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Fecal microbiota potentiate checkpoint inhibitors, unleash microbiome startups Microbiome companies are scrambling for a piece of the action as checkpoint inhibitors combined with fecal microbiome transplants enhance patient responses to .

wo papers published in Science provide the first clinical evidence Tthat fecal microbial transplants (FMTs) can boost the anti-cancer efficacy of inhibitors. At least eight microbiome companies have launched first-in-human trials pairing their microbiome agents with approved (Table 1) to satisfy the growing need to increase the proportion of patients responding to checkpoint inhibitors. “Immune checkpoint inhibitors are terrific,” says Danny Bar-Zohar, global head of development at Merck KGaA in Darmstadt, Germany. “But the vast majority of people still don’t respond.” Various mechanisms may be at play, some related to patient genomics or proteomics, but new data reinforce a role for the gut microbiome in modulating patient response. The two early-stage clinical studies cross-validate each other, says Gal Markel, an immuno-oncologist at Tel Aviv University and a coauthor on the first paper. “It’s very powerful that two independent groups show exactly the same thing.” Both studies took gut microbes from patients with metastatic who had responded to anti–programmed cell death protein 1 Gut bacteria influence patients’ responses to , a finding that has brought a flurry (PD-1) therapy and transplanted them into of studies to test them as combinations. Credit: Steve Gschmeissner/Science Photo Library patients who had never responded or had stopped responding to these drugs. Of ten patients studied in the first paper, three of five patients receiving an FMT from one PD-1 inhibitor treatment. They report were treated with antibiotics to clear donor had an objective response, including that 3 of 16 individuals treated with FMT their existing gut microbiome before one complete response. Of the five who experienced an objective response, including receiving FMT both via colonoscopy received a FMT from the other donor, two 1 complete response, and 3 more had and in oral capsules. In the second study, responded and two had stable disease. durable stable disease. in which patients were treated with In the second paper, a group led by Small differences between the trials make Merck’s checkpoint inhibitor Keytruda researchers from University of Pittsburgh it difficult to draw specific conclusions. In ()—a fully human Ig4κ mAb and the US National Cancer Institute (NCI) the first trial, with ’s that targets PD-1 receptor ligand 1 (PD-L1) describe a two-stage, single-center study of (BMS’s) Opdivo ()—a fully and PD-L2—the researchers avoided concurrent FMT with a checkpoint inhibitor human IgG4 monoclonal antibody (mAb) antibiotics owing to mounting evidence that in patients with melanoma refractory to that targets the PD-1 receptor—patients antimicrobial drugs can negatively impact

