Methods and compositions for treating cancer

Abstract

To provide compositions for treating cancer and for predicting a subjects' response to combination checkpoint inhibitor therapy.SOLUTION: Provided is a composition for treating cancer in a subject, the composition comprising at least one isolated or purified population of bacteria belonging to the genus Flavonifractor, wherein the composition is administered to the subject in combination with (i) an inhibitor of PD-1, PDL1, or PDL2, and (ii) an inhibitor of CTLA-4, B7-1, or B7-2.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 770,603, filed November 21, 2018, and U.S. Provisional Patent Application No. 62 / 826,631, filed March 29, 2019, all of which are incorporated herein by reference in their entireties.

[0002] 1. Field of the Invention The present invention relates to the fields of molecular biology and medicine. [Background technology]

[0003] 2. Background Over the past decade, cancer therapy has made great strides through the use of targeted therapy and immunotherapy. By blocking the immunoinhibitory ligand-receptor interaction involving CTLA-4 and PD-1, checkpoint blockade immunotherapy alleviates key inhibitory signals in T lymphocytes, enhancing the underlying T cell-mediated antitumor immune activity. However, ubiquitous systemic alleviation of inhibitory signals can also activate T lymphocytes reactive to self-antigens, leading to loss of self-tolerance and immune-related adverse events. Patients who develop high-grade toxicity generally require temporary or permanent interruption of treatment and may require prolonged and rigorous immunosuppression to manage toxicity. Among various immunotherapy treatment regimens, anti-CTLA-4 and anti-PD-1 combination therapy offers superior response rates compared with the same agents given as monotherapy, but this is offset by a much higher risk of developing severe toxicity. The high incidence of severe, even life-threatening, toxicity in response to anti-CTLA-4 and anti-PD-1 combination therapy is a limiting factor for clinicians in prescribing this form of therapy.

[0004] While several factors have been identified that are associated with patient response to immune checkpoint inhibitor therapy, there is a need in the art for predictors of toxicity resulting from immune checkpoint blockade therapy and predictors of responders to combination immune checkpoint blockade therapy. Stratifying patients into those likely and unlikely to experience toxicity and / or respond to checkpoint blockade therapy based on one or more biomarkers would provide more effective and therapeutic treatments for patients, as patients could be provided with the most effective therapy before their disease spreads further. Summary of the Invention

[0005] Described herein are methods and compositions for treating cancer and predicting a subject's response to combination checkpoint inhibitor therapy.In one aspect, the disclosure provides for the identification of bacteria in the genera or species of: Flavonifractor, Dielma, Akkermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzzerella, Parabacteroides distasonis, Fournierella, Fournierella massiliensis, Eisenbergiella tayi, Tissierellales, Hungateiclostridium thermocellum, Dorea formisigenerans, formicigenerans, Caloramator coolhaasi, Muricomes, Geosporobacter, Prevotella paludivivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter composti, and Anaerotignum lactifermentans lactatifermentans), or one or more of the bacterial species disclosed in FIG. 28C , and further comprising treating the subject with a combination of (i) an inhibitor of PD-1, PDL1, or PDL2, and (ii) an inhibitor of CTLA-4, B7-1, or B7-2.In some embodiments, the composition comprises at least one isolated or purified population of bacteria belonging to one or more of the following genera or species: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercoris, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, Fungatei, Clostridium thermocellum.

[0006] In another aspect, the disclosure relates to methods of treating cancer and / or reducing toxicity of a therapy in a subject, comprising administering to the subject a composition comprising fecal material from a healthy patient, from a patient determined to be responsive to immune checkpoint blockade monotherapy or combination therapy, or from a patient determined to have a non-toxic response to immune checkpoint blockade monotherapy or combination therapy, and further comprising treating the subject with a combination of (i) an inhibitor of PD-1, PDL1, or PDL2 and (ii) an inhibitor of CTLA-4, B7-1, or B7-2. In some embodiments, the fecal material is implanted into the colon or rectum of the subject.

[0007] In another aspect, the disclosure provides for the identification of any of the following genera or species: Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzerellales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prebote 28C, or a composition comprising at least one isolated or purified population of bacteria belonging to one or more of the bacterial species disclosed in FIG. 28C.

[0008] In another aspect, the disclosure relates to a method of treating cancer and / or reducing toxicity to a therapy in a subject, comprising administering to the subject, determined to have a favorable microbial profile in the gut microbiome, a combination of (i) an inhibitor of PD-1, PDL1, or PDL2 and (ii) an inhibitor of CTLA-4, B7-1, or B7-2.

[0009] In another aspect, the disclosure provides a method of predicting response to combination immune checkpoint inhibitor therapy in a subject having cancer, the method comprising: detecting a microbial profile in a sample obtained from the subject; predicting a toxic response to therapy when one or more bacteria from the following genera: Bacteroides, Dialister, Coprobacter, Intestinibacter, and Parasutterella are detected in a sample from the subject; or predicting a non-toxic response to therapy when one or more of the following genera or species of bacteria are detected in a sample from the subject: Bacteroides fragilis, Vampirovibrio, Taizerella, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Muricomes intestini, Geosporobacter, Geosporobacter subterraneus, Anaerotignum lactifermentans. The present invention relates to a method comprising:

[0010] In another aspect, the disclosure relates to a method for predicting response to combination immune checkpoint inhibitor therapy in a subject having cancer, the method comprising detecting a microbial profile in a sample obtained from the subject; predicting a toxic response to the therapy when a favorable microbial profile is detected in the sample from the subject; or predicting a non-toxic response to the therapy when an unfavorable microbial profile is detected in the sample from the subject.

[0011] In some embodiments, the toxic response includes one or more irAEs. In some embodiments, the toxic response includes a grade 3 or higher adverse event. In some embodiments, the toxic response includes one or more of interstitial pneumonitis, colitis, hypothyroidism, liver dysfunction, skin rash, vitiligo, hypophysitis, type 1 diabetes, renal dysfunction, myasthenia gravis, neuropathy, myositis, and uveitis. In some embodiments, the toxic response excludes one or more of interstitial pneumonitis, colitis, hypothyroidism, liver dysfunction, skin rash, vitiligo, hypophysitis, type 1 diabetes, renal dysfunction, myasthenia gravis, neuropathy, myositis, and uveitis. In some embodiments, the irAEs include one or more of interstitial pneumonitis, colitis, hypothyroidism, liver dysfunction, skin rash, vitiligo, hypophysitis, type 1 diabetes, renal dysfunction, myasthenia gravis, neuropathy, myositis, and uveitis. In some embodiments, the method excludes one or more of interstitial pneumonia, colitis, hypothyroidism, liver dysfunction, skin rash, vitiligo, hypophysitis, type 1 diabetes, renal dysfunction, myasthenia gravis, neuropathy, myositis, and uveitis. In some embodiments, the method excludes treatment of colitis and / or excludes patients diagnosed with or having colitis.

[0012] In some aspects, a subject is predicted to be a non-responder to CICB when one or more of Robertkochia marina, Adlerrcreutizia equolifaciens, Lawsonia intracellularis, or Lactobacillus satsumensis is detected in a biological sample from the subject.

[0013] In another aspect, the disclosure includes: (1) first identifying a strain of bacteria, including: Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tysserrella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tysserrellales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides difficile ... The present invention relates to a method of treating cancer in a subject, comprising: (1) administering to the subject a composition comprising an isolated or purified population of bacteria comprising at least one bacterial species belonging to a genus or species selected from the group consisting of Lactobacillus finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactifermentans; and (2) subsequently administering to the subject a combination immunotherapy consisting essentially of (a) an inhibitor of PD-1, PDL1, or PDL2, and (2) an inhibitor of CTLA-4, B7-1, or B7-2. In some embodiments, the isolated or purified population of bacteria comprises at least one bacterial species belonging to the following genus or species: Flavonifractor, Bacteroides, Butyricimonas, Dierma, Ackermansia, Alistipes, Bacteroides stercoris, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, Fungatei, Clostridium thermocellum.

[0014] In another aspect, the disclosure provides a method for predicting response to combination immune checkpoint inhibitor therapy in a subject having cancer, the method comprising: detecting a microbial profile in a sample obtained from the subject; predicting a beneficial response to therapy when one or more of the following genera or species of bacteria are detected in a sample from the subject: Bacteroides stercoris, Butyricimonas, Flavonifractor, Dielma, Alistipes, and Akkermansia muciniphila; or predicting an ineffective response to therapy when one or more of the following genera or species of bacteria are detected in a sample from a subject: Lactobacillus, Bacteroides fragilis, and Prevotella. The present invention relates to a method comprising:

[0015] In another aspect, the disclosure relates to a method for predicting response to combination immune checkpoint inhibitor therapy in a subject having cancer, the method comprising detecting a microbial profile in a sample obtained from the subject; predicting an effective response to the therapy when a favorable profile is detected in the sample from the subject; or predicting an ineffective response to the therapy when an unfavorable profile is detected in the sample from the subject.

[0016] In another aspect, the disclosure provides for the prevention of Bacteroides stercolis, Bacteroides caccae, Bacteroides intestinalis, Diaryster spp., Bacteroides fragilis, Vampirovibrio spp., Taizerella spp., Bacteroides stercolis, Flavonifractor plautii, Butyricimonas faecihominis, Alistipes indistinctus, Dielma fastidiosa, Ackermansia muciniphila, Lactobacillus logosae in a subject. The present invention relates to a method for detecting one or more of Bacteroides rogosae, Bacteroides fragilis, Prevotella copri, and Prevotella shahii.

[0017] In another aspect, the disclosure provides for the prevention of Bacteroides stercolis, Bacteroides caccae, Bacteroides intestinalis, Diaryster spp., Bacteroides fragilis, Vampirovibrio spp., Taizerella spp., Flavonifractor prautii, Dierma fastidiosa, Butyricimonas faesihominis, Alistipes spp., Ackermansia muciniphila, Lactobacillus logosae, Prevotella copri, Prevotella shahii, Citrobacter spp., Clostridium hylemonae, Hungateiclostridium aldrichii, Citrobacter rodentium, Eubacterium sulci, or the like in a subject. sulci, Hafniaceae, Citrobacter freundii, Eubacterium halii, Enterobacter cloacae, Hafnia alvei, Hafnia spp., Roseburia hominis, Weissella paramesenteroides, Enterobacter spp., Bacilli, Lactobacillales, Klebsiella aerogenes, Klebsiella spp., Coprobacter spp., Intestinibacter bartletti, Intestinibacter spp., Parasutterella secunda secunda), Dialister propionicifaciens (Dialisterpropionicifaciens), Parabacteroides distasonis, Fournierera spp., Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes spp., Muricomes intestini, Geosporobacter spp., Geosporobacter subterraneanus, and Anaerotignum lactifermentans, or one or more of the bacterial species disclosed in FIG. 28C.

[0018] In another aspect, the disclosure provides for the detection of Bacteroides stercolis, Bacteroides caccae, Bacteroides intestinalis, Diaryster spp., Bacteroides fragilis, Vampirovibrio spp., Taizerella spp., Bacteroides stercolis, Flavonifracter prautii, Dierma fastidiosa, Ackermansia muciniphila, Lactobacillus logosae, Bacteroides fragilis, Prevotella copri, Prevotella shahii, Firmicutes, Clostridiales, Ruminococcaceae, Alistipes indistinctus, Bacteroides stercorirosoris, Clostridium lactifermentans in a subject. Clostridium lactatifermentans orus, Abyssivirga alkaniphila, Acetatifactor muris, Acetivibrio cellulolyticus, Acetivibrio ethanolgignens, Acholeplasma vituli, Achromobacter deleyi, Acidovorax radices, Adrecluzia aequorifaciens, Ackermansia muciniphila, Alistipes indistinctus, Alistipes obesi, Alistipes putoresinis putredinis, Alistipes senegalensis, Alistipes timonensis, Alkalibacter saccharofermentans, Alkalibaculum bacchi, Allobaculum stercolicanisstercoricanis, Anaerobacterium chartisolvens, Anaerocolumna cellulosilytica, Anaerosporobacter mobilis, Anaerotaenia torta, Anaerotorruncus colihominis, Anaerotorruncus rubiinfantis, Anaerovorax odorimutans, Bacteroides acidifaciens, Bacteroides caecimuris, Bacteroides dorei dorei, Bacteroides faecichinchillae, Bacteroides rodentium, Bacteroides stercolirosolis, Bacteroides xylanolyticus, Barnesiella intestinihominis, Beduini massiliensis, Bifidobacterium pseudolongum, Blautia luti, Breznakia blatticola, Breznakia pachnodae, Butyricicoccus plicaecorum pullicaecorum, Butyrivibrio crossotus, Catabacter hongkongensis, Christensenella massiliensismassiliensis, Christensenella minuta, Christensenella timonensis, Clostridium aerotolerans, Clostridium aldenense, Clostridium alkalicellulosi, Clostridium asparagiforme, Clostridium celerecrescens, Clostridium cellobioparum, Clostridium cellulolyticum, Clostridium clariflavum, Clostridium cochleatum cocleatum, Clostridium colinum, Clostridium hylemonae, Clostridium indolis, Clostridium jejuense, Clostridium lactifermentans, Clostridium lavalense, Clostridium methylpentosum, Clostridium oroticum, Clostridium oryzae, Clostridium papyrosolvens, Clostridium polysaccharolyticum, Clostridium populeti, Clostridium saccharolyticum saccharolyticum), Clostridium saudiensesaudiense, Clostridium scindens, Clostridium straminisolvens, Clostridium viride, Clostridium xylanolyticum, Coprobacter secundus, Coprococcus catus, Culturomica massiliensis, Defluviitalea saccharophila, Desulfitobacterium hafniense, Desulfitobacterium metallireducens metallireducens, Desulfosporosinus orientis, Desulfovibrio desulfuricans, Desulfovibrio simplex, Dorea formisigenerans, Eisenbergiella massiliensis, Emergencia timonensis, Enterococcus hirae, Enterorhabdus mucosicola, Enterorhabdus muris, Erysipelatoclostridium ramosum, Erysipelothrix larvae larvae, Escherichia fergusonii, Eubacterium coprostanoligenes, Eubacterium dorichumdolichum, Eubacterium ruminantium, Eubacterium siraeum, Eubacterium tortuosum, Eubacterium ventriosum, Faecalibaculum rodentium, Flavimarina pacifica, Flavonifracter platii, Flintibacter butyricus, Gordonibacter faecihominis, Gracilibacter thermotolerans, Harryflintia acetispora acetispora, Holdemania massiliensis, Hydrogenoanaerobacterium saccharovorans, Ihubacter massiliensis, Intestinimonas butyriciproducens, Irregularibacter muris, Lachnoclostridium pacaense, Lactobacillus animalis, Lactobacillus faecis, Lactobacillus gasseri, Lactobacillus hominis hominis, Lactobacillus intestinalis, Lactobacillus johnsonii, Lactobacillus reuterireuteri, Lactobacillus logosae, Lactobacillus taiwanensis, Lawsonia intracellularis, Longibaculum muris, Marvinbryantia formatexigens, Millionella massiliensis, Mucispirillum schaedleri, Muribaculum intestinale, Murimonas intestini, Natranaerovirga pectinivora, Neglecta timonensis, Odoribacter plankunnis splanchnicus, Olsenella profusa, Oscillibacter ruminantium, Oscillibacter valericigenes, Papillibacter cinnamivorans, Parabacteroides goldsteinii, Paraeggerthella hongkongensis, Parasutterella excrementihominis, Parvibacter caecicola, Peptococcus niger, Phocea massiliensis massiliensis, Porphyromonas catoniae, Prevotella oralis, Prevotella stercoreastercorea, Prevotellamassilia timonensis, Pseudobutyrivibrio ruminis, Pseudoflavonifractor capillosus, Pseudoflavonifractor phocaeensis, Raoultibacter timonensis, Rhizobium straminoryzae, Roseburia faecis, Roseburia hominis, Roseburia intestinalis, Ruminiclostridium thermocellum thermocellum, Ruminococcus champanellensis, Ruminococcus faecis, Ruminococcus flavefaciens, Ruminococcus gnavus, Ruthenibacterium lactatiformans, Sphingomonas kyeonggiensis, Spiroplasma velocicrescens, Sporobacter termitidis, Stomatobaculum longum, Streptococcus acidominimus acidominimus, Streptococcus danieliae, Syntrophomonas wolfei, Tepidimonas taiwanensistaiwanensis), Tindallia californiensis, Tindallia texcoconensis, Turicibacter sanguinis The present invention relates to a method for detecting one or more of the following bacteria: Pseudomonas uinis, Turicimonas muris, Tyzzerella nexilis, Vallitalea pronyensis, and Vampirovibrio chlorellavorus.

[0019] In another aspect, the disclosure relates to a composition comprising at least one isolated or purified population of bacteria belonging to one or more of the following genera or species: Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzzierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactatifermentans.

[0020] In some embodiments, the composition comprises at least one isolated or purified population of bacteria belonging to one or more of the following genera or species: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercoris, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, Fungatei, Clostridium thermocellum.

[0021] In another aspect, the disclosure relates to a composition comprising an isolated or purified population of at least two bacteria belonging to one or more of the following genera or species: Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzzierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactatifermentans. In some embodiments, the composition comprises at least two isolated or purified populations of bacteria belonging to one or more of the following genera or species: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercoris, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, Fungatei, Clostridium thermocellum.

[0022] In another aspect, the disclosure provides for the detection of Parabacteroides distasonis, Fournierera spp., Fournierera massiliensis, Eisenberghiella tai, Tissierales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes spp., Geosporobacter spp., Prevotella parsidivens, Lactobacillus secariphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, Flavonifractor spp., Bacteroides spp., Butyricimonas spp., Dielma spp., Ackermansia spp., Alistipes spp., Anaerotignum lactifermentans, Ba Cteroides coprophilus, Bacteroides stercolis, Bacteroides caccae, Bacteroides intestinalis, Diaryster spp., Bacteroides fragilis, Vampirovibrio spp., Taiserella spp., Bacteroides stercolis, Flavonifracter prautii, Dielma fastidiosa, Ackermansia muciniphila, Lactobacillus logosae, Bacteroides fragilis, Prevotella copri, Prevotella shahii, phylum Firmicutes, order Clostridiales, family Ruminococcaceae, Alistipes indistinctus, Bacteroides stercolirosolis, Clostridium lactifermentans Orus, Abyssibirga alcaniphila, Acetiviflora muris, Acetivibrio cellulolyticus, Acetivibrio ethanolguignens, Acholeplasma vitulis, Achromobacter derayi, Acidovorax radices, Adrecluzia aequorifaciens, Ackermansia muciniphila, Alistipes indistinctus, Alistipes obesi, Alistipes putoreginis, Alistipes senegalensis, A Ristipes timonensis, Alcalibacter saccharofermentans, Alcalibacter bacchii, Alcalibacter stercolicanis, Anaerobacterium chalcisorbens, Anaerocorumna cellulosilitica, Anaerosporobacter mobilis, Anaerotaenia torta, Anaerotoruncus corihominis, Anaerotoruncus rubiinfantis, Anaerovorax odrimtans, Bacteroides acidifaciens,Bacteroides caecimulus, Bacteroides dorei, Bacteroides faesiquinchirae, Bacteroides rodentium, Bacteroides stercolirosolis, Bacteroides xylanolyticus, Barnesiella intestinihominis, Beduini massiliensis, Bifidobacterium pseudolongum, Blautia luci, Bresnakia bratticola, Bresnakia pachinodae, Butyricoccus plicaecorum, Butyrivibrio crossotus, Catabacter hongkongenesis, Christensenella massiliensis, K. Listensenera minuta, Listensenera timonensis, Clostridium aerotolerans, Clostridium ardenense, Clostridium alkalicellulosi, Clostridium asparagiforme, Clostridium cererecrescens, Clostridium cellobiopalum, Clostridium cellulolyticum, Clostridium clariflavum, Clostridium cochleatum, Clostridium corinum, Clostridium hylemonae, Clostridium indris, Clostridium jejuense, Clostridium Clostridium lactifermentans, Clostridium labarens, Clostridium methylpentosum, Clostridium oroticum, Clostridium oryzae, Clostridium papyrosolvens, Clostridium polysaccharolyticum, Clostridium popleci, Clostridium saccharolyticum, Clostridium saudiens, Clostridium saindens, Clostridium straminisorbens, Clostridium viride, Clostridium xylanolyticum, Coprobacter secundus, Copro Coccus catus, Curturomica massiliensis, Defluviitarea saccharophila, Desulfitobacterium hafniens, Desulfitobacterium metallireducens, Desulfosporosinus orientis, Desulfovibrio desulfuricans, Desulfovibrio simplex, Dorea formisigenerans, Eisenberghiella massiliensis, Emergencia timonensis, Enterococcus hirae, Enterorhabdus mucosicola, Enterorhabdus muris, Erysipelothrix clostridium ramosum,Erysipelothrix larvae, Escherichia fergusonii, Eubacterium coprostanoligenes, Eubacterium doricum, Eubacterium ruminantium, Eubacterium silaeum, Eubacterium tortuosum, Eubacterium ventriosum, Faecalibaculum rodentium, Flavimarina pacifica, Flavonifractor prautii, Flinchibacter butyricus, Gordonibacter faesihominis, Gracilibacter thermotolerans, Harryflintia acetispora, Hordemannii Lactobacillus massiliensis, Hydrogenoanaerobacterium saccharovorans, Ifubacter massiliensis, Intestinimonas butyriciproducens, Irregularibacter muris, Lachnoclostridium pacaceans, Lactobacillus animalis, Lactobacillus faeces, Lactobacillus gasseri, Lactobacillus hominis, Lactobacillus intestinalis, Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus logosae, Lactobacillus taiwanensis, Lawsonia intracellularis, Ron Gibaculum muris, Malvinbrianchia formatexigens, Millionella massiliensis, Mucispirillum scaedreri, Mulibacrum intestinale, Murimonas intestini, Natlanaerovirga pectinivora, Neglecta timonensis, Odoribacter plankunix, Orsenella profusa, Oscillibacter ruminantium, Oscillibacter valericigenes, Papilibacter cinnamivorans, Parabacteroides gordosteinii, Paraeggertella hongkongenesis, Parasterella exclementi hominis, Parvibacter caesicola, Peptococcus niger, Phocea massiliensis, Porphyromonas catoniae, Prevotella oralis, Prevotella stercorea, Prevotella massilia timonensis, Pseudobutyrivibrio ruminis, Pseudoflavonifractor capillosus, Pseudoflavonifractor hocaensis, Raoultibacter timonensis, Rhizobium straminorhizae, Roseburia faeces, Roseburia hominis, Roseburia intestinalis, Ruminiclostridium thermocellum,Ruminococcus champanerensis, Ruminococcus faeces, Ruminococcus flavefaciens, Ruminococcus gnavus, Rutenibacterium lactatiformans, Sphingomonas kieongiensis, Spiroplasma velocyclescens, Sporobacter thermitizis, Stomatobaculum longum, Streptococcus acidominimus, Streptococcus danieriae, Syntrohomonas wolfei, Tepizimonas ta and / or Vampirovibrio chlorellavorus.

[0023] In some embodiments, the composition comprises, or further comprises, at least one isolated or purified population of bacteria belonging to one or more of the following species: Bacteroides flavonifractor, Bacteroides stercolis, Butyricimonas faesihominis, Dielma, Ackermansia, and Alistipes indistatus. In some embodiments, the composition excludes Bacteroides stercoli. In some embodiments, the composition comprises, or further comprises, at least one isolated or purified population of bacteria belonging to one or more of the genera Dielma and Ackermansia. In some embodiments, the composition comprises, or further comprises, at least one isolated or purified population of bacteria belonging to one or more of the genera Alistipes, Dielma, and Ackermansia. In some embodiments, the composition comprises, or further comprises, at least one isolated or purified population of bacteria belonging to the genus Ackermansia. In some embodiments, the composition comprises or further comprises at least one isolated or purified population of Ackermansia muciniphila. In some embodiments, the composition comprises or further comprises a population of bacteria including one or more of Ackermansia muciniphila and Dierma fastidiosa, as well as Alistipes indistinctus. In some embodiments, the bacteria of the genus Flavonifractor comprises Flavonifractor plautii. In some embodiments, the composition comprises or further comprises at least one isolated or purified population of bacteria belonging to one or more of the following genera or species: Bacteroides fragilis, Vampyrovibrio, Taizerella, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Muricomes intestini, Geosporobacter, Geosporobacter subterraneus, and Anaerotignum lactatifermentans. In some embodiments, the composition comprises or further comprises at least one isolated or purified population of Bacteroides intestinalis. In some embodiments, the composition comprises or further comprises at least one isolated or purified population of bacteria belonging to the phylum Firmicutes, the order Clostridiales, and the family Ruminococcaceae.In some embodiments, the composition includes or further comprises Flavonifractor plautii and / or Dielma fastidiosa. In some embodiments, the composition includes or further comprises Bacteroides stercoris, Butyricimonas faesihominis, Flavonifractor plautii, Dielma fastidiosa, Alistipes indistinctus, and Ackermansia muciniphila.

[0024] In some embodiments, the composition comprises 1×10 5 , 1×10 4 , 1×10 3 , or 1 × 10 2 In some embodiments, the composition comprises less than 1 x 10 CFU or cells of bacteria classified as Firmicutes, Clostridiales, and Ruminococcaceae. 5 , 1×10 4 , 1×10 3 , or 1 × 10 2 Less than (or any derivable range therein) CFU or cells of bacteria belonging to the following families: Ruminococcus, Clostridiaceae, Lachnospiraceae, Micrococcaceae, and / or Veilonellaceae.

[0025] In some aspects, the cancer is skin cancer. In some aspects, the cancer is basal cell skin cancer, squamous cell skin cancer, melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, keratoacanthoma, spindle cell tumor, sebaceous gland carcinoma, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, or angiosarcoma. In some aspects, the cancer is melanoma. In some aspects, the melanoma is metastatic melanoma, lentigo maligna, lentigo maligna-derived melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, cutaneous melanoma, or desmoplastic melanoma. In some aspects, the cancer includes cutaneous melanoma.

[0026] In some embodiments, the cancer includes recurrent cancer. In some embodiments, the cancer includes recurrent metastatic cancer. In some embodiments, the cancer includes cancer recurrence in the area of ​​the primary tumor. In some embodiments, the cancer includes metastatic cancer. In some embodiments, the cancer includes stage III or IV cancer. In some embodiments, the cancer includes stage I or II cancer. In some embodiments, the cancer excludes stage I or II cancer.

[0027] In some embodiments, the method further comprises administering at least one additional anti-cancer treatment. In some embodiments, the at least one additional anti-cancer treatment is surgical therapy, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, small molecule therapy, receptor kinase inhibitor therapy, anti-angiogenic therapy, cytokine therapy, cryotherapy, or biological therapy. In some embodiments, the additional anti-cancer treatment comprises a cancer treatment described herein.

[0028] In some embodiments, (i) the inhibitor of PD-1, PDL1, or PDL2, (ii) the inhibitor of CTLA-4, B7-1, or B7-2, and / or at least one additional anti-cancer treatment is administered intratumorally, intraarterially, intravenously, intravascularly, intrapleurally, intraperitoneally, intratracheally, intrathecally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, topically, stereotactically, orally, or by direct injection or perfusion. In some embodiments, the route of administration is a route described herein.

[0029] In some embodiments, the method is defined as a method of treating cancer in a subject diagnosed with cancer. In some embodiments, the method comprises or further comprises reducing or preventing one or more adverse events. In some embodiments, the method comprises or further comprises reducing or preventing one or more severe adverse events. In some embodiments, treating cancer comprises reducing or preventing one or more severe adverse events. In some embodiments, the method is for reducing the toxicity of immunotherapy, such as combination immune checkpoint blockade therapy. In some embodiments, reducing toxicity comprises reducing adverse events. In some embodiments, the adverse events or severe adverse events are further classified as immune-related adverse events. In some embodiments, the method comprises preventing or reducing immune-related adverse events. In some embodiments, the adverse events are classified as severe adverse events. In some embodiments, adverse events of grade 3 or higher are prevented. The grade of the adverse events is scored by methods known in the art, such as, for example, scoring based on the NCI Common Terminology Criteria for Adverse Events (CTCAE).

