as a reset button in the gut, said Dr Diwakar Davar, medical oncologist, University of Pittsburgh Medical Center, Pennsylvania. The investigator-led Phase Ib trial studying Seres’ SER-401 includes a four-day vancomycin pretreatment before SER- 401 and Bristol-Myers Squibb’s (NYSE:BMY) anti-PD1 Opdivo (nivolumab). Vedanta’s basket Phase I/II trial has a five-day vancomycin pretreatment before VE800/Opdivo.
Administering vancomycin before the microbiome therapeutic may be necessary, as the antibiotic acts as a reset button in the gut
Antibiotic use could make way for the introduced bacterial strains in the microbiome therapeutic to proliferate, added Meenhard Herlyn, director, The Wistar Institute Melanoma Research Center, Philadelphia, Pennsylvania. Without the antibiotic pretreatment, it could be hard to repopulate the gut, noted Steven Fiering, PhD, professor of microbiology and immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
The strategy in the investigator-led Phase II trial of Evelo’s EDP1503 to skip antibiotic pretreatment but administer EDP1503 for two weeks before combining it with Merck’s (NYSE:MRK) anti-PD1 Keytruda (pembrolizumab) may also work, noted Claudia Gravekamp, PhD, associate professor, Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York. This would allow time for bacterial engraftment such that the immune system is triggered systemically before immunotherapy is administered, she said.
4D Pharma’s basket Phase I/II trial administers MRx0518 on the same day as Keytruda. This approach would make it easier to link any observed efficacy to the two therapies, Gravekamp noted. If the microbiome therapy is administered earlier, there is the risk the introduced bacteria would be overpowered by existing gut microbiome, she explained. But administering the microbiome therapy beforehand could allow for stool sample checks to see if the introduced bacteria are successfully proliferating before administering the checkpoint inhibitor, Fiering noted.
A 4D Pharma spokesperson said while stool samples are collected during the trial, MRx0518 is not intended to recolonise the gut microbiome but to directly stimulate the innate immune system and so pretreatment may not be critical. He also pointed to initial six-patient data from the 12-patient part A cohort, which showed two had partial response with evidence of tumour shrinkage and a third had stable disease. The three other companies did not respond to comment request.
4D’s trial also includes renal cell carcinoma, bladder and non-small cell lung cancer (NSCLC). In the part A cohort, two other patients reportedly withdrew due to progressive disease and the sixth withdrew due to a disease-related adverse event.
The 4D study is recruiting anti-PD1 failure patients, and Davar said in such melanoma patients, even a 10–20% overall response rate (ORR) is significant. Yet, ORR would only confirm mechanism rather than lay a foundation for efficacy profiles, he explained. Anti- PD1-refractory patients are also recruited in the Phase II cohort 2 studying Evelo’s therapy. The Vedanta VE800 study limits accrual to patients who have received no more than three lines of prior systemic therapy.
On the other hand, the Phase II cohort 1 studying EDP1503 is recruiting anti-PD1-naïve patients, as is the Phase Ib Seres trial. All four studies have safety and tolerability primary endpoints and ORR as a secondary endpoint, except for the Phase II EDP1503 trial, which has it as a coprimary endpoint.
Gut flora approach has many blind spots
Nevertheless, it is still unclear which microbiome approach is better—boosting a specific bacterial strain’s frequency versus introducing a broad variety of bacteria, Davar said. MRx0518’s Enterococcus gallinarum was selected for its in vitro immunostimulatory profile, with the bacteria’s flagellin shown to be a potent agonist of toll-like receptor 5 (TLR5), the 4D spokesperson said. Evelo’s EDP1503 is derived from a single clone of the Bifidobacterium bacteria. In contrast, Vedanta’s VE800 employs 11 bacterial strains, and Seres’ SER-401 features a variety of gut bacteria derived from melanoma immunotherapy responders.
The upside of introducing a specific bacterial strain is that it sidesteps the risk of unknown bacteria to proliferate, Davar said, adding that the cause of any potential efficacy signal would be clear. However, which specific bacterial strain should be introduced is still up for debate, Fiering noted.
While preclinical data show immunotherapy responders harbour specific bacteria, overall gut flora composition may be more critical than individual strains, Gravekamp said. Preclinical data show a variety of bacteria could cause a cytokine boost, making the immune system better at recognising the tumour, she added. Faecal microbiota transplantation from cancer patients into mice models show this procedure ameliorated antitumour effect of anti-PD1 blockade (Routy, B, et. al, Science. 2018 Jan 5;359(6371):91-97).
But it is challenging to identify the ideal bacterial ratio or gut bacterial composition that each patient should have for efficacy due to the immense variety of bacteria involved, noted Herlyn.
Yet, a wealth of preclinical data show gut bacteria ratio and composition can impact the immune system in a variety of ways, supporting these trials’ exploratory rationale, added Fiering. SER-401 preclinical research demonstrates that response to anti-PD1 is restored in mice with the introduction of bacteria chosen based on in vivo and microbiome signatures, an April 2019 media release states.
There are no severe toxicity concerns with gut flora manipulation based on experience, Fiering added. No therapeutic-related serious adverse events were reported in the first six patients in the Phase I/II MRx0518 trial. Still, gut inflammation, stomach upset or increased inflammatory cytokines in the blood should be monitored, Fiering added.
However, since gut flora is different among patients, each could react differently to the same approach, Gravekamp said. Patient diversity makes it hard to study these therapy options in a controlled environment like clinical trials, Herlyn added. The four aforementioned trials are all US-based. But Herlyn noted there could be regional US gut flora diversity. MRx0518’s mechanism targeting TLR5 may mean that its efficacy may be independent of background microbiota, the 4D spokesperson said.
Another point that needs to be understood further is the bacterial diversity in a patient’s gut, Fiering said. For example, bacteria can reside closer to the gut wall or in the lumen, and the former may be more therapeutically important, he explained.
It is unclear if melanoma would be more susceptible to the microbiome/checkpoint inhibitor approach compared with other solid tumours, Gravekamp said. While melanoma is an ideal target for checkpoint inhibition as such tumours express their own neoantigens, the same could be said for NSCLC and renal cell carcinoma, she added. Seres’ SER-401 is the only therapeutic under clinical investigation in melanoma only.
Seres has a USD 254.8m market cap, while Evelo's and 4D Pharma’s are USD 137.7m and GBP 55.7m (USD 72.3m), respectively.
Reynald Castaneda, prior to moving to London, was a journalist for healthcare newspaper New Zealand Doctor, covering primary care health politics and medical research. He has a BSc in Biological Sciences from the University of Auckland and a postgraduate diploma in journalism from AUT University. Prior to venturing into journalism, Reynald worked as a laboratory technician for Massey University’s Institute of Molecular Biosciences.