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Table 1 | Selected companies with microbiome or microbiome-derived product–checkpoint inhibitor combinations in the clinic Companies Microbiome-based Checkpoint Indication Type of microbiome-based Clinical stage therapy inhibitor intervention 4D Pharma, Merck MRx0518 Keytruda Solid tumors not responding E. gallinarum strain Phase 2 to Keytruda 4D Pharma, Merck MRx0518 Bavencio Locally advanced or E. gallinarum strain Phase 1 KGaA, Pfizer metastatic urothelial carcinoma Enterome EO2401 Opdivo Recurrent glioblastoma Cocktail of microbiome-derived Phase 1b/2a derived peptides with homology to tumor-associated antigens Enterome EO2401 Opdivo Adrenal tumors Cocktail of microbiome-derived Phase 1/2 derived peptides with homology to tumor-associated antigens Genome & GEN-001 Bavencio Solid tumor Enteric-coated capsule Phase 1 Company, Merck encapsulating Lactococcus lactis KGaA and Pfizer Synlogic, Roche SYNB1891 Tecentriq Advanced solid tumors and E. coli Nissle engineered with Phase 1 lymphoma diadenylate cyclase gene and dual dapA and thyA auxotrophies Vedanta Biosciences, VE800 Opdivo Advanced or metastatic 11-strain consortium of Open-label phase 1 BMS cancers non-pathogenic, non-toxigenic, commensal bacterial strains functionally identified as activating CTLs in mice Osel CBM588 Yervoy and Stage IV or advanced renal Clostridium butyricum Phase 1 Opdivo cell carcinoma NuBiyota MET-4 Unnamed Advanced or metastatic solid Bacterial consortium possibly Open-label phase 1 anti-PD-1 or tumors selected by culturing to form a stable -PD-L1 mAb community cancer patients’ survival. The FMT was from melanoma. Subsequently, a team at the that has shown potent activation of effector a single donor and delivered by colonoscopy. University of Chicago led by oncologist lymphocyte populations in the tumor Nonetheless, there are similarities. Thomas Gajewski showed that bacteria from microenvironment. Hassane Zarour, a medical researcher at the a distinct genus, Bifidobacterium, improved Single strains have certain practical University of Pittsburgh Medical Center the efficacy of an anti-PD-L1 agent in mouse advantages over FMTs: they are simpler to Hillman Cancer Center and coauthor of models of melanoma. Another landmark characterize and manufacture. As a result, the second paper, notes that typically fewer paper came in 2018, when researchers led by several drug developers are pursuing this than 10% of patients who fail to respond oncologist Jennifer Wargo at the University route. 4D Pharma, for example, located in initially to anti-PD-1 therapies can become of Texas MD Anderson Cancer Center Leeds, UK, is testing MRx0518, an orally responders. Whereas in his trial 44% of identified the Ruminococcaceae family delivered strain of Enterococcus gallinarum patients responded with at least stable of bacteria as key to a clinical response to that functions as a Toll-like receptor (TLR)-5 disease, and half did so in the other study. anti-PD-1 therapies in humans. agonist, in phase 1/2 trials combined with “It’s not statistical proof, but it’s clearly much Gajewski’s research led to a partnership Keytruda. Interim data announced last year more than expected.” with Evelo Therapeutics, a company that showed the therapy was well tolerated in The notion that gut microbes might launched one of the earliest microbiome– 12 patients with renal cell carcinoma and influence cancer patients’ responses to checkpoint inhibitor combination clinical non-small-cell lung cancer that previously immunotherapy came to light soon after trials, in 2019, testing a single strain had been refractory to immune checkpoint the first checkpoint inhibitor, Keytruda, was of Bifidobacterium animalis lactis both inhibitors. “We’re seeing very similar approved in 2015. At the time, Laurence as a monotherapy and in partnership biology in the tumor post-treatment” Zitvogel, an immunologist and oncologist with Merck’s Keytruda. Evelo, which is compared with what was reported in the at Institut Gustave Roussy, used a mouse developing therapeutics based on both single recent FMT studies, says Alex Stevenson, model to link the commensal bacterial bacterial strains and extracellular vesicles CSO of 4D. Merck and 4D plan to expand strain Bacteroides fragilis with the antitumor derived from them, presented interim trial the cohort to include up 120 patients with immune response seen with cytotoxic data with Merck in December 2020 showing renal cell carcinoma, non-small-cell lung T lymphocyte (CTL) antigen 4 (CTLA- the B. animalis lactis–Keytruda therapy was cancer or other solid tumors that had been 4)-blocking antibodies, and connected safe and well tolerated. Even so, it has since unresponsive to immunotherapy. the strain’s presence in the gut to a clinical shelved the program in favor of EDP1908, In February, 4D announced a partnership response to Yervoy (), an IgG1κ an extracellular vesicle therapy derived from with two other companies, Merck KGaA and mAb against CTLA-4, in patients with an undisclosed Oscillospiraceae species Pfizer, to launch a phase 1 trial for MRx0518