[0030] In some embodiments, a subject has been determined to have an unfavorable microbial profile in their gut microbiome. In some embodiments, the unfavorable profile comprises a population of bacteria including bacteria belonging to one or more of the following genera: Bacteroides, Dialister, Coprobacter, Intestinibacter, and Parasterella. In some embodiments, the unfavorable profile comprises a population of bacteria including one or more of Bacteroides stercoris, Bacteroides caccae, Bacteroides intestinalis, Coprobacter, Intestinibacter bartoletti, Parasterella secunda, and Dialister propionicifaciens. In some embodiments, the unfavorable profile comprises Erysipellatoclostridium ramosum. In some embodiments, the unfavorable profile comprises a population of bacteria including bacteria belonging to one or more of the following genera: Lactobacillus, Bacteroides, Prevotella, Citrobacter, Clostridium, Fungatei, Clostridium, Eubacterium, Hafniaceae, Enterobacter, Hafnia, Roseburia, Weissella, Bacillaceae, Lactobacillales, and Klebsiella. In some embodiments, the unfavorable profile comprises a population of bacteria including one or more of Lactobacillus logosae, Bacteroides fragilis, Prevotella copri, and Prevotella shahii. In some embodiments, the unfavorable profile includes one or more of Prevotella copri, Prevotella shahii, Butyrivibrio, Blautia hydrogenotrophica, Bacteroides fragilis, Butyrivibrio corssotus, Lactobacillales, Lactobacillus, Lactobacillaceae, Lactobacillus logosae, Clostridium saccharagumia, and Megasphaera massiliensis.In some embodiments, the unfavorable profile is Citrobacter spp., Clostridium hylemonae, fungatei, Clostridium aldritii, Citrobacter rodentium, Eubacterium sursi, Hafniaceae, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Hafnia spp., Roseburia hominis, Weissella paramesenteroides, Enterobacter spp., Bacillales, Lactobacillales, Klebsiella aerogenes, Klebsiella spp., Bacteroides intestinalis, Coprobacter spp., Intestinibacter barthii, The unfavorable profile may comprise at least, at most, or exactly one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen (or any derivable range therein) of Lactobacillus rettii, Intestinibacter sp., Parasterella secunda, Diaryster propionicifaciens, Prevotella copri, Prevotella shahii, Butyrivibrio sp., Blautia hydrogenotrophica, Bacteroides fragilis, Butyrivibrio colussotus, Lactobacillales, Lactobacillus sp., Lactobacillaceae family, Lactobacillus logosae, Clostridium saccharomyces, and Megasphaera massiliensis. In some embodiments, the unfavorable profile is further classified as a non-responsive or ineffective profile. A non-responsive profile refers to a microbial profile present in a subject, particularly the gut of a subject, that is non-responsive to combination immune checkpoint blockade therapy.In some embodiments, the non-responsive profile is selected from the group consisting of Citrobacter spp., Clostridium hylemonae, fungatei, Clostridium aldritii, Citrobacter rodentium, Eubacterium sursi, Hafniaceae, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Hafnia, Roseburia hominis, Weissella paramesenteroides, Enterobacter spp., Lactobacillus logosae, Bacillales, Lactobacillales, Klebsiella aerogenes, Klebsiella spp., Prevotella coprilans, and the like. li, Prevotella shahii, Butyrivibrio spp., Blautia hydrogenotrophica, Bacteroides fragilis, Butyrivibrio colussotus, Lactobacillales, Lactobacillus, Lactobacillaceae, Lactobacillus logosae, Clostridium saccharomyces, and Megasphaera massiliensis. In some embodiments, the unfavorable profile includes one or more of Bacteroides stercoris, Bacteroides caccae, Negativicutes, Bacteroides intestinalis, Clostridium species, Clostridium clostridioforme, and Diarrister species. In some embodiments, the unfavorable profile includes at least, at most, or exactly one, two, three, four, five, six, or seven (or any derivable range therein) of Coprobacter spp., Intestinibacter bartoli, Intestinibacter spp., Parasterella secunda, Dialister propionicifaciens, Bacteroides stercoris, Bacteroides caccae, Negatiwicki, Bacteroides intestinalis, Clostridium spp., Clostridium clostridioforme, and Dialister spp. In some embodiments, the unfavorable profile is further classified as a toxicity-associated profile.A toxicity-associated profile refers to a microbial profile in a subject, particularly the gut of a subject, that is present in a subject who experiences toxicity in response to combination immune checkpoint blockade therapy. In some embodiments, a non-responsive profile includes at least, at most, or exactly one, two, three, four, five, six, or seven (or any derivable range therein) of Bacteroides stercoris, Bacteroides caccae, Negatiwicki, Bacteroides intestinalis, Clostridium species, Clostridium clostridioforme, and Diarrister.

[0031] In some embodiments, the compounds of the present invention include Citrobacter, Clostridium hilemonae, fungatei, Clostridium aldrizii, Citrobacter rodentium, Eubacterium sulci, Hafniaceae, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Hafnia, Roseburia hominis, Weissella paramesenteroides, Enterobacter, Lactobacillus logosae, Bacillus subtilis ... Bacteria belonging to the following genus or species were determined to be at least 10% in relative abundance: Ralstonia, Lactobacillales, Klebsiella aerogenes, Klebsiella, Bacteroides intestinalis, Coprobacter, Intestinibacter bartoli, Intestinibacter, Parasterella secunda, Diaryster propionicifaciens, Bacteroides, Diaryster, Lactobacillus, and / or Prevotella. The term relative abundance is the percentage of a particular type of organism relative to the total number of organisms in an area, such as a sample from a subject. In some embodiments, the compounds of the present invention are selected from the group consisting of Citrobacter, Clostridium hilemonae, fungatei, Clostridium aldritii, Citrobacter rodentium, Eubacterium sulci, Hafniaceae, Citrobacter freundii, Eubacterium harii, Enterobacter cloacae, Hafnia alvei, Hafnia, Roseburia hominis, Weissella paramesenteroides, Enterobacter, Lactobacillus logosae, Bacillales, Lactobacillales, Klebsiella aerogenes, Klebsiella, Bacteroides Bacteria belonging to the genus or species Ides intestinalis, Coprobacter, Intestinibacter bartoli, Intestinibacter, Parasterella secunda, Diarrister propionicifaciens, Diarrister, Lactobacillus, Bacteroides, and / or Prevotella were determined to be present at a relative abundance of at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).In some embodiments, the compounds of the present invention are selected from the group consisting of Citrobacter spp., Clostridium hylemonae, fungatei, Clostridium aldritii, Citrobacter rodentium, Eubacterium sulci, Hafniaceae, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Hafnia spp., Roseburia hominis, Weissella paramesenteroides, Enterobacter spp., Lactobacillus logosae, Bacillales, Lactobacillales, Klebsiella aerogenes, Klebsiella spp., Bacteroides indicus ... The combined relative abundance of bacteria classified as one or more of the genera P. testinalis, Coprobacter spp., Intestinibacter bartoli, Intestinibacter spp., Parasterella secunda, Diarrister propionicifaciens, Diarrister spp., Lactobacillus spp., Bacteroides spp., and / or Prevotella spp. was determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Bacteroides is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Diaryster is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Lactobacillus is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Prevotella is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).

[0032] In some aspects, the methods further comprise comparing the microbial profile determined in the sample from the patient to a control sample, which may be a microbial profile derived from a sample taken from a patient who is a non-responder, a responder, who experienced toxicity, or who did not experience toxicity to the combination immune checkpoint blockade therapy.

[0033] In some embodiments, the subject is determined to have or be determined to have an unfavorable microbial profile by analyzing the microbiome of a sample from the subject.In some embodiments, the sample is a fecal sample or a buccal sample.In some embodiments, the analysis comprises performing 16S ribosomal sequencing and / or metagenomics whole genome sequencing.

[0034] In some embodiments, the subject has previously received treatment for cancer. In some embodiments, the subject has been determined to be a non-responder to the previous treatment. In some embodiments, the patient has been determined to have had a toxic response to the previous treatment. In some embodiments, the previous treatment comprises immune checkpoint blockade monotherapy or immune checkpoint blockade combination therapy. In some embodiments, the previous treatment comprises immune checkpoint blockade monotherapy comprising only one of an inhibitor of PD-1, PDL1, PDL2, CTLA-4, B7-1, or B7-2. In some embodiments, the combination immune checkpoint blockade therapy comprises a combination of (i) an inhibitor of PD-1, PDL1, or PDL2 and (ii) an inhibitor of CTLA-4, B7-1, or B7-2. In some embodiments, (i) is a PD-1 antibody, and / or inhibitor (ii) is a CTLA-4 inhibitor. In some embodiments, (i) is an anti-PD-1 monoclonal antibody and / or (ii) is an anti-CTLA-4 monoclonal antibody. In some embodiments, (i) comprises nivolumab, pembrolizumab, or pidilizumab. In some embodiments, (ii) comprises ipilimumab or tremelimumab. In some embodiments, the subject has not previously been treated with immune checkpoint blockade monotherapy or combination immune checkpoint blockade therapy.

[0035] In some embodiments, the subject is treated with the isolated population of bacteria prior to or concurrently with the treatment in (i) and (ii). In some embodiments, the subject is treated with the isolated population of bacteria after the treatment in (i) and (ii). In some embodiments, the treatment with the microbial composition occurs at least or at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 24 hours, or 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, 4, 5, or 6 weeks (or any derivable range therein) before or after the treatment with the inhibitor of (i) and (ii). In some embodiments, the treatment with the microbial composition occurs within at least or at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 24 hours, or 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, 4, 5, or 6 weeks (or any derivable range therein) of the treatment with the inhibitors of (i) and (ii).

[0036] In some embodiments, the purified population of bacteria includes bacteria from at least two genera or species, and the ratio of the two bacteria is 1: 1. In some embodiments, the purified population of bacteria includes bacteria from at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 20, 30, 40, or 50 (or any derivable range therein) different families, genera, or species of bacteria. In some embodiments, the ratio of bacteria of one family, genus, or species to bacteria of another family, genus, or species present in the composition is at least, at most, or exactly 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, 1:100, 1:150, 1:200, 1:250, 1:300, 1:350, 1:400, 1:450, 1:500, 1:600, 1:700, 1:800, 1:95 :900, 1:1000, 1:1500, 1:2000, 1:2500, 1:3000, 1:3500, 1:4000, 1:4500, 1:5000, 1:1550, 1:6000, 1:6500, 1:7000, 1:7500, 1:8000, 1:8500, 1:9000, 1:9500, 1 :10000, 1:1200, 1:14000, 1:16000, 1:18000, 1:20000, 1:30000, 1:40000, 1:50000, 1:60000, 1:70000, 1:80000, 1:90000, or 1:100000 (or a derivable range therein).

[0037] In some embodiments, the composition provides an alpha diversity that is at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. Methods for calculating alpha diversity are known in the art. For example, the taxonomic alpha diversity of a sample can be estimated using the inverse of Simpson's index, as described in Example 1. In some embodiments, the composition is administered in an effective amount. In some embodiments, an effective amount comprises an amount that provides an alpha diversity in a subject that is at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 (or any derivable range therein).

[0038] In some embodiments, the number of bacteria belonging to the genus or species of Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzzerellales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactifermentans is at least, at most, or exactly 1 x 10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 , or 1 × 10 16In some embodiments, the bacteria belonging to the genus or species of Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercolis, Parabacteroides distasonis, Fourniella, Fourniella massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierellales, Fungatei, Clostridium thermocellum are administered in an amount of at least, at most, or exactly 1 x 10 cells or CFU (or any derivable range therein). 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 , or 1 × 10 16 In some embodiments, the total amount of bacteria administered is at least, at most, or exactly 1 x 10 cells or CFU (or any derivable range therein). 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 , or 1 × 10 16 In some embodiments, a particular amount of bacteria, such as a particular species of bacteria, is at least, at most, or exactly 1 x 10 cells or CFU (or any derivable range therein). 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7, 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 , or 1 × 10 16 In some embodiments, the composition may contain at least, at most, or exactly 1 x 10 cells or CFU (or any derivable range therein) from a bacterial phylum, family, genus, or species described herein. 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 , or 1 × 10 16 In some embodiments, the composition may contain at least, at most, or exactly 1 x 10 cells or CFU (or any derivable range therein) from a bacterial phylum, family, genus, or species described herein. 6 , 1×10 5 , 1×10 4 , 1×10 3 , or 1 × 10 2 The antibody may contain less than 100 cells or CFU (or any derivable range therein).

[0039] In some embodiments, the method further comprises administering an antibiotic. In some embodiments, the antibiotic may be a broad-spectrum antibiotic. In some embodiments, a mixture of at least 1, 2, 3, 4, or 5 antibiotics is administered. In some embodiments, the antibiotics include ampicillin, streptomycin, and colistin, and combinations thereof. In some embodiments, the antibiotic is administered prior to the composition comprising at least one isolated or purified population of bacteria. In some embodiments, the antibiotic is administered simultaneously with the composition comprising at least one isolated or purified population of bacteria. In some embodiments, the antibiotic is administered at least or at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 24 hours, or 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, 4, 5, or 6 weeks (or any derivable range therein) before or after the microbial composition.

[0040] In some embodiments, a preferred profile comprises a population of bacteria including bacteria belonging to one or more of the genera Bacteroides, Vampirovibrio, and Teisserella. In some embodiments, a preferred profile comprises a population of bacteria including one or more of Bacteroides fragilis, Vampirovibrio, Teisserella, Dorea formisigenerans, Caloramater kurhaasi, Muricomes, Muricomes intestini, Geosporobacter, Geosporobacter subterraneus, and Anaerotignum lactifermentans. In some embodiments, a preferred profile comprises bacteria from one or more of the phyla Firmicutes, order Clostridiales, and family Ruminococcaceae at a relative abundance of less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%. In some embodiments, the preferred profile is Parabacteroides distasonis, Fournierera spp., Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes spp., Muricomes intestini, Geospora bacter, Geospora bacter subterraneanus, Anaerotignum laevigata, lactifermentans, Bacteroides fragilis, Vampirovibrio spp., Taizerella spp., Ackermansia muciniphila, Bacteroides stercolis, Dielma fastidiosa, Phylum Firmicutes, Order Clostridiales, Family Ruminococcaceae, Flavonifracter prautii, Alistipes indistinctus, Ackermansia muciniphila, Bacteroides stercolirosolis, Clostridium lactifermentans Orus, Abyssibirga alcaniphila, Acetiviflora muris, Acetivibrio cellulolyticus, Acetivibrio ethanolguignens, Acholeplasma vitulis, Achromobacter derayi, Acidovorax radices, Adrecluzia aequorifaciens, Ackermansia muciniphila, Alistipes indistinctus, Alistipes obesi, Alistipes putoreginis, Alistipes senegalensis,Alistipes timonensis, Alcalibacter saccharofermentans, Alcalibacter bacchii, Alcalibacter stercolicanis, Anaerobacterium chalcisorbens, Anaerocorumna cellulosilitica, Anaerosporobacter mobilis, Anaerotaenia torta, Anaerotoruncus corihominis, Anaerotoruncus rubiinfantis, Anaerovorax odrimtans, Bacteroides acidifaciens, Bacteroides caesimulis, Bacteroides dorei, Bacteroides faesicinki lae, Bacteroides rodentium, Bacteroides stercolirosolis, Bacteroides xylanolyticus, Barnesiella intestinihominis, Beduini massiliensis, Bifidobacterium pseudolongum, Blautia luci, Bresnakia bratticola, Bresnakia pachinodae, Butyricoccus plicaecorum, Butyrivibrio crossotus, Catabacter hongkongenesis, Christensenella massiliensis, Christensenella minuta, Christensenella timonensis, Clostridium aerotre Lance, Clostridium ardenense, Clostridium alkalicellulosi, Clostridium asparagiforme, Clostridium cererecrescens, Clostridium cellobiopalum, Clostridium cellulolyticum, Clostridium clariflavum, Clostridium cochleatum, Clostridium corinum, Clostridium hylemonae, Clostridium indris, Clostridium jejuense, Clostridium lactifermentans, Clostridium labarens, Clostridium methylpentosum, Clostridium oroticum, Clostridium oryzae, Clostridium papyrosolvens, Clostridium polysaccharolyticum, Clostridium popleci, Clostridium saccharolyticum, Clostridium saudiens, Clostridium saindens, Clostridium straminisorbens, Clostridium viride, Clostridium xylanolyticum, Coprobacter secundus, Coprococcus catus, Curturomica massiliensis, Defluviitarea saccharophila,Desulfitobacterium hafniens, Desulfitobacterium metallireducens, Desulfosporosinus orientis, Desulfovibrio desulfuricans, Desulfovibrio simplex, Dorea formisigenerans, Eisenberghiella massiliensis, Emergencia timonensis, Enterococcus hirae, Enterorrhabdus mucosicola, Enterorrhabdus muris, Erysipelothrix ramosum, Erysipelothrix larvae, Escherichia fergusonii, Eubacterium coprophaga rostanoligenes, Eubacterium doricum, Eubacterium ruminantium, Eubacterium silaeum, Eubacterium tortuosum, Eubacterium ventriosum, Faecalibaculum rodentium, Flavimarina pacifica, Flavonifractor prautii, Flinchibacter butyricus, Gordonibacter faesihominis, Gracilibacter thermotolerans, Harryflintia acetispora, Hordemania massiliensis, Hydrogenoanaerobacterium saccharovorans, Ifubacter massiliensis, Intestinimonas butyriciproducens, Irregularibacter muris, Lachnoclostridium pacaceans, Lactobacillus animalis, Lactobacillus faeces, Lactobacillus gasseri, Lactobacillus hominis, Lactobacillus intestinalis, Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus logosae, Lactobacillus taiwanensis, Lawsonia intracellularis, Longibacrum muris, Malvinbrianchia formatexigens, Millionella massiliensis s, Mucispirillum scaedreri, Muribacrum intestinale, Murimonas intestini, Natlanaerovirga pectinivora, Neglecta zimonensis, Odoribacter plankunix, Orsenera profusa, Oscillibacter ruminantium, Oscillibacter valericigenes, Papilibacter cinnamivorans, Parabacteroides gordosteinii, Paraeggertella hongkongenesis, Parasterella exclementihominis, Parvibacter caesicola, Peptococcus niger, Phosea massiliensis,Porphyromonas catoniae, Prevotella oralis, Prevotella stercorea, Prevotella massilia timonensis, Pseudobutyrivibrio ruminis, Pseudoflavonifructor capillosus, Pseudoflavonifructor hocaensis, Raoultibacter timonensis, Rhizobium straminorhizae, Roseburia faeces, Roseburia hominis, Roseburia intestinalis, Ruminiclostridium thermocellum, Ruminococcus champanerensis, Ruminococcus faeces, Ruminococcus flavefaciens, Ruminococcus gnavus, Rutenibacter The bacterial population includes one or more of: Tertium lactiformans, Sphingomonas kieongiensis, Spiroplasma velocyclescens, Sporobacter thermitizis, Stomatobaculum longum, Streptococcus acidominimus, Streptococcus danieriae, Syntrohomonas wolfei, Tepizimonas taiwanensis, Chindaria californiensis, Chindaria texcoconensis, Turicibacter sanguinis, Turicimonas muris, Taizerella nexilis, Baritarea proniensis, and Vampirovibrio chlorelavorus.

[0041] In some embodiments, the preferred profile is Parabacteroides distasonis, Fournierera spp., Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes spp., Muricomes intestini, Geospora bacter, Geospora bacter subterraneanus, Anaerotignum laevigata, lactifermentans, Bacteroides fragilis, Vampirovibrio spp., Taizerella spp., Ackermansia muciniphila, Bacteroides stercolis, Dielma fastidiosa, Phylum Firmicutes, Order Clostridiales, Family Ruminococcaceae, Flavonifracter prautii, Alistipes indistinctus, Ackermansia muciniphila, Bacteroides stercolirosolis, Clostridium lactifermentans Orus, Abyssibirga alcaniphila, Acetatifactor muris, Acetivibrio cellulolyticus, Acetivibrio ethanolguignens, Acholeplasma vituri, Achromobacter derayi, Acidovorax radices, Adrecluzia aequorifaciens, Ackermansia muciniphila, Alistipes indistinctus, Alistipes obesi, Alistipes putoreginis, Alistipes senegalensis, Alistipes timonensis, Alcalibacter saccharofermentans, Alcalibacter bacchii, Alobaculum stercolicanis, Anaerobacterium chalcisorbens, Anaerocorumna cellulosilisica, Anaerosporobacter mobilis, Anaerotaenia torta, Anaerotorunculus corihominis, Anaerotorunculus rubiinfantis, Anaerovorax odrimtans, Bacteroides acidifaciens, Bacteroides caesimris, Bacteroides dorei, Bacteroides faesiquinchirae, Bacteroides rodentium, Bacteroides stercolirosolis, Bacteroides xylanolyticus, Barnesiella intestinihominis, Beduini massiliensis, Bifidobacterium pseudolongum, Blautia luci, Bresnakia bratschicola,Bresnakia pachinodae, Butyricoccus plicaecorum, Butyrivibrio crossotus, Catabacter hongkongenesis, Christensenella massiliensis, Christensenella minuta, Christensenella timonensis, Clostridium aerotolerans, Clostridium ardenense, Clostridium alkalicellulosi, Clostridium asparagiforme, Clostridium cerelecrens, Clostridium cellobiopalum, Clostridium cellulolyticum, Clostridium clariflavum, Clostridium Clostridium cochleatum, Clostridium corinum, Clostridium hylemonae, Clostridium indris, Clostridium jejuense, Clostridium lactifermentans, Clostridium labarens, Clostridium methylpentosum, Clostridium oroticum, Clostridium oryzae, Clostridium papyrosolvens, Clostridium polysaccharolyticum, Clostridium populeci, Clostridium saccharolyticum, Clostridium saudiense, Clostridium Clostridium saindens, Clostridium straminisolvens, Clostridium viride, Clostridium xylanolyticum, Coprobacter secundus, Coprococcus catus, Curturomica massiliensis, Defluvitalea saccharophila, Desulfitobacterium hafniens, Desulfitobacterium metallireducens, Desulfosporosinus orientis, Desulfovibrio desulfuricans, Desulfovibrio simplex, Dorea formisigenerans, Eisenberghiella massilii ensis, Emergencia timonensis, Enterococcus hirae, Enterorhabdus mucosicola, Enterorhabdus muris, Erysipelothrix ramosum, Erysipelothrix larvae, Escherichia fergusonii, Eubacterium coprostanoligenes, Eubacterium doricum, Eubacterium ruminantium, Eubacterium silaeum, Eubacterium tortuosum, Eubacterium ventriosum, Faecalibacum rodentium, Flavimarina pacifica,Flavonifractor plautii, Flintibacter butyricus, Gordonibacter faesihominis, Gracilibacter thermotolerans, Harryflintia acetispora, Hordemania massiliensis, Hydrogenoanaerobacterium saccharovorans, Ifubacter massiliensis, Intestinimonas butyriciproducens, Irregularibacter muris, Lachnoclostridium pacaceans, Lactobacillus animalis, Lactobacillus faecius, Lactobacillus gasseri, Lactobacillus hominis, Lactobacillus Rhus intestinalis, Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus logosae, Lactobacillus taiwanensis, Lawsonia intracellularis, Longibacrum muris, Malvinbrianchia formatexigens, Millionella massiliensis, Mucispirillum scaedlerii, Muribaculum intestinale, Murimonas intestini, Natlanaerovirga pectinivora, Neglecta timonensis, Odoribacter splanchnicus, Olsenella profusa, Oscillibacter ruminantium, Oscillibacter valericigenes, Papilibacter cinnamivorans, Parabacteroides gordosteinii, Paraeggertella hongkongenesis, Parasterella exclementhihominis, Parvibacter caesicola, Peptococcus niger, Phocea massiliensis, Porphyromonas catoniae, Prevotella oralis, Prevotella stercorea, Prevotella massilia timonensis, Pseudobutyrivibrio ruminis, Pseudoflavonifractor capirosus, Pseudoflavonifractor hocaensis, Raoul Rhizobium straminorhizae, Roseburia faeces, Roseburia hominis, Roseburia intestinalis, Ruminiclostridium thermocellum, Ruminococcus champanensis, Ruminococcus faeces, Ruminococcus flavefaciens, Ruminococcus gnavus, Ruthenibacterium lactiformans, Sphingomonas kieongiensis, Spiroplasma velocyclescens, Sporobacter thermitizus, Stomatobaculum longum, Streptococcus acidominimus,A bacterial population excluding one or more of Streptococcus danielliae, Syntrohomonas wolfei, Tepizimonas taiwanensis, Chindaria californiensis, Chindaria texcoconensis, Turicibacter sanguinis, Turicimonas muris, Taiserella nexilis, Baritarea proniensis, and Vampirovibrio chlorelavorus.

[0042] In some embodiments, the preferred profile is Parabacteroides distasonis, Fournierera spp., Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes spp., Muricomes intestini, Geospora bacter, Geospora bacter subterraneanus, Anaerotignum laevigata, lactifermentans, Bacteroides fragilis, Vampirovibrio spp., Taizerella spp., Ackermansia muciniphila, Bacteroides stercolis, Dielma fastidiosa, Phylum Firmicutes, Order Clostridiales, Family Ruminococcaceae, Flavonifracter prautii, Alistipes indistinctus, Ackermansia muciniphila, Bacteroides stercolirosolis, Clostridium lactifermentans Orus, Abyssibirga alcaniphila, Acetatifactor muris, Acetivibrio cellulolyticus, Acetivibrio ethanolguignens, Acholeplasma vituri, Achromobacter derayi, Acidovorax radices, Adrecluzia aequorifaciens, Ackermansia muciniphila, Alistipes indistinctus, Alistipes obesi, Alistipes putoreginis, Alistipes senegalensis, Alistipes timonensis, Alcalibacter saccharofermentans, Alcalibacter bacchii, Alobaculum stercolicanis, Anaerobacterium chalcisorbens, Anaerocorumna cellulosilisica, Anaerosporobacter mobilis, Anaerotaenia torta, Anaerotorunculus corihominis, Anaerotorunculus rubiinfantis, Anaerovorax odrimtans, Bacteroides acidifaciens, Bacteroides caesimris, Bacteroides dorei, Bacteroides faesiquinchirae, Bacteroides rodentium, Bacteroides stercolirosolis, Bacteroides xylanolyticus, Barnesiella intestinihominis, Beduini massiliensis, Bifidobacterium pseudolongum, Blautia luci, Bresnakia bratschicola,Bresnakia pachinodae, Butyricoccus plicaecorum, Butyrivibrio crossotus, Catabacter hongkongenesis, Christensenella massiliensis, Christensenella minuta, Christensenella timonensis, Clostridium aerotolerans, Clostridium ardenense, Clostridium alkalicellulosi, Clostridium asparagiforme, Clostridium cerelecrens, Clostridium cellobiopalum, Clostridium cellulolyticum, Clostridium clariflavum, Clostridium Clostridium cochleatum, Clostridium corinum, Clostridium hylemonae, Clostridium indris, Clostridium jejuense, Clostridium lactifermentans, Clostridium labarens, Clostridium methylpentosum, Clostridium oroticum, Clostridium oryzae, Clostridium papyrosolvens, Clostridium polysaccharolyticum, Clostridium populeci, Clostridium saccharolyticum, Clostridium saudiense, Clostridium Clostridium saindens, Clostridium straminisolvens, Clostridium viride, Clostridium xylanolyticum, Coprobacter secundus, Coprococcus catus, Curturomica massiliensis, Defluvitalea saccharophila, Desulfitobacterium hafniens, Desulfitobacterium metallireducens, Desulfosporosinus orientis, Desulfovibrio desulfuricans, Desulfovibrio simplex, Dorea formisigenerans, Eisenberghiella massilii ensis, Emergencia timonensis, Enterococcus hirae, Enterorhabdus mucosicola, Enterorhabdus muris, Erysipelothrix ramosum, Erysipelothrix larvae, Escherichia fergusonii, Eubacterium coprostanoligenes, Eubacterium doricum, Eubacterium ruminantium, Eubacterium silaeum, Eubacterium tortuosum, Eubacterium ventriosum, Faecalibacum rodentium, Flavimarina pacifica,Flavonifractor plautii, Flintibacter butyricus, Gordonibacter faesihominis, Gracilibacter thermotolerans, Harryflintia acetispora, Hordemania massiliensis, Hydrogenoanaerobacterium saccharovorans, Ifubacter massiliensis, Intestinimonas butyriciproducens, Irregularibacter muris, Lachnoclostridium pacaceans, Lactobacillus animalis, Lactobacillus faecius, Lactobacillus gasseri, Lactobacillus hominis, Lactobacillus Rhus intestinalis, Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus logosae, Lactobacillus taiwanensis, Lawsonia intracellularis, Longibacrum muris, Malvinbrianchia formatexigens, Millionella massiliensis, Mucispirillum scaedlerii, Muribaculum intestinale, Murimonas intestini, Natlanaerovirga pectinivora, Neglecta timonensis, Odoribacter splanchnicus, Olsenella profusa, Oscillibacter ruminantium, Oscillibacter valericigenes, Papilibacter cinnamivorans, Parabacteroides gordosteinii, Paraeggertella hongkongenesis, Parasterella exclementhihominis, Parvibacter caesicola, Peptococcus niger, Phocea massiliensis, Porphyromonas catoniae, Prevotella oralis, Prevotella stercorea, Prevotella massilia timonensis, Pseudobutyrivibrio ruminis, Pseudoflavonifractor capirosus, Pseudoflavonifractor hocaensis, Raoul Rhizobium straminorhizae, Roseburia faeces, Roseburia hominis, Roseburia intestinalis, Ruminiclostridium thermocellum, Ruminococcus champanensis, Ruminococcus faeces, Ruminococcus flavefaciens, Ruminococcus gnavus, Ruthenibacterium lactiformans, Sphingomonas kieongiensis, Spiroplasma velocyclescens, Sporobacter thermitizus, Stomatobaculum longum, Streptococcus acidominimus,The bacterial population includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 (or any derivable range therein) of Streptococcus danielliae, Syntrohomonas wolfei, Tepizimonas taiwanensis, Chindaria californiensis, Chindaria texcoconensis, Turicibacter sanguinis, Turicimonas muris, Taiserrella nexilis, Baritarea proniensis, and Vampirovibrio chlorelavorus.

[0043] In some embodiments, a preferred profile has a relative abundance of at least, at most, or exactly 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein) of Parabacteroides distasonis, Fournierera spp., Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Caloramater kurhaasi, Muricomes spp. , Muricomes intestini, Geosporobacter spp., Geosporobacter subterraneanus, Anaerotignum lactatifermentans, Bacteroides fragilis, Vampirovibrio spp., Taizerella spp., Ackermansia muciniphila, Bacteroides stercolis, Dielma fastidiosa, Phylum Firmicutes, Order Clostridiales, Family Ruminococcaceae, Flavonifracter prautii, Alistipes indistinctus, Ackermansia muciniphila, Bacteroides stercolissolis, Clostridium lactatifermentans Orus, Abyssibirga alcaniphila, Acetatifactor muris, Acetivibrio cellulolyticus, Acetivibrio ethanolguignens, Acholeplasma vituri, Achromobacter derayi, Acidovorax radices, Adrecluzia aequorifaciens, Ackermansia muciniphila, Alistipes indistinctus, Alistipes obesi, Alistipes putoresinis, Alistipes senegalensis, Alistipes timonensis, Alcalibacter saccharofer Menthans, Alkalibacrum bacchii, Alkalibacrum stercolicanis, Anaerobacterium chalcisorbens, Anaerocolumna cellulosilitica, Anaerosporobacter mobilis, Anaerotaenia torta, Anaerotorunculus corihominis, Anaerotorunculus rubiinfantis, Anaerovorax odrimtans, Bacteroides acidifaciens, Bacteroides caesimris, Bacteroides dorei, Bacteroides faesiquinchirae, Bacteroides rodentium,Bacteroides stercolirosolis, Bacteroides xylanolyticus, Barnesiella intestinihominis, Beduini massiliensis, Bifidobacterium pseudolongum, Blautia luci, Bresnakia bratticola, Bresnakia pachinodae, Butyricoccus plicaecorum, Butyrivibrio crossotus, Catabacter hongkongenesis, Christensenella massiliensis, Christensenella minuta, Christensenella timonensis, Clostridium aerotolerans, Clostridium arde nense, Clostridium alkalicellulosi, Clostridium asparagiforme, Clostridium cererecrescens, Clostridium cellobiopalum, Clostridium cellulolyticum, Clostridium clariflavum, Clostridium cochleatum, Clostridium corinum, Clostridium hylemonae, Clostridium indris, Clostridium jejuense, Clostridium lactifermentans, Clostridium labarens, Clostridium methylpentosum, Clostridium Clostridium orolyticum, Clostridium oryzae, Clostridium papyrosolvens, Clostridium polysaccharolyticum, Clostridium popleci, Clostridium saccharolyticum, Clostridium saudiens, Clostridium saindens, Clostridium straminisorbens, Clostridium viride, Clostridium xylanolyticum, Coprobacter secundus, Coprococcus catus, Curturomica massiliensis, Defluviitarea saccharophila, Desulfitobacterium hafniens, Desulfitobacterium metallireducens, Desulfosporosinus orientis, Desulfovibrio desulfuricans, Desulfovibrio simplex, Dorea formisigenerans, Eisenberghiella massiliensis, Emergencia timonensis, Enterococcus hirae, Enterorrhabdus mucosicola, Enterorrhabdus muris, Erysipelothrix ramosum, Erysipelothrix larvae, Escherichia fergusonii, Eubacterium coprostanoligenes,Eubacterium doricum, Eubacterium ruminantium, Eubacterium silaeum, Eubacterium tortiosum, Eubacterium ventriosum, Faecalibaculum rodentium, Flavimarina pacifica, Flavonifractor prautii, Flinchibacter butyricus, Gordonibacter faesihominis, Gracilibacter thermotolerans, Harryflintia acetispora, Hordemania massiliensis, Hydrogenoanaerobacterium saccharovorans, Ifubacter massiliensis, Intestinimonas butyriciproducens, Irregularibacter muris, Lachnoclostridium pacaceans, Lactobacillus animalis, Lactobacillus faeces, Lactobacillus gasseri, Lactobacillus hominis, Lactobacillus intestinalis, Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus logosae, Lactobacillus taiwanensis, Lawsonia intracellularis, Longibacrum muris, Malvinbrianchia formatexigens, Millionella massiliensis, Muscipiri Lum scaedreri, Muribacrum intestinale, Murimonas intestini, Natlanaerovirga pectinivora, Neglecta timonensis, Odoribacter plankunix, Orsenera profusa, Oscillibacter ruminantium, Oscillibacter valericigenes, Papilibacter cinnamivorans, Parabacteroides gordosteinii, Paraeggertella hongkongenesis, Parasterella exclementihominis, Parvibacter caesicola, Peptococcus niger, Phosea massiliensis, Porphyro Monas catoniae, Prevotella oralis, Prevotella stercorea, Prevotella massilia timonensis, Pseudobutyrivibrio ruminis, Pseudoflavonifractor capillosus, Pseudoflavonifractor hocaensis, Raoultibacter timonensis, Rhizobium straminorhizae, Roseburia faeces, Roseburia hominis, Roseburia intestinalis, Ruminiclostridium thermocellum, Ruminococcus champanerensis, Ruminococcus faeces, Ruminococcus flavefaciens,The bacterial population includes one or more of Ruminococcus gnavus, Ruthenibacterium lactiformans, Sphingomonas kieongiensis, Spiroplasma velocyclescens, Sporobacter thermitizis, Stomatobaculum longum, Streptococcus acidominimus, Streptococcus danieriae, Syntrohomonas wolfei, Tepizimonas taiwanensis, Chindaria californiensis, Chindaria texcoconensis, Turicibacter sanguinis, Turicimonas muris, Taizerella nexilis, Baritarea proniensis, and Vampirovibrio chlorelavorus.

[0044] In some embodiments, a preferred profile is further classified as a non-toxicity-associated profile. A non-toxicity-associated profile refers to a microbial profile in a subject, particularly the gut of a subject, that is present in subjects that experience no toxicity, low levels of toxicity, or immune-related adverse events of less than Grade 3 in response to combination immune checkpoint blockade therapy. In some embodiments, a preferred profile comprises a population of bacteria that includes bacteria belonging to one or more of the following genera: Dorea, Carolactamer, Muricomes, Geosporactor, Geosporactor, Anaerotignum, Bacteroides, Butyricimonas, Flavonifractor, Dielma, Alistipes, and Ackermansia. In some embodiments, the preferred profile comprises a bacterial population comprising one or more of Dorea formisigenerans, Caloramater kurhaasi, Muricomes spp., Muricomes intestini, Geosporobacter spp., Geosporobacter subterraneanus, Anaerotignum lactifermentans, Bacteroides stercoris, Butyricimonas faesihominis, Flavonifractor plautii, Dielma fastidiosa, Alistipes indistinctus, and Ackermansia muciniphila. In some embodiments, the preferred profile is further defined as an effective profile. An effective profile refers to a microbial profile in a subject, particularly the subject's gut, that is present in a subject that responds to combination immune checkpoint blockade therapy. In some embodiments, an effective response comprises an increase in CD8+ cells in tumor samples or infiltrates. In some embodiments, the effective response comprises an increase in the number and / or density of T cells or the entropy of tumor T cell infiltrates. Entropy can be determined by methods known in the art and described herein. For example, Shannon entropy and Renyi entropy can be used to compare the diversity of TCRs between different humans or different T cell phenotypes.

[0045] In some embodiments, the following genera or species are present: Alistipes, Bacteroides, Butyricimonas, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tissierales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobaccilla ulcerans, Lactobacillus casei, Lactobacillus ... Bacteria belonging to the genera Tobacillus johnsonii, Parapedobacter compostii, Anaerotignum lactifermentans, Bacteroides fragilis, Vampirovibrio, Taizerella, Flavonifractor, Dielma, or Ackermansia were determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein) in relative abundance. In some embodiments, the genus Alistipes, Bacteroides, Butyricimonas, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tissierales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsidivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus Bacteria belonging to the genera S. johnsonii, Parapedobacter compostii, Anaerotignum lactifermentans, Bacteroides fragilis, Vampirovibrio, Taizerella, Flavonifractor, Dielma, or Ackermansia were determined to be present at a relative abundance of at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).In some embodiments, the strains of bacteria that are present in the strains include Alistipes spp., Bacteroides spp., Butyricimonas spp., Parabacteroides distasonis, Fournierera spp., Fournierera massiliensis, Eisenberghiella tai, Tissierales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes spp., Geosporobacter spp., Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobanaeroticum lactifermentans, Parapedobanaeroticum lactatifermentans), Bacteroides fragilis, Vampirovibrio, Teisserella, Flavonifractor, Dielma, or Ackermansia, the combined relative abundance of the genus is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Bacteroides fragilis is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Vampirovibrio is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Teisserella is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Flavonifractor is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).In some embodiments, the relative abundance of bacteria belonging to the genus Dielma is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Ackermansia is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, a toxic response is predicted when one or more of Bacteroides stercoris, Bacteroides caccae, Bacteroides intestinalis, Coprobacter sp., Intestinibacter bartoletti, Parasterella secunda, and Diarrister propionicifaciens are detected in a sample from the subject. In some embodiments, a toxic response is predicted when one or more of Bacteroides stercoris, Bacteroides caccae, Bacteroides intestinalis, Coprobacter sp., Intestinibacter bartoli, Parasterella secunda, and Diarrister propionicifaciens are determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein) in relative abundance. In some embodiments, bacteria belonging to the genus Bacteroides stercoris, Bacteroides caccae, Bacteroides intestinalis, Coprobacter, Intestinibacter bartoletti, Parasterella secunda, and Diaryster propionicifaciens are determined to be present at a relative abundance of at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).In some embodiments, the combined relative abundance of Bacteroides stercoris, Bacteroides caccae, Bacteroides intestinalis, Coprobacter sp., Intestinibacter bartoletti, Parasterella secunda, and Diarrister propionicifaciens is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Bacteroides stercoli is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Bacteroides caccae is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Bacteroides intestinalis is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Diaryster is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).

[0046] In some embodiments, a non-toxic response is predicted when one or more of Bacteroides fragilis, Vampirovibrio sp., Teizerella sp., Dorea formisigenerans, Caloramater kurhaasi, Muricomes sp., Muricomes intestini, Geosporobacter sp., Geosporobacter subterraneanus, and Anaerotignum lactifermentans are detected. In some embodiments, a non-toxic response is predicted when one or more of Bacteroides fragilis, Vampyrovibrio sp., Teizerella sp., Dorea formisigenerans, Caloramater kurhaasi, Muricomes sp., Muricomes intestini, Geosporobacter sp., Geosporobacter subterraneanus, Anaerotignum lactatifermentans is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein) in relative abundance. In some embodiments, bacteria belonging to the following genus are determined to be present at a relative abundance of at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the combined relative abundance of Bacteroides fragilis, Vampyrovibrio sp., Teizerella sp., Dorea formisigenerans, Caloramater kurhaasi, Muricomes sp., Muricomes intestini, Geosporobacter sp., Geosporobacter subterraneanus, and Anaerotignum lactifermentans is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).In some embodiments, the relative abundance of bacteria belonging to the genus Bacteroides fragilis is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Vampirovibrio is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Teisserella is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).

[0047] In some embodiments, an effective response is predicted when one or more of Parabacteroides distasonis, Fournierera sp., Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierales, Fungateiclostridium thermocellum, Bacteroides stercolis, Flavonifracter plautii, Dielma fastidiosa, and Ackermansia muciniphila are detected in a sample from the subject. In some embodiments, an effective response is predicted when one or more of Parabacteroides sp., Fournierera sp., Eisenberghiella spp., Tissierales, Fungateiclostridium sp., Bacteroides sp., Butyricimonas sp., Flavonifracter spp., Dielma spp., Alistipes spp., and Ackermansia spp. are detected in a sample from the subject. In some embodiments, an effective response is predicted when one or more of Bacteroides stercolis, Butyricimonas faesihominis, Flavonifracter platii, Dielma fastidiosa, Alistipes indistinctus, and Ackermansia muciniphila are detected in a sample from the subject. In some embodiments, an effective response is predicted when one or more of Parabacteroides distasonis, Fournierera sp., Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, Fungatei Clostridium thermocellum, Bacteroides stercolis, Butyricimonas faesihominis, Flavonifracter platii, Dielma fastidiosa, Alistipes indistinctus, and Ackermansia muciniphila are determined to be in a relative abundance of at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).In some embodiments, bacteria belonging to the order Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, fungatei, Clostridium thermocellum, Bacteroides stercolis, Butyricimonas faesihominis, Flavonifracter platii, Dielma fastidiosa, Alistipes indistinctus, and Ackermansia muciniphila are determined to be present at a relative abundance of at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the combined relative abundance of Parabacteroides distasonis, Fournierera sp., Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, fungatei Clostridium thermocellum, Bacteroides stercolis, Butyricimonas faesihominis, Flavonifracter platii, Dielma fastidiosa, Alistipes indistinctus, and Ackermansia muciniphila is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Bacteroides stercoli is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Flavonifractor platii is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).In some embodiments, the relative abundance of bacteria belonging to the genus Dierma fastidiosa is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Ackermansia muciniphila is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Butyricimonas faesihominis is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Alistipes indistinctus is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).

[0048] In some embodiments, detection of one or more of Lactobacillus logosae, Bacteroides fragilis, Prevotella copri, Prevotella shahii, Clostridium hylemonae, fungatei, Clostridium aldritii, Citrobacter rodentium, Eubacterium sulci, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Roseburia hominis, Weissella paramesenteroides, and Klebsiella aerogenes predicts an ineffective response. In some embodiments, a non-effective response is predicted when one or more of Lactobacillus logosae, Bacteroides fragilis, Prevotella copri, Prevotella shahii, Clostridium hylemonae, fungatei, Clostridium aldritii, Citrobacter rodentium, Eubacterium sulci, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Roseburia hominis, Weissella paramesenteroides, and Klebsiella aerogenes are determined to have a relative abundance of at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, bacteria belonging to the species Lactobacillus logosae, Bacteroides fragilis, Prevotella copri, Prevotella shahii, Clostridium hylemonae, fungatei, Clostridium aldritii, Citrobacter rodentium, Eubacterium sulci, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Roseburia hominis, Weissella paramesenteroides, and Klebsiella aerogenes are determined to be present at a relative abundance of at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).In some embodiments, the combined relative abundance of Lactobacillus logosae, Bacteroides fragilis, Prevotella copri, Prevotella shahii, Clostridium hylemonae, fungatei, Clostridium aldritii, Citrobacter rodentium, Eubacterium sulci, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Roseburia hominis, Weissella paramesenteroides, and Klebsiella aerogenes is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Lactobacillus logosae is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to the genus Bacteroides fragilis is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to Prevotella copri is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein). In some embodiments, the relative abundance of bacteria belonging to Prevotella shahii is determined to be at least 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90% (or any derivable range therein).

[0049] In some embodiments, a preferred profile, a non-virulence-associated profile, and / or an effective profile excludes bacteria from one or more of the following families: Ruminococcus, Clostridium, Lachnospira, Micrococcus, and / or Veillonella, or includes bacteria from one or more of the following families: Ruminococcus, Clostridium, Lachnospira, Micrococcus, and / or Veillonella at a relative abundance of less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% (or any derivable range therein).

[0050] In some embodiments, a preferred profile, a non-virulence-associated profile, and / or an effective profile excludes bacteria from one or more of the following, or includes bacteria from one or more of the following at a relative abundance of less than 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% (or any derivable range therein): Bacteroides stercoli, Parabacteroides distaso, Bacteroides diffusifera ... Niss, Fournierera spp., Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierales, Fungatei Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes spp., Muricomes intestini, Geosporobacter spp., Geosporobacter subterraneanus, Anaerotignum lactifermentans, Bacteroides coagulans (Bacteroides coagulans, Clostridium ardenense, Clostridium aldritii, Clostridium alkalicellulosi, Clostridium amygdalinum, Clostridium asparagiforme, Clostridium cellulosi, Clostridium citroniae, Clostridium clariflavum DSM 19732, Clostridium clostridioforme, Clostridium corinum, Clostridium fimetarium, Clostridium hiranonis, Clostridium hungatei, Clostridium hilemonae DSM 15053, Clostridium indris, Clostridium lactifermentans, Clostridium leptum, Clostridium methylpentosum, Clostridium oroticum, Clostridium papyrosolvens DSM 2782, Clostridium popleci, Clostridium propionicumpropionicum, Clostridium saccharolyticum, Clostridium sine dens, Clostridium sporosphaeroides, Clostridium stercorarium, Clostridium straminisorbens, Clostridium sufflavum, Clostridium thermitizis, Clostridium thermosuccinogenes, Clostridium viride, Clostridium xylanolyticum, Desulfotomaculum guttoideum, Eubacterium rectale ATCC 33656, Eubacterium doricum, Eubacterium eligens ATCC 27750, Eubacterium hallii, Eubacterium infirmum, Eubacterium silaeum, Eubacterium tenue, Ruminococcus torques, Acetanaerobacterium elongatum, Acetatifactory muris, Acetivibrio cellulolyticus, Acetivibrio ethanolignens, Acholeplasma brassicae 0502, Acholeplasma parvum, Acholeplasma vituri, Acinetobacter junii, Actinobacillus porcinus, Actinomyces bowdenii, Actinomyces dentalis, Actinomyces odontolyticusodontolyticus, Acutalibacter muris, Aerococcus viridans, Aeromicrobium fastidiosum, Alistipes finegoldii, Alistipes obesi, Alistipes onderdonkii, Alistipes putoresinis, Alistipes shahii, Alistipes shahii WAL 8301, Alistipes zimonensis JC136, Alkalibacter saccharofermentans, Alkaliphilus metalliredigens QYMF, Allisonella histaminiformans histaminiformans, Allobaculum stercolicanis DSM 13633, Alloprevotella rava, Alloprevotella tannerae, Anaerobacterium chalcisorbens, Anaerobiospirillum thomasii, Anaerobium acetethylicum, Anaerococcus octavius ​​NCTC 9810, Anaerococcus provenciensis, Anaerococcus vaginalis ATCC 51170, Anaerococna jejuensis jejuensis, Anaerofilum agile, Anaerofustis stercorihominis, Anaeroglobus geminatus, Anaeromassilibacillus senegalensissenegalensis, Anaeroplasma abactoclasticum, Anaerorhabdus furcosa, Anaerosporobacter mobilis, Anaerostipes butyraticus, Anaerostipes caccae, Anaerostipes hadrus, Anaerotorunculus corihominis, Anaerovorax odrimtans, Anoxybacillus rupiensis, Aquabacterium limnoticum, Arcobacter butzleri, Arthrospira platensis platensis, Asaccharobacter celatus, Atopobium parvulum, Bacteroides caccae, Bacteroides caecimulis, Bacteroides cellulosilyticus, Bacteroides clarus YIT 12056, Bacteroides dorei, Bacteroides eggerthii, Bacteroides finegoldii, Bacteroides fragilis, Bacteroides gallinarum, Bacteroides massiliensis, Bacteroides oleiciplenus YIT 12058, Bacteroides plebeius DSM 17135, Bacteroides rodentium JCM 16496, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides xylanisorbensxylanisolvens XB1A, Bacteroides xylanolyticus, Barnesiella intestinihominis, Beduini massiliensis, Bifidobacterium bifidum, Bifidobacterium dentium, Bifidobacterium longum subsp. infantis, Blautia caecimuris, Blautia coccoides, Blautia faeces, Blautia glucerasea, Blautia hansenii DSM 20583, Blautia hydrogenotrophica, Blautia luchi, Blautia luchi DSM 14534, Blautia wexlerae DSM 19850, Budvicia aquatica, Butyricicoccus pullicaecorum, Butyricimonas paravirosa, Butyrivibrio crossotus, Caldicoprobacter oshimai, Caloramator kurhaashii, Caloramator proteoclasticus, Caloramator quimbayensis, Campylobacter gracilis, Campylobacter rectus rectus, Campylobacter ureolyticus DSM 20703, Capnocytophaga gingivalis, Capnocytophaga leadbetteri, Capnocytophaga sputigena, Casaltella massiliensismassiliensis, Catabacter hongkongenesis, Catenibacterium mitsuokai, Christensenella minuta, Christensenella zimonensis, Chryseobacterium taklimakanense, Citrobacter freundii, Cloacibacillus porcorum, Clostridioides difficile ATCC 9689=DSM 1296, Clostridium amylolyticum, Clostridium bowmanii, Clostridium butyricum, Clostridium cadaveris cadaveris, Clostridium colicanis, Clostridium gasigenes, Clostridium lentocellum DSM 5427, Clostridium oceanicum, Clostridium oryzae, Clostridium paraputrificum, Clostridium pascui, Clostridium perfringens, Clostridium quinii, Clostridium saccharobutylicum, Clostridium sporogenes, Clostridium ventriculi ventriculi, Collinsella aerofaciens, Comamonas testosteronitestosteroni, Coprobacter fastidiosus NSB1, Coprococcus eutactus, Corynebacterium diphtheriae, Corynebacterium durum, Corynebacterium mycetoides, Corynebacterium pyruviciproducens ATCC BAA-1742, Corynebacterium tuberculostearicum, Culturomica massiliensis, Cuneatibacter caesimulis caecimuris, Defluvitalea saccharophila, Delftia acidovorans, Desulfitobacterium chlororespirans, Desulfitobacterium metalliereducens, Desulfosporosinus acididurans, Desulfotomaculum halophilum, Desulfotomaculum intricatum, Desulfotomaculum tongense, Desulfovibrio desulfuricans subsp. desulfuricans Desulfovibrio desulfuricans, Desulfovibrio idahonensis, Desulfovibrio litoralis, Desulfovibrio piger, Desulfovibrio simplex, Desulfovibrio zosterae, Desulfuromonas acetoxidans, Dethiobacter alkaliphilus AHT 1, Dethiosulfatibacter aminovorans, Dialister invisus, Dialister propionicifaciens, Dielma fastidiosa, Dietzia alimentaria alimentaria 72, Dorea longicatena, Dysgonomonas gadei ATCC BAA-286, Dysgonomonas mossii, Eggerthella lenta, Eikenella corrodens, Eisenberghiella tai, Emergensia timonensis, Enorma massiliensis phI, Enterococcus faecalis, Enterorrhabdus muris, Ethanoligenens harbinense YUAN-3, Eubacterium coprostanoligenes, Eubacterium limosum limosum, Eubacterium oxidoreducens, Eubacterium sulci ATCC 35585, Eubacterium uniforme, Eubacterium ventriosum, Eubacterium xylanophilumxylanophilum, Extibacter muris, Ezakiella peruensis, Faecalibacterium prausnitzii, Faecalicoccus acidiformans, Faecalitalea cylindroides, Filifactor villosus, Flavonifractor prautii, Flintibacter butyricus, Frisingicoccus caecimuris, Fucophilus fucoidanolyticus, Fusicatenibacter saccharivorans saccharivorans, Fusobacterium mortiferum, Fusobacterium nucleatum subsp. vincentii, Fusobacterium simiae, Fusobacterium varium, Garciella nitratireducens, Gemella haemolysans, Gemmiger formicilis, Gordonibacter urolithinfaciens, Gracilibacter thermotolerans JW / YJL-S1, Granulicatella elegans elegans, Guggenheimella bovis, Haemophilus haemolyticus, Helicobacter typhlonius, Hesperia stercolistercorisuis, Holdemanella biformis, Holdemania massiliensis AP2, Howardella ureilytica, Hungatella effluvii, Hungatella hathewayi, Hydrogenoanaerobacterium saccharovorans, Ifubacter massiliensis, Intestinibacter bartoletti, Intestinimonas butyriciproducens, Irregularibacter muris, Kiloniella laminariae DSM 19542, Kroppenstedtia guangzhouensis, Lachnoanaerobaculum orale orale, Lachnoanaerobaculum umeaense, Lachnoclostridium phytofermentans, Lactobacillus acidophilus, Lactobacillus algidus, Lactobacillus animalis, Lactobacillus casei, Lactobacillus delbrueckii, Lactobacillus fornicalis, Lactobacillus iners, Lactobacillus pentosus, Lactobacillus logosae, Lactococcus garvieae, Lactonifactor longoviformis longoviformis, Leptotrichia buccalis, Leptotrichia hofstadii, Leptotrichia hongkongensis, Leptotrichia wadiiwadei, Leuconostoc inhae, Levyella massiliensis, Loriellopsis cavernicola, Lutispora thermophila, Marinilabilia salmonicolor JCM 21150, Malvinbrianchia formatexigens, Mesoplasma photuris, Methanobrevibacter smithii ATCC 35061, Methanomassiliicoccus luminyensis B10, Methylobacterium exotorchiens extorquens, Mitsuokella jalaludinii, Mobilitalea sibirica, Mobiluncus curtisii, Mogibacterium pumilum, Mogibacterium timidum, Moorella glycerini, Moorella humiferrea, Moraxella nonliquefaciens, Moraxella osloensis, Morganella morganii, Moriella indrigenes indoligenes, Murivaculum intestinale, Murimonas intestini, Natlanaerovirga pectinivora, Neglecta timonensis, Neisseria cinerea, Neisseria oralis, Nocardioides mesophilusmesophilus, Novibacillus thermophilus, Ochrobactrum anthropi, Odoribacter plankunix, Olsenella profusa, Olsenella uli, Oribacterium asaccharolyticum ACB7, Oribacterium sinus, Oscillibacter ruminantium GH1, Oscillibacter valericigenes, Oxobacter pfennigii, Pantoea agglomerans, Papilibacter cinnamivorans, Parabacteroides faecalis faecis, Parabacteroides gordonii, Parabacteroides merdae, Parasporobacterium paucivorans, Parasterella exclementhihominis, Parasterella secunda, Parvimonas micra, Peptococcus niger, Peptoniphilus duerdenii ATCC BAA-1640, Peptoniphilus grossensis ph5, Peptoniphilus koenoeneniae, Peptoniphilus senegalensis senegalensis JC140, Peptostreptococcus stomatis, Phascolarctobacterium succinatutens, Phosea massiliensis, Pontibacter indicusindicus, Porphyromonas bennonis, Porphyromonas endodontalis, Porphyromonas pasteri, Prevotella bergensis, Prevotella buccae ATCC 33574, Prevotella denticola, Prevotella enoeca, Prevotella fusca JCM 17724, Prevotella loescheii, Prevotella nigrescens, Prevotella oris, Prevotella pallens ATCC 700821, Prevotella stercorea DSM 18206, Prevotella macilia timonensis, Propionispira arcuata, Proteus mirabilis, Providencia rettgeri, Pseudobacteroides cellulosolvens ATCC 35603 DSM 2933, Pseudobutyrivibrio ruminis, Pseudoflavonifractor capillosus ATCC 29799, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas mandelii, Pseudomonas nitroreducens nitroreducens, Pseudomonas putida, Raoultella ornithinolytica, Raoultella planticola, Raoultibacter massiliensis, Robinsoniella peoriensispeoriensis, Romboutsia timonensis, Roseburia faeces, Roseburia hominis A2-183, Roseburia intestinalis, Roseburia inulinivorans DSM 16841, Rothia dentocariosa ATCC 17931, Ruminiclostridium thermocellum, Ruminococcus albus, Ruminococcus bromii, Ruminococcus callidus, Ruminococcus champanerensis 18P13 = JCM 17042, Ruminococcus faeces JCM 15917, Ruminococcus flavefaciens, Ruminococcus gauvreauii, Ruminococcus lactaris ATCC 29176, Rummeliibacillus pycnus, Saccharofermentans acetigenes, Scardovia wiggsiae, Schlegelella thermodepolymerans, Sedimentibacter hongkongensis, Selenomonas sputigena ATCC 35185, Slackia exigua exigua ATCC 700122, Slackia piriformis YIT 12062, Solitairea canadensis, Solobacterium moorei, Sphingomonas aquatilis, Spiroplasma alleghenensealleghenense), Spiroplasma chinense, Spiroplasma chrysopiko Spiroplasma chrysopicola, Spiroplasma culicicola, Spiroplasma lampyridicola, Sporobacter thermitizis, Staphylococcus aureus, Stenotrophomonas maltophilia, Streptomyces longum, Streptococcus agalactiae ATCC 13813, Streptococcus cristatus, Streptococcus equinus, Streptococcus gordonii, Streptococcus lactarius lactarius, Streptococcus parauberis, Subdoligranulum variabile, Succinivibrio dextrinosolvens, Strepola stercolicanis, Strepola wadsworthensis, Syntrophococcus sucromutans, Syntrophomonas zehnderi OL-4, Terrisporobacter mayombei, Thermoleophilum album, Treponema denticola, Treponema sokranskii socranskii), Tyzerella nexilis DSM 1787, Vallitalea guaymasensis, Vallitalea proniensis, Vampirovibrio chlorelavorus, Veillonella atypicaatypica, Veillonella denticariosi, Veillonella dispar, Veillonella parvula, Victivallis vadensis, Vulcanibacillus modesticaldus, and Weissella confusa.