530 Nature Biotechnology | VOL 39 | May 2021 | 529–539 | www.nature.com/naturebiotechnology news in combination with the latter’s Bavencio what you get in the end is change that is (), a human IgG1λ mAb against stable and favorable.” First CAR-T therapy PD-L1. Bavencio is the only immunotherapy The search for simpler more defined to target BCMA gets approved for locally advanced or metastatic products is prompting microbiome urothelial carcinoma, and the trial will test companies to use FMT as a starting point FDA nod the combination as first-line maintenance to discover specific microbial strains for The US Food and Drug Administration therapy in patients with that cancer. The incorporation into a LBP. Ella Therapeutics, (FDA) has approved a chimeric antigen South Korean microbiome outfit Genome of which Markel is scientific cofounder receptor (CAR)-T cell immunotherapy & Company of Seongnam is also testing and chief medical officer, is taking this for the treatment of multiple myeloma. Bavencio with GEN-001, an enteric-coated approach by studying the gut microbiomes The first-in-class BCMA-directed CAR-T capsule containing 1 1011 colony-forming of checkpoint responders. Meanwhile, ≥ × therapy received the agency’s go-ahead units of Lactococcus lactis, identified by Microbiotica of Cambridge, UK, has on 26 March for treating adults with 16S ribosomal RNA profiling of microbiota screened patients whose disease did respond relapsed or refractory multiple myeloma, from lung cancer patients who responded to immunotherapy and has identified nine a hematologic neoplastic disease. The to immunotherapy. The investigators dosed strains that can predict a patient’s response. results from the pivotal phase 2 studies their first patients in a phase 1/1b trial in The resulting microbial signature can be with Abecma (idecabtagene vicleucel) solid tumors last year. used as a biomarker by other companies were published in the New England Transferring whole microbiota— to predict immunotherapy response. The Journal of Medicine. The approval was communities present in stool—to a new defined consortium of nine strains is also based on the KarMMa trial of 127 recipient, however, has a much longer the basis for an LBP, with different bacteria patients, 100 of whom received Abecma, clinical track record than the use of in the mixture promoting specific steps in a genetically modified autologous single microbial strains or live microbial tumor immunity, such as the maturation T cell immunotherapy. Their overall biotherapeutic products (LBPs) consisting of dendritic cells, CTL priming via response rate was 72%, and 28% saw a of defined consortia to intervene in disease. interleukin-12, CTL activation via TLR-3, stringent complete response. Abecma is FMTs are generally safe; they are delivered and CTL tumor cell killing via a T helper 1 a personalized one-time treatment with by colonoscopy or oral formulation and are (T 1)-directed response. H 300–460 × 106 CAR-T cells and comes performed regularly as part of the standard Vedanta Biosciences is also pursuing with a boxed warning that includes of care in other disease areas, like recurrent defined consortia of bacterial strains to toxic hematologic effects and cytokine Clostridioides difficile infection. achieve good colonization in the gut while release syndrome. Thus far, the latest guidance from avoiding the inherent unpredictability of The CAR-T cell therapy, developed the FDA on FMT development is a FMT. The company’s lead agent, VE800—an by partners Bristol Myers Squibb and 2016 document specific to use in the 11-strain combination—is in a phase 1 trial bluebird bio, recognizes and binds treatment of C. difficile infections. In 2019, with BMS’s Opdivo. (BMS made an equity BCMA (B cell maturation antigen), when two immunocompromised FMT investment in Vedanta in conjunction with a cell surface protein that is almost recipients developed invasive infections the trial.) “We can shape response and always expressed on cancer B cells of antibiotic-resistant Escherichia coli, get better colonization, but with a known in multiple myeloma. This restricted it prompted the FDA to require FMT product,” says Bernat Olle, CEO of Vedanta. pattern of expression on plasma cells developers to perform additional screening Not all defined bacterial formulations has made BCMA the antigen of choice for multi-drug-resistant bacteria in their have met with success. Earlier this month, for many myeloma immunotherapies products. This was again updated last Seres Therapeutics announced it will in development, including other April to address an infection risk from be discontinuing a phase 1 trial with CAR-T cells and bispecific antibodies. SARS-CoV-2 in FMTs. As FMTs are BMS at the Parker Institute for Cancer In 2020, an antibody–drug conjugate developed for use in cancer immunotherapy, Immunotherapy and MD Anderson for made by GlaxoSmithKline, Blenrep these products would likely follow along SER-401, a defined consortium of bacterial (belantamab mafodotin), was approved similar lines. spores, in metastatic melanoma with by the FDA and the European According to Giorgio Trinchieri, chief Opdivo. Although the company announced Commission. Blenrep combines a of the Laboratory of Integrative Cancer SER-401 was safe and well-tolerated, it humanized monoclonal antibody specific Immunology at NCI, “They cannot regulate decided to “deprioritize further development for BCMA with a cytotoxic agent that [FMTs] as strictly in terms of composition of SER-401” and pursue other programs. inhibits microtubule polymerization: as they would with any normal biologic.” Rather than rely on consortia of defined monomethyl auristatin. For Bristol And, he says, the variability in product unmodified strains, yet another approach is Myers Squibb, this is the second composition and additional screening to create LBPs using molecular engineering. CAR-T cell therapy approval. The first procedures now required to remove Synlogic’s engineered Escherichia coli Nissle was the CD19-directed agent Breyanzi potential of pathogens from FMT donor strain (SYN1891) is designed to be injected (lisocabtagene maraleucel). BMS and samples is likely to make the development of straight into tumors in a similar fashion to bluebird will jointly market the drug these products more challenging. that pioneered by William Bradley Coley at a list price of $419,500. Trinchieri, who is a coauthor on the more than 130 years ago. SYNB1891 contain FMT paper that eschewed antibiotics, also a diadenylate cyclase gene from Listeria Published online: 12 May 2021 notes that the question of colonization monocytogenes and two other genes—dapA https://doi.org/10.1038/s41587-021-00929-0 adds complexity. Adding a FMT to a (encoding dihydrodipicolinate synthase, preexisting microbiome creates a new involved in lysine biosynthesis) and thyA ecology. “When you give 1 species or (encoding thymidylate synthase, involved 10 or 20 species, you have to be sure that in thymidine biosynthesis)—under the those species colonize in the patient, and control of a promoter that switches on only

Nature Biotechnology | VOL 39 | May 2021 | 529–539 | www.nature.com/naturebiotechnology 531 news in the hypoxic tumor microenvironment. drug or LBP. Synlogic is testing SYNB1891 says. Bacteroides, for one, seem to have a This conditional auxotrophy seeks to limit in phase 1 trials with the anti-PD-L1 positive effect with anti-CTLA-4 therapies replication of SYN1891 to the desired Tecentriq (), an Fc-engineered, but negative effects with anti-PD-1 ones. malignant tissue. Needless to say, such humanized, non-glycosylated IgG1κ mAb “Right now, I won’t say that you can just engineered LBPs—which have never been from Roche targeting PD-L1, and extrapolate from one immune checkpoint encountered by the human body—are likely as a monotherapy in solid tumors inhibitor or one type of tumor to another.” to be given the highest level of scrutiny and lymphoma. Of five published clinical microbiome by the FDA. A final approach is to focus instead studies on checkpoint inhibitor response, According to Richard Riese, Synlogic’s on peptides derived from the microbiota. each report associates different species chief medical officer, the heterologous Enterome, headquartered in Paris and with response: the 2017 paper from Arthur diadenylate cyclase increases levels Cambridge, Massachusetts, is testing Frankel associates Bacteroides caccae; of cyclic dinucleotide 2′,3′ guanosine microbiome-derived peptide antigens, which the Zitvogel 2018 paper, Akkermansia monophosphate–adenosine monophosphate the company says stimulate an immune muciniphila; the Gajewski 2018 paper, (cGAMP), a signaling molecule in response to the tumors, in two phase 1/2 Bifidobacterium longum; the Wargo the STING (stimulator of interferon trials combining Opdivo with EO2401, in 2018 paper, Faecalibacterium sp. and genes) protein pathway that is taken collaboration with BMS. Faecalibacterium prausnitzii; and the Markel up preferentially by antigen-presenting For now, companies and researchers 2021 paper, Enterococcaceae, Enterococcus cells, stimulating CD4+ and CD8+ T cell still have more questions than answers. and Streptococcus australis. ❐ responses. Riese says that other investigators NCI’s Trinchieri says it remains unclear have shown gastrointestinal activation which bacteria are responsible for Mark Zipkin of antitumor immunity, but the effect is therapeutic responses in which patients, for Haddon Township, NJ, USA indirect compared with that of tumor-site which tumors, and on which checkpoint injection; as yet, no one has been able inhibitors. “It’s not so clear that what’s Published online: 16 April 2021 to tap gut mechanisms with a successful good for CTLA-4 is good for PD-1,” he https://doi.org/10.1038/d41587-021-00002-w

AGBIOTECH Armyworm meets Friendly moth

The fall armyworm moth, a pest so named for its caterpillar’s invasive and destructive behavior, may now have to contend with a ‘Friendly’ foe. UK-based Oxitec and agbiotech giant Bayer have jointly developed a genetically modified variety to combat the fall armyworm (Spodoptera frugiperda), an insect pest causing severe destruction to corn, rice and sorghum crops in more than 100 countries. Brazil has approved field trials of the GM ‘Friendly’ fall armyworm moths. The technology, originally developed at Oxford University, uses male self-limiting fall armyworm moths. When males are released into infested areas, the moths mate with wild females, but as they produce no female offspring in the next generation, this reduces the population of crop-eating caterpillars. The approach is species specific, is self-limiting in the environment, and has no impact on beneficial insects such as bees. Oxitec has successfully used the technology with mosquitoes to control dengue and Zika in Brazil, and is currently Natural History Collection / Alamy Stock Photo releasing Friendly mosquitoes in the Florida Keys as part of a US Environmental Protection Agency trial. Though some in addition to rotating crops, encouraging Michael Francisco groups remain opposed to the technology, the growth of a pest’s natural predators, most experts agree that GMOs must be part and using pesticides selectively to mitigate Published online: 12 May 2021 of an integrated pest management solution, resistance buildup. ❐ https://doi.org/10.1038/s41587-021-00932-5

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