[0051] In some embodiments, the unfavorable profile, toxicity-associated profile, and / or ineffective profile may be a profile of Citrobacter spp., Clostridium hilemonae, fungatei, Clostridium aldrizii, Citrobacter rodentium, Eubacterium sulci, Hafniaceae, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Hafnia spp., Roseburia hominis, Weisse Lactobacillus paramesenteroides, Enterobacter spp., Lactobacillus logosae, Class Bacillales, Order Lactobacillales, Klebsiella aerogenes, Klebsiella spp., Bacteroides intestinalis, Coprobacter spp., Intestinibacter bartoli, Intestinibacter spp., Parasterella secunda, Diaryster propionicifaciens, Anaerotorunculus colihominis, Klebsiella varicosa variicola, Escherichia coli, Bacteroides thetaiotaomicron, Oxalobacter formigenes, Paraprevotella clara, Adrecluzia aequorifaciens, Clostridium bolteae, Klebsiella pneumoniae, Clostridium spp., Parabacteroides merdae, Klebsiella quasipneumoniae, Lachnoclostridium spp., Bacteroides coprocola coprocola), Prevotella species CAG:255, Lachnospiraceae, Streptococcus pasteurianus, Lactococcus lactis, Clostridiales, Streptococcus mutans, Ruminococcaceae bacteria D16, Firmicutes bacteria CAG:102, Oscillibacter spp.excluding one or more of Clostridium clostridioforme, Bacteroides massiliensis, Clostridium saindens, Parabacteroides merdae, Eubacterium sp. CAG:161, Ruminococcus gnavus, Clostridium clostridioforme, or a relative abundance of less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% (or any derivable range therein) of Citrobacter sp., Clostridium hylemonae, fungatei, Clostridium albicans, or doritii, Citrobacter rodentium, Eubacterium sulci, Hafniaceae, Citrobacter freundii, Eubacterium hallii, Enterobacter cloacae, Hafnia alvei, Hafnia spp., Roseburia hominis, Weissella paramesenteroides, Enterobacter spp., Lactobacillus logosae, Bacillales, Lactobacillales, Klebsiella aerogenes, Klebsiella spp., Bacteroides intestinalis, Coprobacter spp., Intestinibacter bartoli, Intestinibacter spp., Paraster Rella secunda, Diaryster propionicifaciens, Anaerotorunculus colihominis, Klebsiella varicosa, Escherichia coli, Bacteroides thetaiotamicron, Oxalobacter formigenes, Paraprevotella clara, Adrecluzia aequorifaciens, Clostridium volteae, Klebsiella pneumoniae, Clostridium spp., Parabacteroides meldae, Klebsiella quasipneumoniae, Lachnoclostridium spp., Bacteroides coprocola, Prevotella spp. CAG:255, Lachnospiraceae , Streptococcus pasteurianus, Lactococcus lactis, the order Clostridiales, Streptococcus mutans, the family Ruminococcaceae bacteria D16, the phylum Firmicutes bacteria CAG:102, the genus Oscillibacter, Clostridium clostridioforme, Bacteroides massiliensis, Clostridium saindens, Parabacteroides merdae, Eubacterium species CAG:161, Ruminococcus gnavus, and Clostridium clostridioforme.

[0052] In some embodiments, the disclosed microbial compositions exclude bacteria from one or more of the following families: Ruminococcus, Clostridium, Lachnospira, Micrococcus, and / or Veillonella, or contain 1 x 10 6 , 1×10 5 , 1×10 4 , 1×10 3 , or 1×10 2 cells or CFU (or any derivable range therein) of bacteria from one or more of the following families: Ruminococcus, Clostridium, Lachnospira, Micrococcus, and / or Veillonella.

[0053] In some embodiments, the disclosed microbial compositions exclude bacteria from one or more of the following, or from 1 x 10 6 , 1×10 5 , 1×10 4 , 1×10 3 , or 1×10 2cells or CFU (or any derivable range therein) of bacteria from one or more of the following: Bacteroides coagulans, Clostridium ardenense, Clostridium aldritii, Clostridium alkalicellulosi, Clostridium amygdalinum, Clostridium asparagiforme, Clostridium cellulosi, Clostridium citronniae, Clostridium clariflavum DSM 19732, Clostridium clostridioforme, Clostridium corinum, Clostridium fimetallium, Clostridium hyranonis, Clostridium fungatei, Clostridium hylemonae DSM 15053, Clostridium indris, Clostridium lactifermentans, Clostridium leptum, Clostridium methylpentosum, Clostridium oroticum, Clostridium papyrosolvens DSM 15053 2782, Clostridium populeci, Clostridium propionicum, Clostridium saccharolyticum, Clostridium scindens, Clostridium sporosphaeroides, Clostridium stercorarium, Clostridium straminisorbens, Clostridium sufflavum, Clostridium thermitizis, Clostridium thermosuccinogens, Clostridium viride, Clostridium xylanolyticum, Desulfotomaculum guttideum, Eubacterium lectare ATCC 33656, Eubacterium doricum, Eubacterium erigens ATCC27750, Eubacterium hallii, Eubacterium infilmum, Eubacterium silaeum, Eubacterium tenue, Ruminococcus torques, Acetanaerobacterium elongatum, Acetatifactor muris, Acetivibrio cellulolyticus, Acetivibrio ethanolguignens, Acholeplasma brassicae 0502, Acholeplasma parvum, Acholeplasma vituri, Acinetobacter ji Actinobacillus junii, Actinobacillus porcinus, Actinomyces boudenii, Actinomyces dentalis, Actinomyces odontolyticus, Acutalibacter muris, Aerococcus viridans, Aeromicrobium fastidiosum, Alistipes finegoldii, Alistipes obesi, Alistipes onderdonchii, Alistipes putoreginis, Alistipes shahii, Alistipes shahii WAL 8301, Alistipes timonensis JC136, Alcalibacter saccharofermentans, Alcaliphilus metalliregens QYMF, Alisonella histaminiformans, Allobaculum stercolicanis DSM 13633, Alloprevotella lava, Alloprevotella tannellae, Anaerobacterium chalcisorbens, Anaerobiospirillum tomasii, Anaerobium aceticilicum, Anaerococcus octavius ​​NCTC 9810, Anaerococcus provenciensis, Anaerococcus vaginalis ATCC51170, Anaerocorumna jejuensis, Anaerophyllum aguirre, Anaerophthus stercorihominis, Anaeroglobus geminatus, Anaeromassilibacillus senegalensis, Anaeroplasma abactoclasticum, Anaerorhabdos fulcosa, Anaerosporobacter mobilis, Anaerostipes butyraticus, Anaerostipes caccae, Anaerostipes haddo Rus, Anaerotorunculus colihominis, Anaerovorax odoritans, Anoxybacillus lupiensis, Aquabacterium rimnoticum, Arcobacter butzleri, Arthrospira platensis, Asaccharobacter ceratus, Atopobium parvum, Bacteroides caccae, Bacteroides caesimulis, Bacteroides cellulosilyticus, Bacteroides clarus YIT 12056, Bacteroides dorei, Bacteroides eggertii, Bacteroides finegoldii, Bacteroides fragilis, Bacteroides gallinarum, Bacteroides massiliensis, Bacteroides oleiciplenus YIT 12058, Bacteroides plebeius DSM 17135, Bacteroides rodentium JCM 16496, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides xylanisolvens XB1A, Bacteroides xylanolyticus, Barnesiella intestinihominis, Beduini massiliensis, Bifidobacterium bifidum, Bifidobacterium denthium, Bifidobacterium longum subsp. infantis, Blautia caecimulus, Blautia coccoides, Blautia faeces, Blautia glucellacea, Blautia hansenii DSM 20583, Blautia hydrogenotrophica, Blautia luci, Blautia luci DSM 14534, Blautia wexlerae DSM19850, Budvisia aquatica, Butyricicoccus plicaecorum, Butyricimonas paravillosa, Butyrivibrio crossotus, Caldicoprobacter oshimai, Caloramater kurhaashii, Caloramater proteoclasticus, Caloramater kimbaiensis, Campylobacter gracilis, Campylobacter rectus, Campylobacter ureolyticus DSM 20703, Capnocytophaga gingivalis, Capnocytophaga redovetteri, Capnocytophaga sputigena, Casartella massiliensis, Catabacter hongkongenesis, Catenibacterium mitsokai, Christensenella minuta, Christensenella zimonensis, Chryseobacterium takurimacanese, Citrobacter freundii, Cloacibacillus porcorum, Clostridioides difficile ATCC 9689=DSM 1296, Clostridium amylolyticum, Clostridium bowmanii, Clostridium butyricum, Clostridium cadaveris, Clostridium corycanis, Clostridium gassigenes, Clostridium lentotherum DSM 5427, Clostridium oceanicum, Clostridium oryzae, Clostridium paraptrificum, Clostridium pasqui, Clostridium perfringens, Clostridium quinii, Clostridium saccharobutyricum, Clostridium sporogenes, Clostridium ventrici, Collinsella aerofaciens, Comamonas testosteroni, Coprobacter fastidiosus NSB1, Coprococcus eutactus, Corynebacterium diphtheriae, Corynebacterium durum, Corynebacterium mycetoides, Corynebacterium pirubiciproducens ATCCBAA-1742, Corynebacterium tuberculostearicum, Curturomica massiliensis, Kneatibacter caesimulis, Defluviitarea saccharophila, Delftia acidovorans, Desulfitobacterium chlororespirans, Desulfitobacterium metallireducens, Desulfosporosinus acididurans, Desulfotomaculum halophytum, Desulfotomaculum intricatum, Desulfotomaculum tongense, Desulfovibrio desulfuricans subsp. desulfuricans, Desulfovibrio idahonensis, Desulfovibrio litoralis, Desulfovibrio pigel, Desulfovibrio simplex, Desulfovibrio zosterae, Desulfuromonas acetoxydans, Dethiobacter alcaliphilus AHT 1, Dethiosulfatibacter aminovorans, Diaryster invissus, Diaryster propionicifaciens, Dielma fastidiosa, Zietzia alimentaria 72, Dorea longicatena, Dysgonomonas gadei ATCC BAA-286, Dysgonomonas mossii, Egglutella lenta, Eikenella corodens, Eisenberghiella thai, Emergensia timonensis, Enorma massiliensis phI, Enterococcus faecalis, Enterorrhabdus muris, Ethanoligenes harvinens YUAN-3, Eubacterium coprostanoligenes, Eubacterium limosum, Eubacterium oxidoreducens, Eubacterium sulci ATCC35585, Eubacterium uniforme, Eubacterium ventriosum, Eubacterium xylanophilum, Ecchibacter muris, Ezakiella perensis, Faecalibacterium prausnitzii, Faecalibacterium ascidiformans, Faecalibacterium cylindroides, Filifactory bitosus, Flavonifracter prautii, Flinchibacter butyricus, Flinchicoccus caesimulis, Fucophilus fucoidanolyticus, Fusicatenibacter saccharivorans, Fusobacterium mortiferum, Fusobacterium nucleatum subsp. vincentii, Fusobacterium simiae, Fusobacterium valium, Garciella nitrachileducens s, Gemella haemolysans, Gemella formicilis, Gordonibacter urolithinfaciens, Gracilibacter thermotolerans JW / YJL-S1, Granulicatella elegans, Guggenheimella bovis, Haemophilus haemolyticus, Helicobacter typhlonius, Hesperia stercolisuis, Hordemanella biformis, Hordemannia massiliensis AP2, Howardella ureilichia, Fungatela effluvii, Fungatela hatewai, Hydrogenoanaerobacterium saccharovorans, Ifubacter massiliensis, Intestinibacter bartoletti, Intestinimonas butyriciproducens, Irregularibacter muris, Chironiella laminariae DSM19542, Kloppenstedtia guangzouensis, Lachnoanaerobaculum orale, Lachnoanaerobaculum umeaens, Lachnoclostridium phytofermentans, Lactobacillus acidophilus, Lactobacillus algidus, Lactobacillus animalis, Lactobacillus casei, Lactobacillus delbrueckii, Lactobacillus hornicalis, Lactobacillus iners, Lactobacillus pentosus, Lactobacillus logosae, Lactococcus garvieae, Lactonifactor longobiformis, Leptotrichia baccharis, Leptotrichia hofstadii, Leptotrichia hongkongenesis, Leptotrichia wadei, Leuconostoc inhae, Rebiella massiliensis, Lorielopsis cabernicola, Lutispora thermophila, Marinilabiria salmonicola JCM 21150, Malvinbrianchia formatexigens, Mesoplasma fotulis, Methanobilevibacter smithii ATCC 35061, Methanomassiliococcus ruminiensis B10, Methylobacterium exotorchiens, Mitsuokera jalarginiii, Mobilitarea sibirica, Mobiluncus curtisii, Mogibacterium pullulum, Mogibacterium thymidum, Moorella grisellini, Moorella fumifera, Moraxella nonrequefaciens, Moraxella osloensis, Morganella morganii, Moriella indrigenes, Muribacrum intestinale, Murimonas intestini, Natlanaerovirga pectinivora, Neglecta zimonensis, Neisseria cinerea, Neisseria oralis, Nocardioides mesophilus, Novibacillus thermophilus, Ochrobacterum anthropi, Odoribacter splanchnicus, Olsenella profusa, Olsenella uri, Oribacterium asaccharolyticum ACB7, Oribacterium sinus, Oscillibacterium ruminans tium GH1, Oscillibacter valericigenes, Oxobacter fennigii, Pantoea agglomerans, Papilibacter cinnamivorans, Parabacteroides faeces, Parabacteroides gordostainii, Parabacteroides gordonii, Parabacteroides meldae, Parasporobacterium paucivorans, Parasterella exclementhihominis, Parasterella secunda, Parvimonas micra, Peptococcus niger, Peptoniphilus dueldenii ATCC BAA-1640, Peptoniphilus grossensis ph5, Peptoniphilus coenoeneniae, Peptoniphilus senegalensis JC140, Peptostreptococcus stomatis, Phascolarctobacterium succinatus, Phosea massiliensis, Pontibacter indicus, Porphyromonas bennonis, Porphyromonas endodontalis, Porphyromonas pasteuri, Prevotella bergensis, Prevotella buccae ATCC 33574, Prevotella denticola, Prevotella enoeca, Prevotella fusca JCM 17724, Prevotella roesteichii, Prevotella nigrescens, Prevotella oris, Prevotella parens ATCC 700821, Prevotella stercorea DSM 18206, Prevotella macilia timonensis, Propionispira arquata, Proteus mirabilis, Providencia rettgeri, Pseudobacteroides cellulosolvens ATCC 35603=DSM 2933, Pseudobutyrivibrio ruminis, Pseudoflavonifractor capillosus ATCC 29799, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas mandelii, Pseudomonas nitroreducens, Pseudomonas putida, Raoutella ornithinelytica, Raoutella planticola, Raoutibacter massiliensis, Robinsonia peoriensis, Romboutsia timonensis, Roseburia faeces, Roseburia hominis A2-183, Roseburia intestinalis, Roseburia inulinivorans DSM 16841, Rothia dentocariosa ATCC17931, Ruminiclostridium thermocellum, Ruminococcus albus, Ruminococcus bromyii, Ruminococcus calidus, Ruminococcus champanerensis 18P13=JCM 17042, Ruminococcus faeces JCM 15917, Ruminococcus flavefaciens, Ruminococcus gaubireaui, Ruminococcus lactalis ATCC 29176, Rumelii Bacillus pycnus, Saccharofermentans acetigenes, Scardovia wiggsiae, Sclerotinia thermodepolymerans, Sedimentibacter hongkongenesis, Selenomonas sputigena ATCC 35185, Slacchia exigua ATCC 700122, Slacchia pyriformis YIT 12062, Solitarea canadensis, Solobacterium mouleys, Sphingomonas aquatilis, Spiroplasma alleghenense, Spiroplasma chinense, Spiroplasma chrysopicola, Spiroplasma chrysocola, Spiroplasma lampyzicola, Sporobacter thermitizis, Staphylococcus aureus, Stenotrophomonas maltophilia, Stomatobaculum longum, Streptococcus agalactiae ATCC 13813, Streptococcus cristatus, Streptococcus echinus, Streptococcus gordonii, Streptococcus lactarius, Streptococcus parauberis, Subdrigranulum variabile, Succinibrio dextrinsorbens, Sterella stercolicanis, Sterella wadswolltensis, Syntrophococcus scromutans, Syntrophomonas zehnderi OL-4, Terisporobacter mayombei, Thermoreophilum albumen, Treponema denticola, Treponema sokranskii, Tyzerella nexilis DSM 1787, Baritarea guaimacensis, Baritarea proniensis, Vampirovibrio chlorellavorus, Veillonella atypica, Veillonella denticariosi, Veillonella dispar, Veillonella parvula, Victivelis badensis, Vulcanibacillus modesticardus, and Weissella confusa.

[0054] In some embodiments, the methods further comprise treating a subject predicted to have a non-toxic or effective response with a combination immune checkpoint blockade therapy. In some embodiments, the methods further comprise treating a subject predicted to have a toxic and / or ineffective response with a disclosed composition. In some embodiments, the methods further comprise treating a subject with a combination of (i) an inhibitor of PD-1, PDL1, or PDL2 and (ii) an inhibitor of CTLA-4, B7-1, or B7-2.

[0055] In some embodiments, a virulent, non-virulent, efficacious, or ineffective response is predicted when one or more bacteria of the phylum, orders, families, genera, or species described herein are determined to be at least 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% (or any derivable range therein) in relative abundance. In some embodiments, a combination of bacteria is determined to have a combined relative abundance of at least 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% (or any derivable range therein).

[0056] The disclosed compositions may exclude one or more bacterial genera or species described herein, or may contain 1 x 10 6 , 1×10 5 , 1×10 4 , 1×10 3 , or 1×10 2 The bacterial culture may contain less than 100 cells or CFU (or any derivable range therein) of one or more of the bacteria described herein.

[0057] A favorable or unfavorable profile described herein may exclude one or more bacteria described herein or may include one or more of the bacteria described herein at a relative abundance of less than 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% (or any derivable range therein).

[0058] In some embodiments, the populations of bacteria each comprise at least 1 x 10 3 The bacteria are present in the composition at a concentration of CFU. In some embodiments, the composition is a live bacterial product or a live biotreatment product. In some embodiments, the bacteria are lyophilized, freeze-dried, or frozen. In some embodiments, the composition is formulated for oral delivery. In some embodiments, the composition formulated for oral delivery is a tablet or capsule. In some embodiments, the tablet or capsule comprises an acid-resistant enteric coating. In some embodiments, the composition is formulated for rectal administration via colonoscopy, nasogastric sigmoidoscopy, or enema. In some embodiments, the composition can be reconstituted for ultimate delivery, including as a liquid, suspension, gel, gel tab, semisolid, tablet, sachet, lozenge, capsule, or enteral formulation. In some embodiments, the composition is formulated for multiple administration. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient.

[0059] It is specifically intended that any limitation discussed with respect to one embodiment herein may also apply to any other embodiment herein. Moreover, any composition of the present invention may be used in any method of the present invention, and any method of the present invention may be used to produce or utilize any composition of the present invention. Aspects of embodiments described in the Examples are also embodiments that can be practiced in the context of embodiments discussed elsewhere in different Examples or elsewhere in this application, e.g., in the Summary of the Invention, Detailed Description of the Embodiments, Claims, and Figure Legends. [The present invention 1001] (a) The following genera or species: Flavonifractor, Dielma, Akkermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzzerella, Parabacteroides distasonis, Fournierella, Fournierella massiliensis, Eisenbergiella tayi, Tissierellales, Hungateiclostridium thermocellum, Dorea formisigenerans formicigenerans, Caloramator coolhaasi, Muricomes, Geosporobacter, Prevotella paludivivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter composti, and Anaerotignum lactatifermentans administering to a subject a composition comprising at least one isolated or purified population of bacteria belonging to one or more of: (b) treating the subject with a combination of (i) an inhibitor of PD-1, PDL1, or PDL2, and (ii) an inhibitor of CTLA-4, B7-1, or B7-2. 10. A method of treating cancer in a subject, comprising: [The present invention 1002] The composition is selected from the group consisting of: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercoris, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierales, Fungatei Clostridium thermocellum 1001. The method of claim 1001, comprising at least one isolated or purified population of bacteria belonging to one or more of the following: [The present invention 1003] 1002. The method of claim 1002, wherein said composition comprises at least one isolated or purified population of bacteria belonging to the genus Ackermansia. [The present invention 1004] The composition is selected from the group consisting of: Bacteroides fragilis, Vampirovibrio, Taiserella, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Muricomes intestini, Geosporobacter, Geosporobacter subterraneus, Anaerotignum lactatifermentans 1001. The method of claim 1001, comprising at least one isolated or purified population of bacteria belonging to one or more of the following: [The present invention 1005] The method according to any one of claims 1001 to 1004, wherein the cancer is skin cancer. [The present invention 1006] Any of the methods of inventions 1001 to 1004, wherein the cancer is basal cell skin cancer, squamous cell skin cancer, melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, keratoacanthoma, spindle cell tumor, sebaceous gland carcinoma, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, or angiosarcoma. [The present invention 1007] The method according to any one of claims 1001 to 1004, wherein the cancer is melanoma. [The present invention 1008] 1007. The method of claim 1007, wherein the melanoma is metastatic melanoma, lentigo maligna, lentigo maligna-derived melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, cutaneous melanoma, or desmoplastic melanoma. [The present invention 1009] The method of claim 1008, wherein the melanoma comprises cutaneous melanoma. [The present invention 1010] The method of any of claims 1001 to 1009, further comprising the step of administering at least one additional anti-cancer treatment. [The present invention 1011] The method of the present invention 1010, wherein the at least one additional anti-cancer treatment is surgical therapy, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, small molecule therapy, receptor kinase inhibitor therapy, anti-angiogenic therapy, cytokine therapy, cryotherapy, or biological therapy. [The present invention 1012] 10. The method of any of claims 1001-1011, wherein the inhibitor of (i), the inhibitor of (ii), and / or at least one additional anti-cancer treatment is administered intratumorally, intra-arterially, intravenously, intravascularly, intrapleurally, intraperitoneally, intratracheally, intrathecally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, topically, stereotactically, orally, or by direct injection or perfusion. [The present invention 1013] The method of any of claims 1001 to 1012, defined as a method of treating cancer in a subject diagnosed with a cancerous tumor. [The present invention 1014] The method of any of claims 1001 to 1013, comprising or further comprising the step of reducing or preventing one or more adverse events. [The present invention 1015] The method of any of claims 1001 to 1014, comprising or further comprising the step of reducing or preventing one or more severe adverse events. [The present invention 1016] The method of any one of claims 1014 to 1015, wherein the adverse event or severe adverse event is further classified as an immune-related adverse event. [The present invention 1017] The method of any of claims 1001 to 1016, wherein the subject has been determined to have an unfavorable microbial profile in the gut microbiome. [The present invention 1018] The unfavorable profile is classified as: Bacteroides, Dialister, Coprobacter, Intestinibacter, and Parasutterella The method of the present invention 1017, comprising a population of bacteria comprising bacteria belonging to one or more of: [The present invention 1019] 1018. The method of claim 1018, wherein the unfavorable profile comprises a population of bacteria including one or more of Bacteroides stercolis, Bacteroides caccae, Bacteroides intestinalis, Coprobacter, Intestinibacter bartletti, Parasutterella secunda, and Dialister propionicifaciens. [The present invention 1020] The method of any one of claims 1018 to 1019, wherein the unfavorable profile is further defined as a toxicity-associated profile. [The present invention 1021] The unfavorable profile is classified as: Lactobacillus, Bacteroides, Prevotella, Citrobacter, Clostridium, Hungateiclostridium, Eubacterium, Hafniaceae, Enterobacter, Hafnia, Roseburia, Weissella, Bacilli, Lactobacillales, and Klebsiella The method of claim 1017, comprising a population of bacteria comprising bacteria belonging to one or more of: [The present invention 1022] Unfavorable profiles were observed in Lactobacillus rogosae, Bacteroides fragilis, Prevotella copri, Prevotella shahii, Clostridium hylemonae, Hungateiclostridium aldrichii, Citrobacter rodentium, Eubacterium sulci, Citrobacter freundii, Eubacterium halii, Enterobacter cloacae, Hafnia alvei, Roseburia hominis, hominis, Weissella paramesenteroides, and Klebsiella aerogenes. [The present invention 1023] The method of any one of claims 1021 to 1022, wherein the unfavorable profile is further defined as a non-responder profile. [The present invention 1024] Any of the methods of claims 1017 to 1023, wherein the subject is determined to contain an unfavorable microbial profile by analyzing the microbiome in a sample from the subject. [The present invention 1025] The method of claim 1024, wherein the sample is a fecal sample. [The present invention 1026] 1026. The method of claim 1024 or 1025, wherein the analysis comprises performing 16S ribosomal sequencing and / or metagenomic whole genome sequencing. [The present invention 1027] The method of any of claims 1001 to 1026, wherein the subject has previously been treated for cancer. [The present invention 1028] The method of claim 1027, wherein the subject has been determined to be a non-responder to a previous treatment. [The present invention 1029] The method of any one of claims 1027 to 1028, wherein the patient has been determined to have had a toxic response to a previous treatment. [The present invention 1030] The method of any of claims 1027 to 1029, wherein the prior treatment comprises immune checkpoint blockade monotherapy or combination therapy. [The present invention 1031] The method of claim 1030, wherein the previous treatment comprises immune checkpoint blockade monotherapy comprising only one of an inhibitor of PD-1, PDL1, PDL2, CTLA-4, B7-1, or B7-2. [The present invention 1032] The method of any one of claims 1001 to 1031, wherein the cancer is recurrent. [The present invention 1033] The method of any of claims 1001 to 1032, wherein the inhibitor (i) is an anti-PD-1 monoclonal antibody, and / or the inhibitor (ii) is an anti-CTLA-4 monoclonal antibody. [The present invention 1034] The method of claim 1033, wherein (i) comprises nivolumab, pembrolizumab, or pidilizumab. [This invention 1035] The method of any one of claims 1033 to 1034, wherein (ii) comprises ipilimumab or tremelimumab. [The present invention 1036] The method of any of claims 1001 to 1035, wherein the subject is treated with the isolated population of bacteria prior to or concurrently with treatment in (i) and (ii). [This invention 1037] The method of any of claims 1001 to 1036, wherein the purified population of bacteria comprises bacteria from at least two genera or species, and the ratio of the two bacteria is 1:1. [The present invention 1038] The method of any of claims 1001 to 1037, wherein said composition comprises at least two different species or genera or genera of bacteria. [This invention 1039] The method of any of claims 1001 to 1038, wherein the composition provides an alpha diversity that is at least 5 after administration to a subject. [The present invention 1040] The method of any of claims 1001 to 1039, wherein the subject has been diagnosed with stage III or IV cancer. [The present invention 1041] The method of any one of claims 1001 to 1040, wherein the cancer comprises stage III or IV cancer. [The present invention 1042] The method of any one of claims 1001 to 1041, further comprising administering an antibiotic. [This invention 1043] The method of claim 1042, wherein the antibiotic is administered prior to or simultaneously with the composition comprising at least one isolated or purified population of bacteria. [This invention 1044] A method for treating cancer in a subject, comprising administering to the subject, who has been determined to have a favorable microbial profile in the intestinal microbiome, a combination of (i) an inhibitor of PD-1, PDL1, or PDL2 and (ii) an inhibitor of CTLA-4, B7-1, or B7-2. [This invention 1045] The method of claim 1044, wherein the cancer is skin cancer. [The present invention 1046] The method of claim 1044, wherein the cancer is basal cell skin cancer, squamous cell skin cancer, melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, keratoacanthoma, spindle cell tumor, sebaceous gland carcinoma, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, or angiosarcoma. [This invention 1047] The method of claim 1044, wherein the cancer is melanoma. [This invention 1048] 1047. The method of claim 1047, wherein the melanoma is metastatic melanoma, lentigo maligna, lentigo maligna-derived melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, cutaneous melanoma, or desmoplastic melanoma. [This invention 1049] The method of claim 1048, wherein the melanoma comprises cutaneous melanoma. [The present invention 1050] The method of any of claims 1044 to 1049, further comprising the step of administering at least one additional anti-cancer treatment. [This invention 1051] The method of claim 1050, wherein the at least one additional anti-cancer treatment is surgical therapy, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, small molecule therapy, receptor kinase inhibitor therapy, anti-angiogenic therapy, cytokine therapy, cryotherapy, or biological therapy. [This invention 1052] 10. The method of any of claims 1044 to 1051, wherein the inhibitor of (i), the inhibitor of (ii), and / or at least one additional anti-cancer treatment is administered intratumorally, intra-arterially, intravenously, intravascularly, intrapleurally, intraperitoneally, intratracheally, intrathecally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, topically, stereotactically, orally, or by direct injection or perfusion. [This invention 1053] 1052. The method of any of claims 1044 to 1052, defined as a method of treating cancer in a subject having a cancerous tumor. [This invention 1054] The method of any of claims 1044 to 1053, wherein treating cancer comprises reducing or preventing one or more adverse events. [This invention 1055] The method of any of claims 1044 to 1053, wherein treating cancer comprises reducing or preventing one or more severe adverse events. [This invention 1056] The method of any one of claims 1054 to 1055, wherein the adverse event or severe adverse event is further classified as an immune-related adverse event. [This invention 1057] The preferred profile is for the following genera or species: Bacteroides fragilis, Vampirovibrio, Tyzerella, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Muricomes intestini, Geosporobacter, Geosporobacter subterraneus, Anaerotignum lactifermentans The method of any of claims 1044 to 1056, comprising a population of bacteria comprising bacteria belonging to one or more of: [This invention 1058] The method of claim 1057, wherein the preferred profile comprises a population of bacteria comprising one or more of Bacteroides fragilis, Vampirovibrio, and Taiserella. [This invention 1059] The method of any one of claims 1057 to 1058, wherein the preferred profile is further defined as a non-toxic profile. [The present invention 1060] The preferred profile is for the following genera or species: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercolis, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierellales, Fungatei Clostridium thermocellum The method of any of claims 1044 to 1056, comprising a population of bacteria comprising bacteria belonging to one or more of: [This invention 1061] 1060. The method of claim 1060, wherein the preferred profile comprises a population of bacteria comprising one or more of Bacteroides stercolis, Butyricimonas faecihominis, Flavonifractor plautii, Dielma fastidiosa, Alistipes, and Akkermansia muciniphila. [The present invention 1062] The method of any one of claims 1060 to 1061, wherein the preferred profile is further defined as an effective profile. [This invention 1063] Any of the methods of claims 1044 to 1062, wherein the subject is determined to contain a favorable microbial profile by analyzing the microbiome in a sample from the subject. [This invention 1064] 1063. The method of claim 1063, wherein the sample is a fecal sample or a buccal sample. [This invention 1065] 1065. The method of claim 1063 or 1064, wherein the analysis comprises performing 16S ribosomal sequencing and / or metagenomic whole genome sequencing. [The present invention 1066] Any of the methods of claims 1044 to 1065, wherein the subject has previously been treated for cancer. [This invention 1067] The method of claim 1066, wherein the subject has been determined to be a non-responder to a previous treatment. [The present invention 1068] The method of any one of claims 1066 to 1067, wherein the patient has been determined to have had a toxic response to a previous treatment. [This invention 1069] The method of any of claims 1066 to 1068, wherein the prior treatment comprises immune checkpoint blockade monotherapy or combination therapy. [The present invention 1070] The method of claim 1069, wherein the previous treatment comprises immune checkpoint blockade monotherapy comprising only one of an inhibitor of PD-1, PDL1, PDL2, CTLA-4, B7-1, or B7-2. [This invention 1071] The method of any one of claims 1044 to 1070, wherein the cancer is recurrent. [This invention 1072] The method of any of claims 1044 to 1071, wherein the inhibitor of (i) and / or (ii) is an anti-PD-1 monoclonal antibody or an anti-CTLA-4 monoclonal antibody. [This invention 1073] The method of claim 1072, wherein (i) comprises nivolumab, pembrolizumab, or pidilizumab. [This invention 1074] The method of any one of claims 1072 to 1073, wherein (ii) comprises ipilimumab or tremelimumab. [This invention 1075] The method of any of claims 1044 to 1062, wherein the subject has not previously been treated with a single or combination immune checkpoint blockade therapy. [This invention 1076] The method of any of claims 1044 to 1075, wherein the subject has been diagnosed with stage III or IV cancer. [This invention 1077] The method of any one of claims 1044 to 1076, wherein the cancer comprises stage III or IV cancer. [This invention 1078] 1. A method of predicting response to combination immune checkpoint inhibitor therapy in a subject with cancer, comprising: (a) detecting a microbial profile in a sample obtained from a subject; (b) the following genera: Bacteroides, Diaryster, Coprobacter, Intestinibacter, and Parasatellella predicting a toxic response to the therapy when one or more of the bacteria are detected in a sample from the subject; or (c) the following genera or species: Bacteroides fragilis, Vampirovibrio, Tyzerella, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Muricomes intestini, Geosporobacter, Geosporobacter subterraneus, Anaerotignum lactifermentans predicting a non-toxic response to the therapy when one or more of the bacteria are detected in a sample from the subject. [This invention 1079] The method of the present invention 1078, wherein a toxic response is predicted when one or more of Bacteroides stercoris, Bacteroides caccae, Bacteroides intestinalis, Coprobacter, Intestinibacter bartoletti, Parasatella secunda, and Diarrister propionicifaciens are detected in a sample from the subject. [The present invention 1080] The method of claim 1078, wherein a non-toxic response is predicted when one or more of Bacteroides fragilis, Vampirovibrio, and Taisserella are detected in a sample from the subject. [This invention 1081] 1. A method of predicting response to combination immune checkpoint inhibitor therapy in a subject with cancer, comprising: detecting a microbial profile in a sample obtained from the subject; The following genera or species: Bacteroides stercoris, Butyricimonas, Flavonifractor, Dielma, Alistipes, Ackermansia muciniphila, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierellales, and Fungatei Clostridium thermocellum predicting an effective response to said therapy when one or more of the bacteria selected from the group consisting of: The following genera or species: Lactobacillus, Bacteroides fragilis, Prevotella, Citrobacter, Clostridium hilemonae, fungatei, Clostridium aldritii, Citrobacter rodentium, Eubacterium sursi, Hafniaceae, Citrobacter freundii, Eubacterium harii, Enterobacter cloacae, Hafnia alvei, Hafnia, Roseburia hominis, Weissella paramesenteroides, Enterobacter, Lactobacillus logosae, Class Bacillales, Order Lactobacillales, Klebsiella aerogenes, and Klebsiella predicting an ineffective response to the therapy when one or more of the bacteria are detected in a sample from the subject. [This invention 1082] The method of the present invention 1081, wherein an effective response is predicted when one or more of Bacteroides stercoris, Butyricimonas faesihominis, Flavonifracter platii, Dielma fastidiosa, Alistipes, and Ackermansia muciniphila are detected in a sample from the subject. [This invention 1083] The method of claim 1081, wherein an ineffective response is predicted when one or more of Lactobacillus logosae, Bacteroides fragilis, Prevotella copuri, and Prevotella shahii are detected. [This invention 1084] In subjects, Bacteroides stercoris, Bacteroides caccae, Bacteroides intestinalis, Diaryster, Bacteroides fragilis, Vampirovibrio, Taiserella, Flavonifracter prautii, Dielma fastidiosa, Butyricimonas faesihominis, Alistipes, Ackermansia muciniphila, Lactobacillus logosae, Prevotella copri, Prevotella shahii, Citrobacter, Clostridium hilemonae, fungatei, Clostridium aldriichii, Citrobacter rodentium, Eubacterium sursi, Hafniaceae, Citrobacter freundii, Eubacterium harii, Enterobacter cloacae, Hafnia alvei, Hafnia, Roseburia hominis, Weissella pa ramesenteroides, Enterobacter, Bacilli, Lactobacillales, Klebsiella aerogenes, Klebsiella, Coprobacter, Intestinibacter bartoli, Intestinibacter, Parasatella secunda, Diaryster propionicifaciens, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kuhlhaasii, Muricomes, Muricomes intestini, Geosporobacter, Geosporobacter subterraneanus, and Anaerotignum lactifermentans. [This invention 1085] The method of claim 1084, wherein the subject has been diagnosed with cancer. [This invention 1086] The method of any one of claims 1078 to 1083 or 1085, wherein the cancer is skin cancer. [This invention 1087] The method of claim 1086, wherein the cancer is basal cell skin cancer, squamous cell skin cancer, melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, keratoacanthoma, spindle cell tumor, sebaceous gland carcinoma, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, or angiosarcoma. [This invention 1088] The method of any one of claims 1078 to 1083 or 1085, wherein the cancer is melanoma. [This invention 1089] 108. The method of claim 1088, wherein the melanoma is metastatic melanoma, lentigo maligna, lentigo maligna-derived melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, cutaneous melanoma, or desmoplastic melanoma. [The present invention 1090] The method of claim 1089, wherein the melanoma comprises cutaneous melanoma. [This invention 1091] The method of any of claims 1084 to 1090, wherein the subject has been diagnosed with stage III or IV cancer. [This invention 1092] The method of any of claims 1078 to 1083 or 1086 to 1091, further comprising treating a subject predicted to have a non-toxic or effective response with a combination immune checkpoint blockade therapy. [This invention 1093] Subjects predicted to have toxicity or ineffective response were selected from the following genera or species: Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzerellales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactatifermentans The method of any of claims 1078 to 1083 or 1086 to 1092, further comprising the step of treating with a composition comprising at least one isolated or purified population of bacteria belonging to one or more of the following: [This invention 1094] The composition is selected from the group consisting of: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercolis, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierellales, Fungatei Clostridium thermocellum 1093. The method of claim 1093, comprising at least one isolated or purified population of bacteria belonging to one or more of the following: [This invention 1095] The method of any one of claims 1093 to 1094, further comprising treating the subject with a combination of (i) an inhibitor of PD-1, PDL1, or PDL2, and (ii) an inhibitor of CTLA-4, B7-1, or B7-2. [This invention 1096] The method of any of claims 1078 to 1095, further comprising administering at least one additional anti-cancer treatment. [This invention 1097] The method of claim 1096, wherein the at least one additional anti-cancer treatment is surgical therapy, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, small molecule therapy, receptor kinase inhibitor therapy, anti-angiogenic therapy, cytokine therapy, cryotherapy, or biological therapy. [This invention 1098] The method of invention 1095 or 1096, wherein the inhibitor of (i), the inhibitor of (ii), and / or at least one additional anti-cancer treatment is administered intratumorally, intra-arterially, intravenously, intravascularly, intrapleurally, intraperitoneally, intratracheally, intrathecally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, topically, stereotactically, orally, or by direct injection or perfusion. [This invention 1099] The method of any of claims 1078 to 1098, wherein the subject has previously been treated for cancer. [The present invention 1100] The method of claim 1099, wherein the subject has been determined to be a non-responder to a previous treatment. [The present invention 1101] The method of any one of claims 1099 to 1100, wherein the patient has been determined to have had a toxic response to a previous treatment. [The present invention 1102] The method of any of claims 1078 to 1101, wherein the prior treatment comprises immune checkpoint blockade monotherapy or combination therapy. [The present invention 1103] The method of claim 1102, wherein the previous treatment comprises immune checkpoint blockade monotherapy comprising only one of an inhibitor of PD-1, PDL1, PDL2, CTLA-4, B7-1, or B7-2. [The present invention 1104] The method of any one of claims 1078 to 1103, wherein the cancer is recurrent. [This invention 1105] The method of any of claims 1095 to 1104, wherein the inhibitor of (i) and / or (ii) is an anti-PD-1 monoclonal antibody or an anti-CTLA-4 monoclonal antibody. [The present invention 1106] The method of claim 1105, wherein (i) comprises nivolumab, pembrolizumab, or pidilizumab. [This invention 1107] The method of any one of claims 1105 to 1106, wherein (ii) comprises ipilimumab or tremelimumab. [This invention 1108] The method of any of claims 1078 to 1102, wherein the subject has not previously been treated with a single or combination immune checkpoint blockade therapy. [This invention 1109] The method of any one of claims 1078 to 1108, wherein said sample is a fecal sample or a buccal sample. [The present invention 1110] 107. The method of any of claims 1078 to 1109, wherein the detecting comprises performing 16S ribosomal sequencing and / or metagenomic whole genome sequencing. [The present invention 1111] The following genera or species: Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzerellales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactatifermentans A composition comprising at least one isolated or purified population of bacteria belonging to one or more of the following: [The present invention 1112] The following genera or species: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercolis, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierellales, Fungatei Clostridium thermocellum A composition comprising at least one isolated or purified population of bacteria belonging to one or more of the following: [The present invention 1113] The following genera or species: Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzerellales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactatifermentans A composition comprising at least two isolated or purified populations of bacteria belonging to one or more of the following: [This invention 1114] The following genera or species: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercolis, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierellales, Fungatei Clostridium thermocellum A composition comprising at least two isolated or purified populations of bacteria belonging to two or more of the following groups: [This invention 1115] Bacterial populations each contain at least 1 × 10 3 The composition of any one of claims 1111 to 1114, wherein the composition is present in a concentration of CFU. [The present invention 1116] The composition of invention 1113 or 1115, which is a live bacterial product. [This invention 1117] The composition of any one of claims 1111 to 1116, wherein the bacteria is lyophilized, freeze-dried, or frozen. [This invention 1118] 8. The composition of any of claims 1111 to 1117, formulated for oral delivery. [This invention 1119] The composition of claim 1118, wherein the composition formulated for oral delivery is a tablet or capsule. [The present invention 1120] 1119. The composition of claim 1119, wherein the tablet or capsule comprises an acid-resistant enteric coating. [This invention 1121] Any of the compositions of claims 1111 to 1116, wherein the composition comprising at least one isolated or purified population of bacteria, or at least two isolated or purified populations of bacteria, is formulated for rectal administration via colonoscopy, sigmoidoscopy with a nasogastric tube, or enema. [This invention 1122] Any of the compositions of inventions 1111 to 1116, which can be reconstituted for ultimate delivery as a liquid, suspension, gel, geltabs, semisolid, tablet, sachet, lozenge, capsule, or as an enteral formulation. [This invention 1123] Any of the compositions of claims 1111 to 1122, which is formulated for multiple administration. [This invention 1124] The composition of any one of claims 1111 to 1123, further comprising a pharmaceutically acceptable excipient. [Invention 1125] The composition of any of claims 1111 to 1124, wherein the purified population of bacteria comprises bacteria from at least two genera or species, and the ratio of the two bacteria is 1:1. [The present invention 1126] The composition of any of claims 1111 to 1125, comprising bacteria of at least two different species or genera. [This invention 1127] Any of the compositions of claims 1111 to 1126, which provides an alpha diversity of at least 5 after administration to a subject. [Brief explanation of the drawings]

[0060] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. A better understanding of the invention may be obtained by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [Figure 1] Patient cohort and biospecimen scheme. Advanced melanoma patients (n = 53) were evaluated for clinical outcomes and correlative biospecimen (tumor, peripheral blood mononuclear cells, fecal microbiome) analysis before and after initiating combined anti-CTLA-4 and anti-PD-1 blockade. [Figure 2A]Figure 2A-G. Molecular and immunological predictors of response. (A) Nonsynonymous variants (NSVs) counts in pretreatment tumor samples (n=26) grouped by binary best overall response (BOR; R=responder, n=20; NR=non-responder, n=6). Specific objective responses are indicated by the color of each data point (p=0.20, Mann-Whitney test). [Figure 2B] Figure 2A-G. Molecular and immune predictors of response. (B) Copy number loss burden (affected genomic region) in pretreatment tumor samples (n=26) grouped by dichotomized best overall response (p<0.05, Mann-Whitney test). [Figure 2C] Figure 2A-G. Molecular and immunological predictors of response. (C) Genes significantly affected by copy number variation (CNV). [Figure 2D] Figure 2A-G. Molecular and immune predictors of response. (D) CNV landscape assessed by whole-exome sequencing (n = 26 tumors), showing loss and gain of CNVs affecting selected genes recurrently mutated in melanoma, IFN signaling genes, and antigen processing / presentation genes. [Figure 2E] Figure 2A-G. Molecular and immunological predictors of response. (E) Density of infiltrating CD8+ cells (number / mm2) in pretreatment tumors by singlet stain immunohistochemistry, grouped by binary response (n=19 R, n=6 NR; p=0.052, one-sided Mann-Whitney test). [Figure 2F] Figure 2A-G. Molecular and immunological predictors of response. (F) Entropy of pre-treatment intratumoral T cell receptor (TCR) repertoires comparing R (n=19) vs. NR (n=6) repertoires (p=0.058, Mann-Whitney test). [Figure 2G]Figure 2A-G. Molecular and immune predictors of response. (G) Pretreatment intratumoral TCR repertoire clonality grouped by response (n=19 R, n=6 NR; p=0.28, Mann-Whitney test). [Figure 3-1] Figure 3A-F. Circulating T cell repertoire composition and phenotype predict toxicity. (A) Comparison of Ki67+ cells within CD8+ T effector (Teff) cells in early-treatment blood samples among patients (n=14) grouped according to high-grade irAEs (p<0.01 and p=0.013, respectively, Mann-Whitney test). (B) Circulating T cell repertoire diversity (inverse Simpson's function) as measured from TCR sequencing data of pre-treatment peripheral blood lymphocytes (n=24) according to the occurrence (or absence) of ≥Gr3 irAEs (p=0.028, Mann-Whitney test). Receipt of prior systemic immunotherapy is indicated by the color of each data point. (C) Grade 3 or higher immune-related adverse events (≥Gr3) Entropy of the circulating T cell repertoire derived from TCR sequencing in pretreatment peripheral blood lymphocytes (n=24) grouped according to the occurrence (or absence) of an irAE (p<0.01, Mann-Whitney test). Prior systemic immunotherapy is indicated by color. (D) Percentage of CD27+ cells among CD4+ T effector cells (Teff) and (E) Percentage of CD28+ cells among CD8+ Teff cells in pretreatment peripheral blood samples (Mann-Whitney test as shown; prior immunotherapy is indicated by color). (F) Stacked bar graph (top) and contingency table (bottom) showing the relationship between prior immunotherapy exposure and the risk of developing a high-grade immune-related adverse event after combination anti-CTLA-4 and anti-PD-1 blockade (p=0.016, Fisher's exact test). [Figure 3-2] See description of Figure 3-1. [Figure 4A] Figure 4A-F. Gut microbiome profiles correlate with response and toxicity to CICB. (A) Stacked bar graphs showing the microbial composition at the order level of each analyzed fecal sample (n = 31). [Figure 4B]Figure 4A-F. Gut microbiome profiles correlate with response and toxicity to CICB. (B) Alpha diversity (inverse Simpson's function) of fecal microbiomes grouped by response to concomitant immune checkpoint blockade (p=0.14, Mann-Whitney test). R = responders, NR = non-responders. [Figure 4C] Figure 4A-F. Gut microbiome profiles correlate with response and toxicity to CICB. (C) Alpha diversity (inverse Simpson's function) of the fecal microbiome grouped by the onset of high-grade immune-related adverse events after CICB initiation (p=0.59, Mann-Whitney test). [Figure 4D] Figure 4A-F. Gut microbiome profiles correlate with response and toxicity to CICB. (D) LEfSe plot of bacterial taxa differentially associated with response or non-response to CICB. LDA = Linear Discriminant Analysis. [Figure 4E] Figure 4A-F. Gut microbiome profiles correlate with response and toxicity to CICB. (E) LEfSe plot of bacterial taxa differentially associated with the development or absence of high-grade (≥grade 3) immune-related adverse events (irAEs). [Figure 4F] Figure 4A-F. Gut microbiome profiles correlate with response and toxicity to CICB. (F) Heatmap of correlations (Spearman's rho) between key virulence-associated or non-virulence-associated bacterial taxa quantified by multiparameter flow cytometry of baseline blood samples (n = 9) and circulating immune subsets. Teff = T effector cells, Tcm = T central memory, Tem = T effector memory, Treg = regulatory T cells. [Figure 5A]Figure 5A-E. CICB-induced microbiome shift correlates with tumor size. (A) Tumor size of MCA205 sarcoma (left panel) or RET melanoma (right panel) after four injections of the indicated antibodies (x-axis). Overall, mice were treated with six or five injections of anti-PD-1 and anti-CTLA-4, or the relevant isotype control, respectively. Experimental conditions consisted of anti-PD-1-treated mice (n = 6 MCA205, n = 6 RET), CICB-treated mice (n = 6 MCA205, n = 10 RET), or isotype-treated mice (n = 6 MCA205, n = 8 RET). Responders are shown in blue, corresponding to tumors that escape therapy, and non-responders are shown in red. Mann-Whitney test was used: *p<0.05, **p<0.01, ***p<0.001. [Figure 5B] Figure 5A-E. CICB-induced microbiome shifts correlate with tumor size. (B) Fecal microbiome beta diversity over time in MCA205 (left panel) and RET (right panel) (orange: before treatment; blue: 48 hours after two injections; red: 48 hours after five injections). [Figure 5C] Figure 5A-E. CICB-induced microbiome shifts correlate with tumor size. (C) Beta diversity colored according to tumor size for MCA205 (left panel) and RET (right panel). Purple intensity indicates increasing tumor size. ANOSIM defines group separation; p-values ​​define the significance of such separation after permuting samples 999 times. [Figure 5D] Figure 5A-E. CICB-induced microbiome shifts correlate with tumor size. (D) Venn diagram showing overlapping bacterial species before treatment initiation that are shared or not shared between tumor models corresponding to responders to CICB (left panel). Flavonifractor platyphyli (right panel), shared with melanoma patients, is preferentially found in R mice (Figure 4D-E). [Figure 5E]Figure 5A-E. CICB-induced microbiome shifts are associated with tumor size. (E) Time course of relative abundance in mice of taxa detected before treatment that were found to differ in abundance between R (blue) and NR (red) in both patient and mouse tumor types, contrasting species-level variations in abundance over time. [Figure 6-1]Figure 6A-I. Microbiota-dependent ileitis and colitis in tumor-bearing mice. (A-B) Representative photomicrographs of ileum from MCA205-bearing mice treated with isotype control, CICB, or CICB + ATB followed by recolonization with Erysipelotoclostridium ramosum or Bacteroides intestinalis (scale bar: 50 μm). Detailed scoring of H&E-stained ileum from MCA205 tumor-bearing mice treated with isotype control, CICB, or antibiotics alone, or followed by monocolonization with Bacteroides intestinalis (BI), Dierma fastidiosa (DF), or E. ramosum (ER); n = 9-22 per group. Student's t-test: *p < 0.05. (C) Relative ileal IL1□ expression in MCA205- and RET-bearing mice treated with or without antibiotics or monocolonized with the indicated bacteria. n=5–22. (D) Scoring of H&E-stained ileum from MCA205 tumor-bearing mice treated with CICB or CICB with an IL1R1 receptor blocker, n=10–12 mice / group. (E) Pathological assessment of inflammatory areas in the lamina propria after H&E staining of the colon in RET or MCA205 tumor-bearing mice treated with isotype control or CICB, n=7–16 / group. (F) Beta diversity (Bray-Curtis dissimilarity) of fecal microbiota assessed by 16S rDNA sequencing of gene amplicons colored according to the colonic inflammatory infiltrate score in RET tumor-bearing mice. Purple intensity indicates an increase in the inflammatory infiltrate score (left panel). Relative abundance of Bacteroides intestinalis and Vampirovibrio chlorellavorus, which are shared between mice and patients, contrasting their abundance in responders (NR, red; R, blue) and hosts with and without colonic toxicity (high inflammation score, green; low inflammation score, yellow) (right panel). (G) Experimental setup used in (H) and (I): FMT was performed using feces from non-responder (NR) kidney cancer patients after 3 days of antibiotic treatment in SPF mice. Two weeks later, luciferase-expressing RENCA cells were orthotopically implanted.Five days later, CICB was performed with or without oral gavage of isotype control or FMT using feces from responder (R) patients who did not experience Akkermansia muciniphila (Akk) or grade 3-4 irAEs. (H-I) Pathological assessment of inflammatory areas in the colonic lamina propria after H&E staining in RENCA tumor-bearing mice treated with isotype control or CICB on day 15. (I) ELISA of fecal lipocalin-2 levels (n=16 / group). Mann-Whitney test for C, D, E, H, I: *p<0.05, **p<0.01, ***p<0.001. [Figure 6-2] See description of Figure 6-1. [Figure 7] Figure 7A-B. Related to Figure 1 and Table 3: Patient treatment outcomes. (A) Kaplan-Meier curves of progression-free survival for the patient cohort (n=53). (B) Swimmer plot showing best overall response (shade of color), duration of best overall response (length of shaded portion of bar), and overall follow-up time (shaded + unshaded portion of bar) per patient, measured from the date of first dose of combination immune checkpoint blockade therapy. [Figure 8A] Figure 8A-E. Related to Figure 2: Molecular markers for combination immune checkpoint blockade. (A) Landscape of nonsynonymous polymorphisms (NSVs) identified by whole-exome sequencing affecting selected recurrently mutated genes, IFN signaling genes, and antigen processing / presentation genes in melanoma (n = 26 tumors). [Figure 8B] Figure 8A-E. Related to Figure 2: Molecular markers of combined immune checkpoint blockade. (B) NSV counts compared between BRAF V600 mutant patients (n=19) and wild-type patients (n=6) (p<0.001, permutation test). [Figure 8C] Figure 8A-E. Related to Figure 2: Molecular markers of combined immune checkpoint blockade. (C) Differences in the total number of predicted neoantigens, as well as the number of all, strongly, or weakly binding neoantigens, in patients grouped by best overall response (R = responder (blue), n = 20; NR = non-responder (red), n = 6; all p > 0.05, Mann-Whitney test). [Figure 8D] Figure 8A-E. Related to Figure 2: Molecular markers of combination immune checkpoint blockade. (D) Bar graph of the number of genes affected by copy number loss by chromosome, showing the dominant load within chromosomes 5, 10, and 15. [Figure 8E] Figure 8A-E. Related to Figure 2: Molecular markers for combination immune checkpoint blockade. (E) Genome-wide SGOL score shows enrichment for CNVs affecting chromosome 10. [Figure 9A] Figure 9A-E. Related to Figure 2 and Figure 3: Immune markers of CICB response and toxicity. (A) Comparison of intratumoral CD8+ cell density before (Pre) and after (Post) initiation of CICB (n=19 R, n=6 NR; p=ns, Mann-Whitney test; best overall response (BOR) indicated by the color of each data point). [Figure 9B] Figure 9A-E. Related to Figures 2 and 3: Immune markers of CICB response and toxicity. (B) Boxplot of the number of significantly expanded T cell clones (pre-treatment → on-treatment) detected by TCR sequencing of the peripheral blood immune repertoire, grouped by the presence or absence of high-grade immune-related adverse events (Gr3 irAE; n=7 present, n=9 absent; p=0.22, Mann-Whitney test). [Figure 9C] Figure 9A-E. Related to Figures 2 and 3: Immune markers of CICB response and toxicity. (C) Comparison of Ki67+ cells within T central memory (TCM) cells in blood samples taken early during treatment between patients (n=14) grouped according to high-grade irAEs (p<0.01 and p=0.013, respectively, Mann-Whitney test). (D) Percentage of CD28+ cells within CD4+ Teffs and (E) Percentage of CD27+ cells within CD8+ Teffs before treatment initiation according to high-grade irAEs (p=0.014 and p>0.05, respectively, Mann-Whitney test). Percentage of CD27+ cells within CD28+ cells within CD4+ Teffs. [Figure 9D] See legend to Figure 9C. [Figure 9E] See legend to Figure 9C. [Figure 10-1]Figure 10A-E. Related to Figure 4: Fecal microbiome characteristics associated with CICB response and toxicity. (A) Alpha diversity of the gut microbiota in CICB-treated patients (n=31) collected before or immediately after initiation of therapy, as measured by the indicated metrics (p-values ​​as shown, Mann-Whitney test). [Figure 10-2] Figure 10A-E. Related to Figure 4: Fecal microbiome characteristics associated with CICB response and toxicity. (B-C) Volcano plots of pairwise comparisons of OTUs (all taxonomic levels) by dichotomous response category (B) or development of high-grade toxicity (C). [Figure 10-3] See description of Figure 10-2. [Figure 10-4] Figure 10A-E. Related to Figure 4: Fecal microbiome features associated with CICB response and toxicity. (D) Heatmap of correlations (Spearman's r) between taxa and circulating immune cell populations associated with response or non-response at baseline (n=9). [Figure 11-1] Figure 11A-D. Related to Figure 5. Kinetics of treatment-induced shifts in gut bacterial composition and correlation with tumor size. (A, C) LEfSe plots identifying species 48 hours after two (A) or five (C) injections of mAb (orange: isotype control antibody, purple: anti-PD-1 antibody, green: CICB). Linear discriminant analysis (LDA) combined with effect size measures was used to identify species differentially present between each treatment group. (B, D) LDA score ≥ 2. Heatmap of Spearman correlation index showing correlation between each bacterial species identified from LEfSe analysis and tumor size after two (B) or five (D) injections for each tumor model, listed alphabetically. Red indicates a positive correlation with tumor size, while blue indicates a negative correlation. *p<0.05. [Figure 11-2] See description of Figure 11-1. [Figure 11-3] See description of Figure 11-1. [Figure 12A]Microbiota-dependent inflammatory cytokine patterns in the ileum and colon of tumor-bearing mice. (A) Heatmap of the log2-fold change in relative pro-inflammatory gene expression of CICB / isotype control ratios in the ileum and colon of MCA205- and RET-tumor-bearing mice treated with or without antibiotics or monocolonized with the indicated bacteria. n=5–22 / group. *p<0.05, **p<0.01, Mann-Whitney test. [Figure 13A] Figure 13A-F. The gut microbiome influences response to anti-PD1 therapy in late-stage melanoma patients through beneficial changes in anti-tumor immune infiltrate. (A) Comparison of alpha diversity in the gut microbiome between responders (R) and non-responders (NR). [Figure 13B] Figure 13A-F. The gut microbiome influences response to anti-PD1 therapy in late-stage melanoma patients through beneficial changes in anti-tumor immune infiltration. (B) LDA effect size histogram showing differentially enriched bacteria in R vs. NR, with bar length indicating the effect size associated with the taxon. [Figure 13C] Figure 13A-F. The gut microbiome influences response to anti-PD1 therapy in patients with late-stage melanoma through beneficial changes in anti-tumor immune infiltrate. (C) Spearman correlation matrix between pro-R gut bacteria and intratumoral immune infiltrate, as quantified by immunohistochemistry (n=15). [Figure 13D] Figure 13A-F. The gut microbiome influences response to anti-PD1 therapy in late-stage melanoma patients through beneficial changes in anti-tumor immune infiltration. (D) Experimental design of the study in germ-free mice. [Figure 13E] Figure 13A-F. The gut microbiome influences response to anti-PD1 therapy in late-stage melanoma patients through beneficial changes in anti-tumor immune infiltration. (E) Tumor growth curves of mice treated with anti-PDL1 after fecal transplantation of responders (R-FMT) or non-responders (NR-FMT), or mice without FMT. [Figure 13F]Figure 13A-F. The gut microbiome influences response to anti-PD1 therapy in late-stage melanoma patients through beneficial changes in anti-tumor immune infiltration. (F) Faecalibacterium levels in feces of R-FMT vs. NR-FMT mice at day 14 after tumor injection. [Figure 14] A cohort of patients with advanced melanoma (n=77) evaluated for clinical outcomes and correlative biospecimen analyses before and after initiating combined anti-CTLA-4 and anti-PD-1 blockade. [Figure 15-1] Figure 15A-D. Molecular and immune predictors of response. (A) Copy number loss burden (CNV) (affected genomic region) in pretreatment tumor samples (n=26) grouped by binary best overall response (p<0.05, Mann-Whitney test). [Figure 15-2] Figure 15A-D. Molecular and immune predictors of response. (B) CNV landscape assessed by whole-exome sequencing of selected recurrently mutated genes, IFN signaling genes, and antigen processing / presentation genes in melanoma (n=26 tumors). [Figure 15-3] Figure 15A-D. Molecular and immunological predictors of response. (C) Top) Diversity (inverse Simpson's function) of the pre-treatment circulating T-cell repertoire (n=24) according to the onset (or absence) of ≥Gr3 irAEs (p=0.028, Mann-Whitney test) and bottom) entropy of the circulating T-cell repertoire of peripheral blood lymphocytes (n=24) according to the onset (or absence) of ≥Gr3 irAEs. (D) Top) Expression of CD27 in CD4+ T effector cells and bottom) expression of CD28 in CD8+ T effector cells, grouped according to < or ≥Gr3 irAEs (n=15; p<0.01, p<0.05, respectively, Mann-Whitney test). [Figure 16A] Figure 16A-C. Characterization of the gut microbiome by 16S rRNA sequencing. (A) Stacked bar graphs showing the microbial composition of each analyzed fecal sample from the skin and unknown primary cohorts at the eye level (n = 40). [Figure 16B] Figure 16A-C. Characterization of the gut microbiome by 16S rRNA sequencing. (B) Alpha diversity of the fecal microbiome grouped by response in CICB-treated patients with cutaneous or unknown primary melanoma (n=40) collected before or immediately after initiation of therapy, as measured by the indicated metrics (p=0.68, Mann-Whitney test; R=responder, NR=non-responder). [Figure 16C] Figure 16A-C. Characterization of the gut microbiome by 16S rRNA sequencing. (C) Alpha diversity (inverse Simpson's function) of the fecal microbiome grouped by the occurrence of high-grade immune-related adverse events in all patients with fecal samples (p=0.71, Mann-Whitney, n=54). [Figure 17A] Figure 17A-B. Differential enrichment of bacterial taxa by LEfSe. (A) LDA score plot of bacterial taxa significantly enriched in patients with either R or NR for CICB from the skin and unknown primary cohort (n=40). LDA = linear discriminant analysis. p<0.05, or (B) LDA score plot of bacterial taxa significantly associated with the development or absence of high-grade (≥grade 3) immune-related adverse events (irAEs) in all patients with stool samples (n=54). p<0.05. [Figure 17B] See legend to Figure 17A. [Figure 18A]Figure 18A-C. Association between candidate bacterial taxon discovery and progression-free survival. (A) Volcano plot of pairwise comparisons of taxa (at all levels) by dichotomized response category in the cutaneous / unknown primary cohort (n=40) using the Mann-Whitney test applied to 1000 permutations of different bacterial abundances, and (B) Volcano plot of pairwise comparisons of bacterial taxa (at all levels) by dichotomized high-grade (≥grade 3) immune-related adverse event category (n=54) using the Mann-Whitney test applied to 1000 permutations of different bacterial abundances. [Figure 18B] See legend to Figure 18A. [Figure 18C] See legend to Figure 18A. [Figure 19A] Figure 19A-B. Associations between phenotypically distinct and abundant circulating immune populations and bacterial taxa. (A) Heatmap (Spearman's rho) of correlations between response- or non-response-associated taxa and circulating immune cell populations at baseline (n=8), and (B) heatmap (Spearman's rho) of correlations between key virulence- or non-virulence-associated bacterial taxa and circulating immune subsets quantified by multiparameter flow cytometry of baseline blood samples (n=8). TEff = T effector cells, TCM = T central memory, TEM = T effector memory, Treg = regulatory T cells. [Figure 19B] See legend to Figure 19A. [Figure 20]Figure 20A-C. Association of gut bacteria with CICB response. (A) Partial least squares discriminant analysis (PLS-DA) plot of variance of beta diversity at T0 between CICB-treated mice that were ultimately tumor-free or had tumors at sacrifice, for both tumor models combined. LV, latent variable. (B) Bar graph of variable importance (VIP) scores highlighting that bacterial species present at T0 were significantly more abundant in groups defined by bar color compared to groups defined by border color (*p<0.05, **p<0.01, ***p<0.001), showing mice that were ultimately tumor-free after CICB treatment versus mice that had tumors (RET and MCA205 models). For each species, bar color indicates the cohort with the highest mean relative abundance for the defined species, while border color indicates the cohort with the lowest mean relative abundance. Absence of a border indicates a mean relative abundance of zero in the compared cohorts. Green boxes highlight species common to patient data. Mann-Whitney test: *p<0.05, **p<0.01, ***p<0.001, ns=not significant. Bar thickness represents the fold ratio value of the mean relative abundance of each species in the two cohorts. N / A=not applicable. (C) Pearson correlation between the relative abundance of Parabacteroides distasonis (at T0, T2, and T5 time points) and tumor size at T5 time point in CICB-treated mice. [Figure 21] Heatmap of correlations (Spearman's rho) between major virulence-associated or non-virulence-associated bacterial taxa quantified by multiparameter flow cytometry of baseline blood samples (n=8) and circulating immune subsets. TEff=T effector cells, TCM=T central memory, TEM=T effector memory, Treg=regulatory T cells. [Figure 22A]Figure 22A–G. Gut microbiome profile correlates with response and toxicity to CICB. (A) Scoring (range 0–4) of H&E-stained ileums from MCA205 or RET tumor-bearing mice treated with isotype control or CICB ± antibiotics, n = 9–22 per group. Student's t-test. (B) Heatmap of log2 fold change (CICB treatment vs. isotype) in pro-inflammatory immune gene expression in the ileum and colon of MCA205 and RET tumor-bearing mice ± antibiotics (left panel). (C) Relative ileal Il1b expression in tumor-bearing mice treated with isotype / CICB ± antibiotics. Mann-Whitney test. n = 10–22 mice per group. (D) Quantification by qPCR of the relative abundance of Bacteroides intestinalis in feces from mice from the isotype control group vs. the CICB-treated group, paired before vs. after therapy (connected dots). n = 21–26 mice per group. Wilcoxon signed-rank test. Relative ileal Il1b expression (E) and ileal virulence score (F) 48 h after a single CICB injection in mice treated with antibiotics in combined MCA205 (n = 5–32 per group, gray dots) and RET (n = 5–26 per group, white dots), then either naturally recolonized after antibiotic discontinuation or given a single oral gavage dose of Bacteroides intestinalis. Data represent a pool of two separate experiments using three different B. intestinalis strains. For ileal virulence scoring, mice were classified according to low virulence (score 0 or 1) versus high virulence (score 2, 3, or 4), using a chi-square test. Ileal Il1b expression was analyzed using the Mann-Whitney test. (G) Ileal toxicity scores after treatment with CICB (or isotype) comparing mice colonized with FMT from high vs. low donors of B. intestinalis. *p<0.05, **p<0.01, ***p<0.001. [Figure 22B] See legend to Figure 22A. [Figure 22C] See legend to Figure 22A. [Figure 22D] See legend to Figure 22A. [Figure 22E] See legend to Figure 22A. [Figure 22F] See legend to Figure 22A. [Figure 22G] See legend to Figure 22A. [Figure 23] Patient treatment outcomes. Kaplan-Meier curves of progression-free survival in patient cohorts stratified by melanoma subtype (n=77, n=63 cutaneous / unknown primary, n=8 mucosal, n=6 uveal). [Figure 24] Figure 24A-D. Immune markers of CICB response and toxicity. (A, B) and CD8+ Teff (C, D) from separate CICB-treated cohorts in pre-treatment peripheral blood samples (p-values ​​obtained by Mann-Whitney test as indicated). [Figure 25] Prior immunotherapy and toxicity-associated T-cell phenotype. (C) Stacked bar graph (top) and contingency table (bottom) showing the relationship between prior immunotherapy exposure and the risk of developing ≥Gr3 irAEs after concomitant anti-CTLA-4 and anti-PD-1 blockade in patients with cutaneous or unknown primary melanoma (p=0.028, Fisher's exact test). [Figure 26] Figure 26A-B. Comparison of group abundances of Firmicutes (B) and Clostridiales (C) by response outcome in the skin / unknown primary cohort (n=40). [Figure 27A] Figure 27A-D. Microbiome and responses in mouse models. (A) Tumor growth kinetics of MCA205 fibrosarcoma (left panel) or RET melanoma (center panel) and the percentage of tumor-bearing or tumor-free mice at sacrifice after five injections of the indicated antibodies (right panel). Experimental groups consisted of isotype, anti-PD-1, or CICB treatment. Arrows on the x-axis indicate fecal collection time points: TO = before treatment initiation, T2 = 48 hours after two treatments, T5 = 48 hours after five treatments. Tumor growth shown is representative of two experiments. n = 12-16 mice / group. Statistical analysis was performed using the software detailed in the Methods: **p<0.01, ***p<0.001. [Figure 27B]Figure 27A-D. Microbiome and responses in mouse models. (B) Microbial alpha diversity (upper panel) and partial least squares discriminant analysis (PLS-DA) of fecal microbial beta diversity (lower panel) in fecal samples collected before treatment initiation (T0, orange), 48 hours after two injections of CICB or isotype control (T2, blue), and 48 hours after five injections (T5, red) in MCA205 (left panel) and RET (right panel) tumor-bearing mice, assessed by sequencing of 16S rRNA gene amplicons using the Shannon index. Mann-Whitney U test: *p<0.05, **p<0.01. ANOSIM and PERMANOVA define group separation; p-values ​​define the significance of group separation after permuting samples 999 times. [Figure 27C] Figure 27A-D. Microbiome and response in mouse models. (C) Beta diversity at T0 colored according to tumor size at T5 in MCA205 and RET treated with CICB; purple intensity indicates increasing tumor size. For each principal coordinate axis (PCo1 and PCo2), the collected variance, Pearson rho coefficient, and corresponding p-value are shown. [Figure 27D] Figure 27A-D. Microbiome and responses in mouse models. (D) Relative abundance of P. distasonis in feces collected from mice at T0, T2, and T5 for both tumor models combined and mice ultimately found to be tumor-bearing or tumor-free at T5. Mann-Whitney test: *p<0.05. [Figure 28-1] Figure 28A-H. (A) Representative photomicrographs (scale bar: 50 μm, magnification: 100x) of ileum from MCA205 and RET-bearing mice treated with isotype or CICB (left panel). [Figure 28-2] Figure 28A-H. (C) Heatmap of correlations (Pearson's rho) between colon invasion scores and taxon relative abundance at T0, T2, and T5 for RET in the combined discovery and validation cohort data. Red represents a positive correlation with colon invasion score, while blue represents a negative correlation. [Figure 28-3] Figure 28A-H. (D) Beta diversity ordination of fecal microbiota assessed by sequencing of 16S rDNA gene amplicons (Bray-Curtis dissimilarity) colored according to colonic inflammatory infiltrate scores in RET tumor-bearing mice. Purple intensity indicates increased inflammatory infiltrate scores in the discovery (left panel) and validation (right panel) cohorts. Prior to correlation analysis, both bacterial relative abundance and colonic inflammatory infiltrate were normalized and standardized. Pearson correlations comparing each principal component to inflammatory infiltrate and associated p-values ​​are shown. (E) qPCR quantification of the relative abundance of Bacteroides uniformis and Bacteroides fragilis in the feces of mice in isotype control-treated vs. CICB-treated groups, paired before vs. after at least one injection of CICB therapy (connected dots). n = 21–26 per group. [Figure 28-4] Figure 28A-H. (F) Schematic of the experimental setup used in Figure 3K and panels H-I. (G) B. intestinalis abundance in feces of healthy volunteer donors (sorted as low vs. high) and confirmed engraftment in mice after FMT compared to recipient mice from control, B. int low, and B. int high donors (*p<0.05, Mann-Whitney test). (H) Relative Il1b expression in mice after CICB following FMT using feces from low or high B. intestinalis donors (*p<0.05, Mann-Whitney test). DETAILED DESCRIPTION OF THE INVENTION

[0061] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Treatment with combined immune checkpoint blockade (CICB) targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1) has been associated with clinical benefit across several tumor types, but is associated with a high incidence of immune-related adverse events (irAEs). Therefore, biomarkers of response to CICB and the likelihood of irAEs occurring after CICB treatment are needed. Herein, we describe microbiological determinants of response and toxicity to CICB identified in the gut microbiota of human and mouse cohorts. Our examples also provide evidence that targeting these can reduce toxicity in preclinical models. Collectively, these findings have potentially important implications for the clinical management of cancer using CICB.

[0062] I. Definition As used herein, the term "antibody" refers to immunoglobulins, derivatives thereof that retain specific binding ability, and proteins having a binding domain that is homologous or largely homologous to an immunoglobulin binding domain. These proteins may be derived from natural sources or may be partially or wholly synthetically produced. Antibodies may be monoclonal or polyclonal. Antibodies may be members of any immunoglobulin class, including any of the human classes: IgG, IgM, IgA, IgD, and IgE. Antibodies used in the methods and compositions described herein are generally derivatives of the IgG class. The term antibody also refers to antigen-binding antibody fragments. Examples of such antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, scFv, Fv, dsFv diabody, and Fd fragments. Antibody fragments may be produced by any means. For example, antibody fragments may be enzymatically or chemically produced by fragmenting an intact antibody, recombinantly produced from a gene encoding a partial antibody sequence, or synthetically produced in whole or in part. An antibody fragment may optionally be a single-chain antibody fragment. Alternatively, the fragment may comprise multiple chains linked together, for example, by disulfide linkages. The fragment may optionally be a multimolecular complex. A functional antibody fragment retains the ability to bind to its cognate antigen with affinity comparable to that of the intact antibody.

[0063] The term "monoclonal antibody," as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., individual antibodies comprising the population that are identical except for possible minor variations, e.g., naturally occurring variations. Thus, the modifier "monoclonal" indicates the character of the antibody as not being a mixture of antibodies with different epitopic specificities. In certain embodiments, such monoclonal antibodies typically include antibodies comprising a polypeptide sequence that binds to a target, where the target-binding polypeptide sequence is obtained by a process that includes selecting a single target-binding polypeptide sequence from a plurality of polypeptide sequences. For example, the selection process may involve selecting a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, or recombinant DNA clones. It should be understood that the selected target-binding sequence may be further altered, e.g., to improve affinity for the target, humanize the target-binding sequence, improve production in cell culture, reduce immunogenicity in vivo, generate multispecific antibodies, etc., and that antibodies comprising the altered target-binding sequence are also monoclonal antibodies of the present disclosure. In contrast to polyclonal antibody preparations, which typically include several different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are usually uncontaminated by other immunoglobulins.

[0064] The phrases "pharmaceutical composition" or "pharmacologically acceptable composition" refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal, e.g., a human, as appropriate. The preparation of pharmaceutical compositions containing an antibody or additional active ingredient will be known to those of skill in the art in light of the present disclosure. Moreover, it is understood that when administered to an animal (e.g., a human), preparations must meet sterility, pyrogenicity, general safety, and purity standards as required by the FDA Office of Biological Standards.

[0065] As used herein, "pharmaceutically acceptable carriers" includes any and all aqueous solvents (e.g., water, alcohol / water solutions, saline, parenteral vehicles such as sodium chloride, and Ringer's dextrose), non-aqueous solvents (e.g., propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters such as ethyl oleate), dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial or antifungal agents, antioxidants, chelating agents, and inert gases), isotonic agents, absorption delaying agents, salts, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, moisture and nutrient supple- ments, such similar materials, and combinations thereof, as known to those skilled in the art. The pH and exact concentration of the various components in a pharmaceutical composition can be adjusted according to well-known parameters.

[0066] The term "unit dose" or "dosage" refers to a physically discrete unit suitable for use in a subject, each unit containing a predetermined amount of a treatment composition calculated to produce the desired response discussed herein in connection with its administration, i.e., the appropriate route and treatment regimen. The amount administered depends on the desired effect, both according to the number of treatments and the unit dose. The actual dosage of the composition of this embodiment administered to a patient or subject can be determined by physical and physiological factors, such as the subject's weight, age, health, and sex, the type of disease being treated, the extent of disease penetration, previous or concurrent therapeutic interventions, the patient's idiopathic nature, the route of administration, and the efficacy, stability, and toxicity of the particular treatment agent. For example, dosages may range from about 1 μg / kg / body weight to about 1000 mg / kg / body weight per administration (such ranges including doses therebetween) or more, and any specific dosage derivable therein. Non-limiting examples of ranges derivable from the numbers recited herein include ranges from about 5 μg / kg / body weight to about 100 μg / kg / body weight, from about 5 μg / kg / body weight to about 500 μg / kg / body weight, etc. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose for the individual subject.

[0067] A bacterial "population" can refer to a composition of cells containing a single species or a mixture of different species?

[0068] The term "immune checkpoint" refers to a variety of stimulatory, costimulatory, and inhibitory signals that control the breadth and magnitude of immune responses essential for maintaining immune homeostasis and host survival. Known immune checkpoint proteins include CTLA-4, PD-1, and their ligands PD-L1 and PD-L2, as well as LAG-3, BTLA, B7H3, B7H4, TIM3, and KIR. The pathway involving LAG3, BTLA, B7H3, B7H4, TIM3, and KIR is recognized in the art as constituting an immune checkpoint pathway similar to that dependent on CTLA-4 and PD-1 (see, e.g., Pardoll, 2012, Nature Rev Cancer 12:252-264; Mellman et al., 2011, Nature 480:480-489).

[0069] The term "inhibitor" refers to a molecule, which may be an organic or inorganic protein, polypeptide, antibody, small molecule, carbohydrate, or nucleic acid, that blocks or reduces one or more functions of a protein. Inhibitors may be direct inhibitors, which act by interacting directly with the protein, or indirect inhibitors, which cannot interact directly with the protein but nevertheless inhibit one or more functions of the protein.

[0070] An "immune checkpoint inhibitor" refers to any compound that inhibits the function of an immune checkpoint protein. Inhibition includes reduction and complete blocking of function. In particular, the immune checkpoint protein is a human immune checkpoint protein. Thus, an inhibitor of an immune checkpoint protein is particularly an inhibitor of a human immune checkpoint protein.

[0071] "Subject" and "patient" refer to either a human or non-human, e.g., a primate, mammal, or vertebrate. In certain aspects, the subject is a human.

[0072] As used herein, the terms "treat," "treatment," "treating," "ameliorating," or "amelioration," when used in reference to a disease, disorder, or condition, refer to therapeutic treatment of the condition, the purpose of which is to reverse, alleviate, ameliorate, inhibit, slow, or halt the progression or severity of the symptom or condition. The term "treating" includes reducing or alleviating at least one side effect or symptom of the condition. Treatment is generally "effective" if one or more symptoms or clinical markers are reduced. Alternatively, treatment is "effective" if the progression of the condition is reduced or halted. That is, "treatment" includes not only the improvement of symptoms or markers, but also the cessation or at least slowing of the progression or worsening of symptoms that would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms, reduction in the extent of the defect, stabilization (i.e., not worsening) of the tumor or malignant state, delaying or slowing tumor growth and / or metastasis, and an increase in lifespan compared to that expected in the absence of treatment.

[0073] "Gut microbiota" or "gut microbiome" refers to the population of microorganisms (and their genomes) that live in the gut of a subject.

[0074] The term "alpha diversity" is a measure of intra-sample diversity and refers to the distribution and assembly pattern of all microbiota within a sample, calculated as a scalar value for each sample. "Beta diversity" refers to the diversity between samples, including comparing samples to provide a measure of distance or dissimilarity between each pair of samples.

[0075] The term "relative abundance", sometimes referred to as "relative abundance", is defined as the number of bacteria at a certain taxonomic level (from phylum to species) as a proportion of the total number of bacteria at that level in biological samples.This relative abundance can be evaluated, for example, by measuring the proportion of 16S rRNA gene sequences present in samples that are assigned to these bacteria.It can be measured by any suitable technique known to those skilled in the art, such as 454 pyrosequencing of the 16S rRNA gene marker of a specific bacterium, or quantitative PCR of a specific gene.

[0076] In this document, a "good responder to treatment," also referred to as a "responder" or "responsive" patient, or in other words, a patient who "benefits from" this treatment, refers to a patient who has cancer and who has or will have a clinically significant reduction in cancer after receiving this treatment. In contrast, a "bad responder" or "non-responder" refers to a patient who has or will not have a clinically significant reduction in cancer after receiving this treatment. The reduced response to treatment can be evaluated according to art-recognized criteria, such as immune-related response criteria (irRC), WHO or RECIST criteria. For example, a responding patient may be identified as having a complete response (CR) in which all target lesions disappear, or a partial response (PR) in which the sum of the longest diameters (LD) of the target lesions decreases by at least 30% (based on the sum of the LDs at baseline), whereas a non-responding patient may be identified as having stable disease (SD) in which the sum of the LDs of the target lesions decreases by at least 30% (based on the sum of the longest diameters (LDs) at baseline), neither shrinking enough to qualify as a PR nor increasing enough to qualify as progressive disease (PD) (based on the shortest sum of LDs since treatment initiation), or progressive disease (PD) in which the sum of the LDs of the target lesions increases by at least 20% (based on the shortest sum of LDs recorded since treatment initiation or the appearance of one or more new lesions).

[0077] The term "isolated" encompasses bacteria or other entities or substances that (1) have been separated from at least some of the components with which they were originally associated (whether in nature or in an experimental setting) and / or (2) have been produced, prepared, purified, and / or manufactured by the hand of man. Isolated bacteria can be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were originally associated. In some embodiments, isolated bacteria are greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components.

[0078] The terms "purify," "purifying," and "purified" refer to bacteria or other material that has been separated from at least some of the components that accompanied it when it was originally produced or made (e.g., whether in nature or an experimental setting) or any time after it was originally produced. A bacterium or bacterial population can be considered purified if it is isolated at the time of or after production from a material or environment containing the bacterium or bacterial population, and a purified bacterium or bacterial population can contain up to about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than about 90% other materials and still be considered "isolated." In some embodiments, purified bacteria and bacterial populations are greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. In the example bacterial compositions provided herein, one or more bacterial types present in the composition can be independently purified from one or more other bacteria produced and / or present in the material or environment containing the bacterial type. Bacterial compositions and their bacterial components are generally purified from residual habitat products.

[0079] The term "determined to have" refers to a patient population that has been tested and reported to have a particular outcome, such as microbiome status.

[0080] The terms "less," "reduced," "reduced," "decrease," or "inhibition" are all used herein to generally mean a statistically significant decrease. However, for the avoidance of doubt, "less," "reduced," "reduced," "decrease," or "inhibition" means a decrease of at least 10% compared to the reference level, for example, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% decrease, or a decrease up to and including 100% (i.e., non-existent level compared to the reference sample), or any decrease between 10% and 100% compared to the reference level.

[0081] The terms "increased," "increase," "enhancement," or "activation" are all used herein to generally mean an increase by a statistically significant amount; for the avoidance of any doubt, the terms "increased," "increase," "enhancement," or "activation" mean an increase of at least 10% compared to base level, for example, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including 100%, or any increase between 10-100% compared to base level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold increase compared to base level, or any increase between 2-fold and 10-fold or more.

[0082] The term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. The phrase "consisting of" excludes any unspecified elements, steps, or ingredients. The phrase "consisting essentially of" limits the scope of the described subject matter to the specified materials or steps and those that do not materially affect its basic and novel characteristics. The term permits the presence of additional elements that do not materially affect the basic, novel, or functional characteristics of an inventive embodiment. With respect to pharmaceutical compositions, the term "consisting essentially of" includes the recited active ingredients and excludes any other active ingredients, but does not exclude any pharmaceutical excipients or other ingredients that are not therapeutically active. It is contemplated that embodiments described in the context of the term "comprising" can also be practiced in the context of the terms "consisting of" or "essentially consisting of."

[0083] The term "consisting of" refers to compositions, methods, and their respective components described herein, excluding any elements not recited in the description of the embodiment.

[0084] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "method" includes one or more methods, and / or steps of the type described herein and / or that will become apparent to those skilled in the art upon reading this disclosure, and so forth.

[0085] As used herein, " essentially free " in relation to specific components means that the specific components that are intentionally incorporated into the composition do not exist and / or only exist as contaminants or in trace amounts.Therefore, the total amount of specific components that are caused by any unintentional contamination of the composition is far less than 0.01%.Most preferred is a composition that does not have the amount of specific components that can be detected by standard analytical methods.

[0086] As used herein, the terms "or" and "and / or" are used to describe multiple components in combination with or excluding each other. For example, "x, y, and / or z" can refer to "x" alone, "y" alone, "z" alone, "x, y, and z," "(x and y) or z," "x or (y and z)," or "x or y or z." It is specifically contemplated that x, y, or z may be specifically excluded from an embodiment.

[0087] Throughout this application, the term "about" is used in accordance with its plain and ordinary meaning in the field of cell biology to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[0088] The phrases "effective amount," "therapeutically effective amount," or "sufficient amount" refer to the administration of a drug or agent sufficient to produce a desired result, which may be a decrease in tumor size, a decrease in the growth rate of cancer cells, a decrease in metastasis, an increase in CD8+ T lymphocytes in the tumor or tumor immune infiltrate, an increase in CD45+, CD3+ / CD20+ / CD56+, CD68+, and / or HLA-DR+ cells in the tumor, an increase in CD3, CD8, PD1, FoxP3, Granzyme B, and / or PD-L1 expression in the tumor immune infiltrate, a decrease in RORyT expression in the tumor immune infiltrate, an increase in effector CD4+, CD8+ T, monocytes, and / or myeloid dendritic cells in the systemic circulation or peripheral blood, a decrease in B cells, regulatory T cells, and / or myeloid-derived suppressor cells in the systemic circulation or peripheral blood of a subject, or any combination of the above.

[0089] II. Checkpoint Inhibitors and Combination Treatments Embodiments relate to combination treatments including (a) inhibitors of CTLA-4, B7-1, and / or B7-2, and (b) inhibitors of PD-1, PDL1, and / or PDL2. In some embodiments, treatments combine an inhibitor that blocks the interaction between CTLA-4 and B7-1 or B7-2 with an inhibitor that blocks the interaction between PD-1 and PDL1 or PDL2.

[0090] In some embodiments of any one of the provided methods, compositions, or kits, the immune checkpoint inhibitor is a small molecule inhibitor. In some embodiments of any one of the provided methods, compositions, or kits, the immune checkpoint inhibitor is a polypeptide that inhibits an immune checkpoint pathway. In some embodiments of any one of the provided methods, compositions, or kits, the inhibitor is a fusion protein. In some embodiments of any one of the provided methods, compositions, or kits, the immune checkpoint inhibitor is an antibody. In some embodiments of any one of the provided methods, compositions, or kits, the antibody is a monoclonal antibody.

[0091] A. PD-1, PDL1, and PDL2 Inhibitors PD-1 can act in the tumor microenvironment where T cells encounter infections or tumors. Activated T cells upregulate PD-1 and continue to express it in peripheral tissues. Cytokines such as IFN-gamma induce the expression of PDL1 in epithelial cells and tumor cells. The primary role of PD-1 is to limit the activity of effector T cells in the periphery and prevent excessive damage to tissues during immune responses. The disclosed inhibitors can block one or more functions of PD-1 and / or PDL1 activity.

[0092] Aliases for "PD-1" include CD279 and SLEB2. Aliases for "PDL1" include B7-H1, B7-4, CD274, and B7-H. Aliases for "PDL2" include B7-DC, Btdc, and CD273. In some embodiments, PD-1, PDL1, and PDL2 are human PD-1, PDL1, and PDL2.

[0093] In some embodiments, the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its ligand-binding partner. In certain aspects, the ligand-binding partner of PD-1 is PDL1 and / or PDL2. In another embodiment, the PDL1 inhibitor is a molecule that inhibits the binding of PDL1 to its binding partner. In certain aspects, the binding partner of PDL1 is PD-1 and / or B7-1. In another embodiment, the PDL2 inhibitor is a molecule that inhibits the binding of PDL2 to its binding partner. In certain aspects, the binding partner of PDL2 is PD-1. The inhibitor may be an antibody, antigen-binding fragment thereof, immunoadhesin, fusion protein, or oligopeptide. Exemplary antibodies are described in U.S. Patent Nos. 8,735,553, 8,354,509, and 8,008,449, all of which are incorporated herein by reference. Other PD-1 inhibitors for use in the methods and compositions provided herein are known in the art, such as those described in U.S. Patent Application Publication Nos. 2014 / 0294898, 2014 / 022021, and 2011 / 0008369, all of which are incorporated herein by reference.

[0094] In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody). In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab. In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1-binding portion of PDL1 or PDL2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PDL1 inhibitor comprises AMP-224. Nivolumab, also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®, is an anti-PD-1 antibody described in WO 2006 / 121168. MK-3475, available from Merck Pembrolizumab, also known as 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, is an anti-PD-1 antibody described in WO 2009 / 114335. Pidilizumab, also known as CT-011, hBAT, or hBAT-1, is an anti-PD-1 antibody described in WO 2009 / 101611. AMP-224, also known as B7-DCIg, is a PDL2-Fc fusion soluble receptor described in WO 2010 / 027827 and WO 2011 / 066342. Additional PD-1 inhibitors include MEDI0680, also known as AMP-514, and REGN2810.

[0095] In some embodiments, the immune checkpoint inhibitor is a PDL1 inhibitor such as durvalumab, also known as MEDI4736, atezolizumab, also known as MPDL3280A, avelumab, also known as MSB00010118C, MDX-1105, BMS-936559, or a combination thereof. In certain aspects, the immune checkpoint inhibitor is a PDL2 inhibitor such as rHIgM12B7.

[0096] In some embodiments, an antibody described herein (such as an anti-PD-1 antibody, anti-PDL1 antibody, or anti-PDL2 antibody) further comprises a human or mouse constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, and IgG4. In even more particular aspects, the human constant region is IgG1. In even further aspects, the mouse constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, and IgG3. In even more particular aspects, the antibody has reduced or minimal effector function. In even more particular aspects, the minimal effector function results from production in a prokaryotic cell. In even more particular aspects, the minimal effector function results from an "effectorless Fc mutation" or aglycosylation.

[0097] In some embodiments, the inhibitor comprises the heavy and light chain CDRs or VRs of nivolumab, pembrolizumab, or pidilizumab. Thus, in one embodiment, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of nivolumab, pembrolizumab, or pidilizumab, and the CDR1, CDR2, and CDR3 domains of the VL region of nivolumab, pembrolizumab, or pidilizumab. In another embodiment, the antibody competes for binding to and / or binds to the same epitope on PD-1, PDL1, or PDL2 as the above-mentioned antibody. In another embodiment, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) of variable region amino acid sequence identity with the above-mentioned antibody.

[0098] Thus, the antibodies used herein can be aglycosylated. Glycosylation of antibodies is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid except proline) are recognition sequences for enzymatic attachment of a carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Glycosylation sites are conveniently removed from antibodies by altering the amino acid sequence to remove one of the above tripeptide sequences (for N-linked glycosylation sites). This alteration can be made by substituting the asparagine, serine, or threonine residue within the glycosylation site with another amino acid residue (eg, glycine, alanine, or a conservative substitution).

[0099] Antibodies or antigen-binding fragments thereof can be produced using methods known in the art, for example, by a process comprising culturing host cells containing nucleic acid encoding any of the previously described anti-PDL1, anti-PD-1, or anti-PDL2 antibodies or antigen-binding fragments in a form suitable for expression under conditions suitable for producing such antibodies or fragments, and recovering the antibodies or fragments.

[0100] B. CTLA-4, B7-1, and B7-2 Another immune checkpoint that can be targeted using the methods provided herein is cytotoxic T lymphocyte-associated protein 4 (CTLA-4), also known as CD152. The complete cDNA sequence of human CTLA-4 has Genbank accession number L15006. CTLA-4 is found on the surface of T cells and acts as an "off" switch when bound to B7-1 (CD80) or B7-2 (CD86) on the surface of antigen-presenting cells. CTLA4 is a member of the immunoglobulin superfamily that is expressed on the surface of helper T cells and transmits inhibitory signals to T cells. CTLA4 is similar to the T cell costimulatory protein CD28, and both molecules bind to B7-1 and B7-2 on antigen-presenting cells. CTLA-4 transmits inhibitory signals to T cells, while CD28 transmits costimulatory signals. Intracellular CTLA-4 is also found on regulatory T cells and may be important for their function. Activation of T cells through the T cell receptor and CD28 increases the expression of CTLA-4, an inhibitory receptor for the B7 molecule. The disclosed inhibitors can block one or more functions of the activities of CTLA-4, B7-1, and / or B7-2. In some embodiments, the inhibitor blocks the interaction between CTLA-4 and B7-1. In some embodiments, the inhibitor blocks the interaction between CTLA-4 and B7-2.

[0101] In some aspects, the immune checkpoint inhibitor is an anti-CTLA-4 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody), an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide.

[0102] Anti-human CTLA-4 antibodies (or VH and / or VL domains derived therefrom) suitable for use in this method can be produced using methods well known in the art. Alternatively, art-recognized anti-CTLA-4 antibodies can be used. For example, the anti-CTLA-4 antibodies disclosed in U.S. Patent No. 8,119,129, WO 01 / 14424, WO 98 / 42752; WO 00 / 37504 (CP675,206, also known as tremelimumab; formerly known as ticilimab), U.S. Patent No. 6,207,156; Hurwitz et al., 1998; can be used in the methods disclosed herein. The teachings of each of the aforementioned publications are incorporated herein by reference. Antibodies that compete with any of these art-recognized antibodies for binding to CTLA-4 can also be used. For example, humanized CTLA-4 antibodies are described in WO 2001 / 014424, WO 2000 / 037504, and US Pat. No. 8,017,114, all of which are incorporated herein by reference.

[0103] An additional anti-CTLA-4 antibody useful as a checkpoint inhibitor in the disclosed methods and compositions is ipilimumab (also known as 10D1, MDX-010, MDX-101, and Yervoy®) or antigen-binding fragments and variants thereof (see, e.g., WO 01 / 14424).

[0104] In some embodiments, the inhibitor comprises the heavy and light chain CDRs or VRs of tremelimumab or ipilimumab. Thus, in one embodiment, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of tremelimumab or ipilimumab and the CDR1, CDR2, and CDR3 domains of the VL region of tremelimumab or ipilimumab. In another embodiment, the antibody competes for binding to and / or binds to the same epitope on PD-1, B7-1, or B7-2 as the above-mentioned antibody. In another embodiment, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) of variable region amino acid sequence identity with the above-mentioned antibody.

[0105] Other molecules for modulating CTLA-4 include soluble CTLA-4 ligands and receptors such as those described in U.S. Pat. Nos. 5,844,905, 5,885,796, WO 1995001994 and WO 1998042752, all of which are incorporated herein by reference, and immunoadhesins such as those described in U.S. Pat. No. 8,329,867, which is incorporated herein by reference.

[0106] III. Microbial regulators In some aspects, the disclosure provides a method for treating or preventing the development of Bacteroides stercoli, Bacteroides caccae, Bacteroides intestinalis, Diaryster spp., Bacteroides fragilis, Vampirovibrio spp., Taizerella spp., Flavonifractor platycii, Dielma fastidiosa, Butyricimonas faesihominis, Alistipes spp., Ackermansia muciniphila, Lactobacillus lobata, or a combination thereof in a subject. gosae, Prevotella copri, Prevotella shahii, Citrobacter spp., Clostridium hilemonae, fungateiClostridium aldritii, Citrobacter rodentium, Eubacterium sulci, Hafniaceae, Citrobacter freundii, Eubacterium harii, Enterobacter cloacae, Hafnia alvei, Hafnia spp., Roseburia hominis, Weissella paramesentero 28C, or one or more of the bacterial species disclosed in Figure 28C.

[0107] In another aspect, the disclosure provides for the detection of Bacteroides stercolis, Bacteroides caccae, Bacteroides intestinalis, Diaryster spp., Bacteroides fragilis, Vampirovibrio spp., Taizerella spp., Bacteroides stercolis, Flavonifracter prautii, Dierma fastidiosa, Ackermansia muciniphila, Lactobacillus logosae, Bacteroides fragilis, Prevotella copri, Prevotella shahii, Firmicutes, Clostridiales, Ruminococcaceae, Alistipes indistinctus, Bacteroides stercolirosolis, Clostridium lactifermentans in a subject. Orus, Abyssibiriga alcaniphila, Acetatifactor muris, Acetivibrio cellulolyticus, Acetivibrio ethanolguignens, Acholeplasma vituri, Achromobacter derayi, Acidovorax radices, Adrecruzia aequorifaciens, Ackermansia muciniphila, Alistipes indistinctus, Alistipes obesi, Alistipes putoreginis, Alistipes senegalensis, Alistipes zimonensis, Alcalibacter saccharofermentans, Alcalibacter bacchi, Alobaculum stercolicanis, Anaerobacterium chalcisorbens, Anaerocolumna cellulosilisica, Anaerosporobacter mobilis, Anaerotaenia torta, Anaerotor Anaerotorruncus colihominis, Anaerotorruncus rubiinfantis, Anaerovorax odoritans, Bacteroides acidifaciens, Bacteroides caesimris, Bacteroides dorei, Bacteroides faesiquinchirae, Bacteroides rodentium, Bacteroides stercolirosolis, Bacteroides xylanolyticus, Barnesiella inte stinihominis, Beduini massiliensis, Bifidobacterium pseudolongum, Blautia luci, Bresnakia bratchicola, Bresnakia pachinodae, Butyricoccus plicaecorum, Butyrivibrio crossotus, Catabacter hongkongenesis, Christensenella massiliensis, Christensenella minuta, Christensenella timonensis,Clostridium aerotolerans, Clostridium ardenense, Clostridium alkalicellulosi, Clostridium asparagiforme, Clostridium cererecresens, Clostridium cellobiopalum, Clostridium cellulolyticum, Clostridium clariflavum, Clostridium cochleatum, Clostridium corinum, Clostridium hylemonae, Clostridium indris, Clostridium jejuense, Clostridium lactifermentans, Clostridium Um labarens, Clostridium methylpentosum, Clostridium oroticum, Clostridium oryzae, Clostridium papyrosolvens, Clostridium polysaccharolyticum, Clostridium popleci, Clostridium saccharolyticum, Clostridium saudiens, Clostridium saindens, Clostridium straminisorbens, Clostridium viride, Clostridium xylanolyticum, Coprobacter secundus, Coprococcus catus, Curturomyca masilis ensis, Defluviitarea saccharophila, Desulfitobacterium hafniens, Desulfitobacterium metallireducens, Desulfosporosinus orientis, Desulfovibrio desulfuricans, Desulfovibrio simplex, Dorea formisigenerans, Eisenberghiella massiliensis, Emergencia timonensis, Enterococcus hirae, Enterorhabdus mucosicola, Enterorhabdus muris, Erysipelothrix ramosum, Erysipelothrix larvae , Escherichia fergusonii, Eubacterium coprostanoligenes, Eubacterium doricum, Eubacterium ruminantium, Eubacterium silaeum, Eubacterium tortuosum, Eubacterium ventriosum, Faecalibaculum rodentium, Flavimarina pacifica, Flavonifractor prautii, Flinchibacter butyricus, Gordonibacter faesihominis, Gracilibacter thermotolerans, Harryflintia acetispora, Hordemania massiliensis,Hydrogenoanaerobacterium saccharovorans, Ifubacter massiliensis, Intestinimonas butyriciproducens, Irregularibacter muris, Lachnoclostridium pacaceans, Lactobacillus animalis, Lactobacillus faeces, Lactobacillus gasseri, Lactobacillus hominis, Lactobacillus intestinalis, Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus logosae, Lactobacillus taiwanensis, Lawsonia intracellularis, Longibacrum muris, Malvinbrianchia formatexigens, Millionella massiliensis, Mucispirillum scaedreri, Muribacrum intestinale, Murimonas intestini, Natlanaerovirga pectinivora, Neglecta zymonensis, Odoribacter plankunix, Orsenella profusa, Oscillibacter ruminantium, Oscillibacter valericigenes, Papilibacter cinnamivorans, Parabacteroides gordosteinii, Paraeggertella hongkongenesis, Parasterella exclementihominis, Parvibacter - caesicola, Peptococcus niger, Phocea massiliensis, Porphyromonas catoniae, Prevotella oralis, Prevotella stercorea, Prevotella massilia timonensis, Pseudobutyrivibrio ruminis, Pseudoflavonifractor capillosus, Pseudoflavonifractor hocaensis, Raoultibacter timonensis, Rhizobium straminorhizae, Roseburia faeces, Roseburia hominis, Roseburia intestinalis, Ruminiclostridium thermocellum, Ruminococcus champa nerensis, Ruminococcus faecis, Ruminococcus flavefaciens, Ruminococcus gnavus, Ruthenibacterium lactatiformans, Sphingomonas kieongiensis, Spiroplasma velocyclescens, Sporobacter thermitizis, Stomatobacillus longum, Streptococcus acidominimus, Streptococcus danieriae, Syntrohomonas wolfei, Tepizimonas taiwanensis, Chindaria californiensis, Chindaria texcoconensis, Turicibacter sanguinis,28C, and / or detecting one or more of the bacteria disclosed in Fig. 28C.

[0108] In another aspect, the disclosure relates to a composition comprising at least one isolated or purified population of bacteria belonging to one or more of the following genera or species: Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzzierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactatifermentans.

[0109] In some embodiments, the composition comprises at least one isolated or purified population of bacteria belonging to one or more of the following genera or species: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercoris, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, Fungatei, Clostridium thermocellum.

[0110] In another aspect, the disclosure relates to a composition comprising an isolated or purified population of at least two bacteria belonging to one or more of the following genera or species: Flavonifractor, Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzzierales, fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactatifermentans. In some embodiments, the composition comprises at least two isolated or purified populations of bacteria belonging to one or more of the following genera or species: Flavonifractor, Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercoris, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, Fungatei, Clostridium thermocellum.

[0111] In another aspect, the disclosure provides for the detection of Parabacteroides distasonis, Fournierera spp., Fournierera massiliensis, Eisenberghiella tai, Tissierales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes spp., Geosporobacter spp., Prevotella parsidivens, Lactobacillus secariphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, Flavonifractor spp., Bacteroides spp., Butyricimonas spp., Dielma spp., Ackermansia spp., Alistipes spp., Anaerotignum lactifermentans, Ba Cteroides coprophilus, Bacteroides stercolis, Bacteroides caccae, Bacteroides intestinalis, Diaryster spp., Bacteroides fragilis, Vampirovibrio spp., Taiserella spp., Bacteroides stercolis, Flavonifracter prautii, Dielma fastidiosa, Ackermansia muciniphila, Lactobacillus logosae, Bacteroides fragilis, Prevotella copri, Prevotella shahii, phylum Firmicutes, order Clostridiales, family Ruminococcaceae, Alistipes indistinctus, Bacteroides stercolirosolis, Clostridium lactifermentans Orus, Abyssibirga alcaniphila, Acetiviflora muris, Acetivibrio cellulolyticus, Acetivibrio ethanolguignens, Acholeplasma vitulis, Achromobacter derayi, Acidovorax radices, Adrecluzia aequorifaciens, Ackermansia muciniphila, Alistipes indistinctus, Alistipes obesi, Alistipes putoreginis, Alistipes senegalensis, A Ristipes timonensis, Alcalibacter saccharofermentans, Alcalibacter bacchii, Alcalibacter stercolicanis, Anaerobacterium chalcisorbens, Anaerocorumna cellulosilitica, Anaerosporobacter mobilis, Anaerotaenia torta, Anaerotoruncus corihominis, Anaerotoruncus rubiinfantis, Anaerovorax odrimtans, Bacteroides acidifaciens,Bacteroides caecimulus, Bacteroides dorei, Bacteroides faesiquinchirae, Bacteroides rodentium, Bacteroides stercolirosolis, Bacteroides xylanolyticus, Barnesiella intestinihominis, Beduini massiliensis, Bifidobacterium pseudolongum, Blautia luci, Bresnakia bratticola, Bresnakia pachinodae, Butyricoccus plicaecorum, Butyrivibrio crossotus, Catabacter hongkongenesis, Christensenella massiliensis, K. Listensenera minuta, Listensenera timonensis, Clostridium aerotolerans, Clostridium ardenense, Clostridium alkalicellulosi, Clostridium asparagiforme, Clostridium cererecrescens, Clostridium cellobiopalum, Clostridium cellulolyticum, Clostridium clariflavum, Clostridium cochleatum, Clostridium corinum, Clostridium hylemonae, Clostridium indris, Clostridium jejuense, Clostridium Clostridium lactifermentans, Clostridium labarens, Clostridium methylpentosum, Clostridium oroticum, Clostridium oryzae, Clostridium papyrosolvens, Clostridium polysaccharolyticum, Clostridium popleci, Clostridium saccharolyticum, Clostridium saudiens, Clostridium saindens, Clostridium straminisorbens, Clostridium viride, Clostridium xylanolyticum, Coprobacter secundus, Copro Coccus catus, Curturomica massiliensis, Defluviitarea saccharophila, Desulfitobacterium hafniens, Desulfitobacterium metallireducens, Desulfosporosinus orientis, Desulfovibrio desulfuricans, Desulfovibrio simplex, Dorea formisigenerans, Eisenberghiella massiliensis, Emergencia timonensis, Enterococcus hirae, Enterorhabdus mucosicola, Enterorhabdus muris, Erysipelothrix clostridium ramosum,Erysipelothrix larvae, Escherichia fergusonii, Eubacterium coprostanoligenes, Eubacterium doricum, Eubacterium ruminantium, Eubacterium silaeum, Eubacterium tortuosum, Eubacterium ventriosum, Faecalibaculum rodentium, Flavimarina pacifica, Flavonifractor prautii, Flinchibacter butyricus, Gordonibacter faesihominis, Gracilibacter thermotolerans, Harryflintia acetispora, Hordemannii Lactobacillus massiliensis, Hydrogenoanaerobacterium saccharovorans, Ifubacter massiliensis, Intestinimonas butyriciproducens, Irregularibacter muris, Lachnoclostridium pacaceans, Lactobacillus animalis, Lactobacillus faeces, Lactobacillus gasseri, Lactobacillus hominis, Lactobacillus intestinalis, Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus logosae, Lactobacillus taiwanensis, Lawsonia intracellularis, Ron Gibaculum muris, Malvinbrianchia formatexigens, Millionella massiliensis, Mucispirillum scaedreri, Mulibacrum intestinale, Murimonas intestini, Natlanaerovirga pectinivora, Neglecta timonensis, Odoribacter plankunix, Orsenella profusa, Oscillibacter ruminantium, Oscillibacter valericigenes, Papilibacter cinnamivorans, Parabacteroides gordosteinii, Paraeggertella hongkongenesis, Parasterella exclementi hominis, Parvibacter caesicola, Peptococcus niger, Phocea massiliensis, Porphyromonas catoniae, Prevotella oralis, Prevotella stercorea, Prevotella massilia timonensis, Pseudobutyrivibrio ruminis, Pseudoflavonifractor capillosus, Pseudoflavonifractor hocaensis, Raoultibacter timonensis, Rhizobium straminorhizae, Roseburia faeces, Roseburia hominis, Roseburia intestinalis, Ruminiclostridium thermocellum,Ruminococcus champanerensis, Ruminococcus faeces, Ruminococcus flavefaciens, Ruminococcus gnavus, Rutenibacterium lactatiformans, Sphingomonas kieongiensis, Spiroplasma velocyclescens, Sporobacter thermitizis, Stomatobaculum longum, Streptococcus acidominimus, Streptococcus danieriae, Syntrohomonas wolfei, Tepizimonas ta and / or Vampirovibrio chlorellavorus.

[0112] In some embodiments, the composition comprises, or further comprises, at least one isolated or purified population of bacteria belonging to one or more of the following species: Bacteroides flavonifractor, Bacteroides stercolis, Butyricimonas faesihominis, Dielma, Ackermansia, and Alistipes indistatus. In some embodiments, the composition excludes Bacteroides stercoli. In some embodiments, the composition comprises, or further comprises, at least one isolated or purified population of bacteria belonging to one or more of the genera Dielma and Ackermansia. In some embodiments, the composition comprises, or further comprises, at least one isolated or purified population of bacteria belonging to one or more of the genera Alistipes, Dielma, and Ackermansia. In some embodiments, the composition comprises, or further comprises, at least one isolated or purified population of bacteria belonging to the genus Ackermansia. In some embodiments, the composition comprises or further comprises at least one isolated or purified population of Ackermansia muciniphila. In some embodiments, the composition comprises or further comprises a population of bacteria including one or more of Ackermansia muciniphila and Dierma fastidiosa, as well as Alistipes indistinctus. In some embodiments, the bacteria of the genus Flavonifractor comprises Flavonifractor plautii. In some embodiments, the composition comprises or further comprises at least one isolated or purified population of bacteria belonging to one or more of the following genera or species: Bacteroides fragilis, Vampyrovibrio, Taizerella, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Muricomes intestini, Geosporobacter, Geosporobacter subterraneus, and Anaerotignum lactatifermentans. In some embodiments, the composition comprises or further comprises at least one isolated or purified population of Bacteroides intestinalis. In some embodiments, the composition comprises or further comprises at least one isolated or purified population of bacteria belonging to the phylum Firmicutes, the order Clostridiales, and the family Ruminococcaceae.In some embodiments, the composition includes or further comprises Flavonifractor plautii and / or Dielma fastidiosa. In some embodiments, the composition includes or further comprises Bacteroides stercoris, Butyricimonas faesihominis, Flavonifractor plautii, Dielma fastidiosa, Alistipes indistinctus, and Ackermansia muciniphila.

[0113] In some embodiments, the composition comprises 1×10 5 , 1×10 4 , 1×10 3 , or 1 × 10 2 In some embodiments, the composition comprises less than 1 x 10 CFU or cells of bacteria classified as Firmicutes, Clostridiales, and Ruminococcaceae. 5 , 1×10 4 , 1×10 3 , or 1 × 10 2 Less than (or any derivable range therein) CFU or cells of bacteria belonging to the following families: Ruminococcus, Clostridium, Lachnospira, Micrococcus, and / or Veillonella.

[0114] In another aspect, provided herein are microbial modulator compositions for treating cancer, particularly methods for modulating the microbiome of a subject who has been or will be treated with combination immune checkpoint inhibitor therapy.

[0115] The present disclosure also provides pharmaceutical compositions comprising one or more microbial populations as described above and for example in the Summary of the Invention.Therefore, the bacterial species is present in a dosage form as live bacteria, whether in dry form, freeze-dried form, or spore form.This can preferably be adapted for suitable administration; for example, in the case of oral treatment, it is in the form of a tablet or powder, potentially with enteric coating.

[0116] In certain aspects, the composition is formulated for oral administration.Oral administration can be achieved by using chewable formulations, dissolving formulations, encapsulated / coated formulations, multi-layered lozenges (to separate active ingredients and / or active ingredients and excipients), sustained / sustained release formulations, or other suitable formulations known to those skilled in the art.Although the term "tablet" is used herein, the formulation can take various physical forms, which may also be generally referred to as lozenges, pills, capsules, etc.

[0117] The compositions of the present disclosure are preferably formulated for oral administration; however, other routes of administration may be used, including, but not limited to, subcutaneous, intramuscular, intradermal, transdermal, intraocular, intraperitoneal, mucosal, vaginal, rectal, and intravenous.

[0118] The desired dose of the compositions of the present disclosure may be presented in multiple (e.g., 2, 3, 4, 5, 6 or more) sub-doses administered at appropriate intervals throughout the day.

[0119] In one aspect, the disclosed compositions can be prepared as capsules. The capsule (i.e., carrier) can be a hollow, approximately cylindrical capsule formed from a variety of materials, such as gelatin, cellulose, carbohydrates, and the like.

[0120] In another aspect, the disclosed compositions can be prepared as suppositories.Suppositories can include bacteria and one or more carriers, such as, but not limited to, polyethylene glycol, gum arabic, acetylated monoglyceride, carnauba wax, cellulose acetate phthalate, corn starch, dibutyl phthalate, sodium docusate, gelatin, glycerin, iron oxide, kaolin, lactose, magnesium stearate, methylparaben, pharmaceutical glaze, povidone, propylparaben, sodium benzoate, sorbitan monooleate, sucrose talc, titanium dioxide, white wax, and coloring agents.

[0121] In some aspects, the disclosed microorganism regulator compositions may be prepared as tablets. Tablets may include bacteria and one or more tableting agents (i.e., carriers), such as dicalcium phosphate, stearic acid, croscarmellose, silica, cellulose, and cellulose coatings. Tablets can be formed using a direct compression process, although those skilled in the art will recognize that tablets can be formed using a variety of techniques.

[0122] In other aspects, the disclosed microbial regulator compositions may be formulated as a food or beverage, or as an additive to a food or beverage, in which case an appropriate amount of bacteria is added to the food or beverage, making the food or beverage the carrier.

[0123] The microbial regulator compositions of the present disclosure may further include one or more prebiotics known in the art, such as lactitol, inulin, or a combination thereof.

[0124] In some aspects, the microbial modulator composition may further comprise a food or dietary supplement effective in stimulating the growth of Clostridiales bacteria present in the gastrointestinal tract of a subject, hi some aspects, the dietary supplement is produced by bacteria associated with the gut microbiome of healthy humans.

[0125] IV. Additional Therapies The presently disclosed methods and compositions may include one or more additional therapies known in the art and / or described herein. In some embodiments, the additional therapies include additional cancer treatments. Examples of such treatments are described herein.

[0126] A. Immunotherapy In some embodiments, the additional therapy includes further cancer immunotherapy. Cancer immunotherapy (sometimes called immuno-oncology, abbreviated IO) is the use of the immune system to treat cancer. Immunotherapies can be classified as active, passive, or hybrid (active and passive). These approaches take advantage of the fact that cancer cells often have molecules on their surface known as tumor-associated antigens (TAAs) that can be detected by the immune system; these molecules are often proteins or other macromolecules (e.g., carbohydrates). Active immunotherapy directs the immune system to attack tumor cells by targeting TAAs. Passive immunotherapy enhances existing anti-tumor responses and includes the use of monoclonal antibodies, lymphocytes, and cytokines. Immunotherapies are known in the art, and some are described below.

[0127] 1. Inhibition of costimulatory molecules In some embodiments, the immunotherapy comprises an inhibitor of a costimulatory molecule. In some embodiments, the inhibitor comprises an inhibitor of B7-1 (CD80), B7-2 (CD86), CD28, ICOS, OX40 (TNFRSF4), 4-1BB (CD137; TNFRSF9), CD40L (CD40LG), GITR (TNFRSF18), and combinations thereof. Inhibitors include inhibitory antibodies, polypeptides, compounds, and nucleic acids.

[0128] 2. Dendritic cell therapy Dendritic cell therapy induces an anti-tumor response by using dendritic cells to present tumor antigens to lymphocytes, activating the lymphocytes and stimulating them to kill other cells that present the antigens. Dendritic cells are antigen-presenting cells (APCs) in the mammalian immune system. In cancer treatment, dendritic cells assist in the targeting of cancer antigens. One example of a dendritic cell-based cellular cancer therapy is sipuleucel-T, marketed as Provenge®.

[0129] One way to induce dendritic cells to present tumor antigens is by vaccinating with autologous tumor lysates or short peptides (small pieces of protein that correspond to protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) to enhance immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and / or activate dendritic cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF).

[0130] Dendritic cells can also be activated in vivo by expressing GM-CSF in tumor cells, which can be achieved by genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF.

[0131] Another strategy is to extract dendritic cells from the patient's blood and activate them ex vivo. The dendritic cells are activated in the presence of tumor antigens, which can be single tumor-specific peptides / proteins or tumor cell lysates (a solution of dissolved tumor cells). These cells (along with an optional adjuvant) are injected and an immune response is generated.

[0132] Dendritic cell therapy involves using antibodies that bind to receptors on the surface of dendritic cells. Antigens may be added to the antibodies, which can then induce the maturation of dendritic cells to provide immunity against tumors. Dendritic cell receptors such as TLR3, TLR7, TLR8, or CD40 have been used as targets for the antibodies.

[0133] 3. CAR-T cell therapy Chimeric antigen receptors (CARs, also known as chimeric immune receptors, chimeric T cell receptors, or artificial T cell receptors) are genetically engineered receptors that combine immune cells with novel, non-MHC-restricted specificities to target cancer cells. Typically, these receptors transfer the specificity of a monoclonal antibody onto a T cell. The receptors are called chimeric because they combine parts from different sources. CAR-T cell therapy refers to the use of such transformed cells to treat, for example, cancer.

[0134] The basic principle of CAR-T cell design requires a genetically engineered receptor that combines antigen-binding and T cell activation functions. The general premise of CAR-T cells is to engineer T cells that target markers found on cancer cells. Scientists can extract T cells from humans, genetically modify them, and then inject them back into the patient to attack cancer cells. Once engineered, T cells function as a "living drug." CAR-T cells link an extracellular ligand-recognition domain with an intracellular signaling molecule that subsequently activates the T cell. The extracellular ligand-recognition domain is typically a single-chain variable fragment (scFv) derived from an antibody. A key aspect of the safety of CAR-T cell therapy is ensuring that only cancerous tumor cells, and not normal cells, are targeted. The specificity of CAR-T cells is determined by the choice of target molecule.

[0135] Exemplary CAR-T therapies include tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®). In some embodiments, the CAR-T therapy targets CD19.

[0136] 4. Cytokine therapy Cytokines are proteins produced by many types of cells present in tumors. Cytokines can regulate the immune response. Tumors often use cytokines to promote tumor growth and reduce the immune response. These immunomodulatory effects make it possible to use cytokines as drugs to induce an immune response. Two commonly used cytokines are interferons and interleukins.

[0137] Interferons are produced by cells of the immune system. They are typically involved in antiviral responses but also have an effect on cancer. Interferons are classified into three groups: type I (IFNα and IFNβ), type II (IFNγ), and type III (IFNλ).

[0138] Interleukins have numerous immune system effects, with IL-2 being an exemplary interleukin cytokine therapy.

[0139] 5. Adoptive T cell therapy Adoptive T cell therapy is a type of passive immunization through the transfer of T cells (adoptive cell transfer). T cells are found in blood and tissues and are typically activated when they encounter foreign pathogens. Specifically, T cells are activated when their T cell receptors (TCRs) encounter cells displaying a portion of a foreign protein on their surface antigens. These cells may be infected cells or antigen-presenting cells (APCs). T cells are found in normal and tumor tissues, where they are known as tumor-infiltrating lymphocytes (TILs). T cells are activated by the presence of APCs, such as dendritic cells, that present tumor antigens. Although these cells can attack tumors, the highly immunosuppressive environment within tumors prevents immune-mediated tumor death.

[0140] Several methods have been developed to generate and obtain tumor-targeting T cells. T cells specific for tumor antigens can be extracted from tumor samples (TIL) or filtered from the blood. Subsequent activation and culture are performed ex vivo, and the resulting activated T cell preparation is reinfused. Activation can be achieved by exposing T cells to tumor antigens.

[0141] B. Oncolytic Viruses In some embodiments, the additional therapy includes an oncolytic virus. An oncolytic virus is a virus that preferentially infects and kills cancer cells. When infected cancer cells are destroyed by oncolysis, the cancer cells release new infectious virus particles, or virions, to help destroy the remaining tumor. In addition to directly destroying tumor cells, oncolytic viruses are thought to stimulate the host's anti-tumor immune response for long-term immunotherapy.

[0142] C. polysaccharides In some embodiments, the additional therapy includes polysaccharides. Certain compounds found in mushrooms, primarily polysaccharides, can upregulate the immune system and may have anti-cancer properties. For example, beta-glucans such as lentinan have been shown in laboratory studies to stimulate macrophages, NK cells, T cells, and immune system cytokines, and are being investigated in clinical trials as immunological adjuvants.

[0143] D. Neoantigens In some embodiments, the additional therapy includes the administration of neoantigens. Many tumors express mutations. These mutations may generate new targetable antigens (neoantigens) for use in T cell immunotherapy. The presence of CD8+ T cells in cancer lesions is higher in tumors with high mutation burden, as identified using RNA sequencing data. The levels of transcripts associated with the cytolytic activity of natural killer cells and T cells are positively correlated with mutation load in many human tumors.

[0144] E. Chemotherapy In some embodiments, the additional therapy comprises chemotherapy. Suitable classes of chemotherapeutic agents include (a) alkylating agents, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, chlorozocin, streptozocin), and triazines (e.g., dacarbazine); (b) antimetabolites, such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., 5-fluorouracil, floxuridine, cytarabine, azauridine), and purine analogs and related materials (e.g., 6-mercaptopuricin, thiazolinone ... (c) natural products, such as vinca alkaloids (e.g., vinblastine, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin, and mitoxantrone), enzymes (e.g., L-asparaginase), and biological response modifiers (e.g., interferon-α), and (d) miscellaneous agents, such as platinum coordination complexes (e.g., cisplatin, carboplatin), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), and adrenocortical suppressants (e.g., taxol and mitotane). In some embodiments, cisplatin is a particularly preferred chemotherapeutic agent.

[0145] Cisplatin is widely used to treat cancers such as, for example, metastatic testicular or ovarian cancer, advanced bladder cancer, head and neck cancer, cervical cancer, lung cancer, or other tumors. Cisplatin is not absorbed orally and must be delivered via other routes, such as, for example, intravenous, subcutaneous, intratumoral, or intraperitoneal injection. Cisplatin can be used alone or in combination with other agents, and in certain embodiments, is administered at a dose of about 15 mg / m for 5 days every 3 weeks. 2~about 20mg / m 2 In some embodiments, the amount of cisplatin delivered to a cell and / or subject in conjunction with a construct comprising an Egr-1 promoter operably linked to a polynucleotide encoding a therapeutic polypeptide is less than the amount delivered when cisplatin is used alone.

[0146] Other suitable chemotherapeutic agents include microtubule inhibitors, such as paclitaxel ("taxol") and doxorubicin hydrochloride ("doxorubicin"). The combination of an Egr-1 promoter / TNFα construct delivered via an adenoviral vector with doxorubicin has been determined to be effective in overcoming resistance to chemotherapy and / or TNFα, suggesting that combined treatment with the construct and doxorubicin overcomes resistance to both doxorubicin and TNFα.

[0147] Because doxorubicin is poorly absorbed, intravenous administration is preferred. In certain embodiments, a suitable intravenous dose for adults is about 60 mg / m2 at approximately 21-day intervals. 2 ~about 75mg / m 2 or about 25 mg / m on each of 2 or 3 consecutive days repeated at intervals of about 3 to 4 weeks 2 ~about 30mg / m 2 , or approximately 20 mg / m once weekly 2 The lowest doses should be used in elderly patients if prior myelosuppression caused by prior chemotherapy or neoplastic bone marrow infiltration is present, or if this drug is used in combination with other myelopoiesis-suppressing drugs.

[0148] Nitrogen mustard is another suitable chemotherapeutic agent useful in the disclosed methods. Nitrogen mustards can include, but are not limited to, mechlorethamine (HN2), cyclophosphamide, and / or ifosfamide, melphalan (L-sarcolysin), and chlorambucil. Cyclophosphamide (CYTOXAN® available from Mead Johnson and NEOSTAR® available from Adria) is another suitable chemotherapeutic agent. Suitable oral doses for adults include, for example, about 1 mg / kg / day to about 5 mg / kg / day, and intravenous doses include, for example, about 40 mg / kg to about 50 mg / kg initially in divided doses over a period of about 2 to about 5 days, or about 10 mg / kg to about 15 mg / kg every about 7 to about 10 days, or about 3 mg / kg to about 5 mg / kg twice weekly, or about 1.5 mg / kg / day to about 3 mg / kg / day. Because of adverse gastrointestinal effects, the intravenous route is preferred. Drugs may also be administered intramuscularly, by infiltration, or into body cavities.

[0149] Additional suitable chemotherapeutic agents include pyrimidine analogs such as cytarabine (cytosine arabinoside), 5-fluorouracil (fluorouracil; 5-FU), and floxuridine (fluorodeoxyuridine; FudR). 5-FU may be administered to a subject at any dose from about 7.5 to about 1000 mg / m. Furthermore, the administration schedule for 5-FU may be for a variety of periods, for example, up to 6 weeks, or as determined by one of ordinary skill in the art to which this disclosure pertains.

[0150] Another suitable chemotherapeutic agent, gemcitabine diphosphate (GEMZAR®, Eli Lilly & Co., "gemcitabine"), is recommended for the treatment of advanced and metastatic pancreatic cancer and may be useful in the present disclosure for these cancers as well.

[0151] The amount of chemotherapeutic agent delivered to a patient can vary. In a preferred embodiment, when chemotherapy is administered in conjunction with the construct, the chemotherapeutic agent can be administered in an amount effective to arrest or cause regression of cancer in the host. In other embodiments, the chemotherapeutic agent can be administered in any amount between 2 and 10,000 times less than the chemotherapeutic effective dose of the chemotherapeutic agent. For example, the chemotherapeutic agent can be administered in an amount about 20 times less, about 500 times less, or even about 5000 times less than the effective dose of the chemotherapeutic agent. The disclosed chemotherapeutic agents can be tested in vivo for the desired therapeutic activity in combination with the construct and to determine effective dosages. For example, such compounds can be tested in suitable animal model systems, including, but not limited to, rats, mice, chickens, cows, monkeys, rabbits, etc., prior to testing in humans. Additionally, suitable combinations and dosages can be determined using in vitro testing, as described in the Examples.

[0152] F. Radiation Therapy In some embodiments, the additional therapy or pre-therapy comprises radiation, such as ionizing radiation. As used herein, "ionizing radiation" refers to radiation that contains particles or photons that have or can generate sufficient energy through nuclear interaction to cause ionization (gain or loss of electrons). An exemplary and preferred ionizing radiation is X-rays. Means for irradiating target tissues or cells with X-rays are well known in the art.

[0153] In some embodiments, the amount of ionizing radiation is greater than 20 Gray (Gy) and is administered in one fraction. In some embodiments, the amount of ionizing radiation is 18 Gy and is administered in three fractions. In some embodiments, the amount of ionizing radiation is at least, at most, or exactly 2, 4, 6, 8, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 18, 19, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 40 Gy (or any derivable range therein). In some embodiments, the ionizing radiation is administered at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times (or any derivable range therein). When administered more than once, the administration may be about 1, 4, 8, 12, or 24 hours apart, or 1, 2, 3, 4, 5, 6, 7, or 8 days apart, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, or 16 weeks apart, or any derivable range therein.

[0154] In some embodiments, the amount of IR may be presented as a total dose of IR, which is then administered in fractionated doses. For example, in some embodiments, the total dose is 50 Gy, administered in 10 fractionated doses of 5 Gy each. In some embodiments, the total dose is 50-90 Gy, administered in 20-60 fractionated doses of 2-3 Gy each. In some embodiments, the total dose of IR is at least, at most, or about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 125, 130, 135, 140, or 150 (or any derivable range therein). In some embodiments, the total dose is administered in fractions of at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 20, 25, 30, 35, 40, 45, or 50 Gy (or any derivable range therein).In some embodiments, at least, at most, or exactly 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, In some embodiments, the dose is administered in 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 fractionated doses (or any derivable range therein). In some embodiments, the dose is administered in at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 fractionated doses (or any derivable range therein) per day. In some embodiments, at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 fractionated doses (or any derivable range therein) are administered per week.

[0155] G. Surgery Approximately 60% of people with cancer undergo some type of surgery, including preventive, diagnostic, or staging surgery, curative, and palliative surgery. Curative surgery involves resection, which physically removes, excises, and / or destroys all or part of the cancerous tissue, and can be combined with other therapies, such as the present treatment, chemotherapy, radiation therapy, hormone therapy, gene therapy, immunotherapy, and / or alternative therapies. Tumor resection refers to the physical removal of at least part of the tumor. In addition to tumor resection, surgical treatments include laser surgery, cryosurgery, electrosurgery, and microsurgical surgery (Mohs surgery).

[0156] When cancer cells, tissues, or tumors are partially or completely removed, a cavity may form in the body. Treatment is achieved by perfusion, direct injection, or by locally applying additional anti-cancer therapy to the area. Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. These therapies may also be at various dosages.

[0157] H. Other Agents It is contemplated that other agents may be used in combination with certain aspects of this embodiment to improve the therapeutic efficacy of the treatment. These additional agents include agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, cell adhesion inhibitors, agents that sensitize hyperproliferative cells to apoptosis inducers, or other biological agents. Increasing intercellular signaling by increasing the number of GAP junctions will enhance the anti-hyperproliferative effect on adjacent hyperproliferative cell populations. In other embodiments, cytostatic or differentiation agents may be used in combination with certain aspects of this embodiment to improve the anti-hyperproliferative efficacy of the treatment. Cell adhesion inhibitors are contemplated to improve the efficacy of this embodiment. Examples of cell adhesion inhibitors are focal adhesion kinase (FAK) inhibitors and lovastatin. It is further contemplated that other agents that sensitize hyperproliferative cells to apoptosis, such as the antibody c225, may be used in combination with certain aspects of this embodiment to improve the therapeutic efficacy.

[0158] V. Administration of the Treatment Composition Therapies provided herein include administering a combination of an immune checkpoint inhibitor and a microbial regulator. The therapy may be administered by any suitable method known in the art. For example, the immune checkpoint inhibitor (e.g., a PD-1 inhibitor and / or a CTLA-4 inhibitor) and the microbial regulator may be administered sequentially (at different times) or simultaneously (at the same time). In some embodiments, the immune checkpoint inhibitor is present in a separate composition from the microbial regulator. In some embodiments, the immune checkpoint inhibitor is present in the same composition as the microbial regulator.

[0159] Disclosed embodiments relate to compositions and methods comprising one or more of an inhibitor of CTLA-4, B7-1, and / or B7-2 in combination with one or more of an inhibitor of PD-1, PDL1, and / or PDL2. The immune checkpoint inhibitors may be administered in one composition or in more than one composition, such as two, three, or four compositions. Various combinations of inhibitors may be used, for example, an inhibitor of CTLA-4, B7-1, or B7-2 designated "A" and an inhibitor of PD-1, PDL1, or PDL2 designated "B": TIFF2025138762000001.tif22128

[0160] In some embodiments, the methods involve administering one or more inhibitors of CTLA-4, B7-1, and / or B7-2 simultaneously with one or more inhibitors of PD-1, PDL1, and / or PDL2. In some embodiments, the one or more inhibitors of CTLA-4, B7-1, and / or B7-2 are administered before one or more inhibitors of PD-1, PDL1, and / or PDL2. In some embodiments, the one or more inhibitors of CTLA-4, B7-1, and / or B7-2 are administered at least, at most, or exactly 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) before one or more inhibitors of PD-1, PDL1, and / or PDL2. In some embodiments, one or more of the inhibitors of PD-1, PDL1, and / or PDL2 are administered before one or more of the inhibitors of CTLA-4, B7-1, and / or B7-2. In some embodiments, one or more of the inhibitors of PD-1, PDL1, and / or PDL2 are administered at least, at most, or exactly 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) before one or more of the inhibitors of CTLA-4, B7-1, and / or B7-2. In some embodiments, one or more of the CTLA-4, B7-1, and / or B7-2 inhibitors are administered within 1, 2, 3, 4, 5, 6, 7 days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 weeks (or any derivable range therein) of administration of one or more of the PD-1, PDL1, and / or PDL2 inhibitors.

[0161] In some embodiments, the microbial modulator composition is administered before the immune checkpoint inhibitor. In some embodiments, the microbial modulator composition is administered at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) before the immune checkpoint inhibitor. In some embodiments, the microbial modulator composition is administered at least 1, 2, 3, 4, 5, 6, or 7 times (or any derivable range therein) at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) before the immune checkpoint inhibitor. In some embodiments, the microbial modulator composition is administered after the immune checkpoint inhibitor. In some embodiments, the microbial modulator composition is administered at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) after the immune checkpoint inhibitor, or at least one of the immune checkpoint inhibitors, or at least two of the immune checkpoint inhibitors. In some embodiments, the microbial modulator composition is administered at least 1, 2, 3, 4, 5, 6, or 7 times (or any derivable range therein) after the immune checkpoint inhibitor, or at least one of the immune checkpoint inhibitors, or at least two of the immune checkpoint inhibitors.

[0162] Disclosed combination therapies also include a microbial modulator composition. In some embodiments, the microbial modulator composition is administered before one or more of the inhibitors of PD-1, PDL1, and / or PDL2. In some embodiments, the microbial modulator composition is administered at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) before the one or more of the inhibitors of PD-1, PDL1, and / or PDL2. In some embodiments, the microbial modulator composition is administered at least 1, 2, 3, 4, 5, 6, or 7 times (or any derivable range therein) at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) before one or more of the inhibitors of PD-1, PDL1, and / or PDL2. In some embodiments, the microbial modulator composition is administered after one or more of the inhibitors of PD-1, PDL1, and / or PDL2. In some embodiments, the microbial modulator composition is administered at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) after one or more of the inhibitors of PD-1, PDL1, and / or PDL2, or at least one or at least two of PD-1, PDL1, or PDL2. In some embodiments, the microbial modulator composition is administered at least 1, 2, 3, 4, 5, 6, or 7 times (or any derivable range therein) at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) after administration of one or more inhibitors of PD-1, PDL1, or PDL2, or at least one or at least two inhibitors of PD-1, PDL1, or PDL2.

[0163] The disclosed combination therapies also include a microbial modulator composition. In some embodiments, the microbial modulator composition is administered before one or more of the CTLA-4, B7-1, and / or B7-2 inhibitors. In some embodiments, the microbial modulator composition is administered at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) before the one or more of the CTLA-4, B7-1, and / or B7-2 inhibitors. In some embodiments, the microbial modulator composition is administered at least 1, 2, 3, 4, 5, 6, or 7 times (or any derivable range therein) at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) before one or more of the inhibitors of CTLA-4, B7-1, and / or B7-2. In some embodiments, the microbial modulator composition is administered after one or more of the inhibitors of CTLA-4, B7-1, and / or B7-2. In some embodiments, the microbial modulator composition is administered at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) after one or more of the inhibitors of CTLA-4, B7-1, and / or B7-2, or at least one or at least two of the inhibitors of CTLA-4, B7-1, and / or B7-2.In some embodiments, the microbial modulator composition is administered at least 1, 2, 3, 4, 5, 6, or 7 times (or any derivable range therein) at least, at most, or exactly 1, 2, 3, 5, 6, 12, 24 hours, or 2, 3, 4, 6, 8, 10 days, or 2, 3, 4, 5, 6, 7, or 8 weeks (or any derivable range therein) after administration of one or more of the inhibitors of CTLA-4, B7-1, and / or B7-2, or at least one or at least two of the inhibitors of CTLA-4, B7-1, or B7-2.

[0164] In some embodiments, the microbial modulator composition is formulated for oral administration. Those skilled in the art will appreciate a variety of formulations that can include live or dead microorganisms and can be presented as food supplements (e.g., pills, tablets, etc.) or as functional foods such as beverages or fermented yogurt.

[0165] The immune checkpoint inhibitor and the microbial modulator may be administered by the same or different routes of administration. In some embodiments, the immune checkpoint inhibitor is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some embodiments, the microbial modulator is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In certain aspects, the immune checkpoint inhibitor is administered intravenously, and the microbial modulator is administered orally. Effective amounts of the immune checkpoint inhibitor and the microbial modulator may be administered for the prevention or treatment of disease. The appropriate dosage of the immune checkpoint inhibitor and / or the microbial modulator can be determined based on the type of disease being treated, the severity and course of the disease, the individual's clinical condition, the individual's clinical history and response to treatment, and the discretion of the attending physician.

[0166] For example, a therapeutically effective or sufficient amount of at least one isolated or purified population of bacteria, or at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 isolated or purified populations of said bacteria, of an embodiment of a microbial modulator composition administered to a human may be at least about 1×10 3 colony-forming units (CFU) of bacteria, or at least approximately 1 x 10 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 In some embodiments, a single dose is at least, at most, or exactly 1 x 10 CFU (or any derivable range therein). 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 , or 1 × 10 15 In some embodiments, a single dose contains at least, at most, or exactly 1 x 10 CFU (or any derivable range therein) of a specified bacterium, such as a particular bacterium or species, genus, or family described herein. 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×1014 , 1×10 15 , or 1 × 10 15 In certain embodiments, the composition contains more than 1 x 10 CFU (or any derivable range therein) of total bacteria. In certain embodiments, the bacteria are provided in the form of spores or as sporulated bacteria. In certain embodiments, the concentration of spores of each isolated or purified population of bacteria, e.g., each species, subspecies, or strain, is at least, at most, or exactly 1 x 10 per gram of composition or per administered dose. 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 pieces, or 1 x 10 15 In some embodiments, the compositions or methods comprise administering at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 40, or 50 (or any derivable range therein) of different bacterial species, genera, or families.

[0167] In some embodiments, the therapeutically effective or sufficient amount of at least one isolated or purified population of bacteria, or at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 isolated or purified populations of bacteria, of an embodiment of a microbial modulator composition administered to a human is at least about 1 x 10 3 bacteria, or at least about 1 x 10 cells 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×1012 , 1×10 13 , 1×10 14 , 1×10 15 In some embodiments, a single dose is at least, at most, or exactly 1 x 10 cells (or any derivable range therein). 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 pieces, or 1 x 10 15 In some embodiments, a single dose contains an amount of bacteria (such as a particular bacterium or species, genus, or family described herein) of a specified bacterium of greater than 1 x 10 cells (or any derivable range therein). In some embodiments, a single dose contains at least, at most, or exactly 1 x 10 cells. 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 pieces, or 1 x 10 15 In certain embodiments, the composition contains more than 1 x 10 cells (or any derivable range therein) of whole bacteria. In certain embodiments, the bacteria are provided in the form of spores or as sporulated bacteria. In certain embodiments, the concentration of spores of each isolated or purified population of bacteria, e.g., each species, subspecies, or strain, is at least, at most, or exactly 1 x 10 per gram of composition or per administered dose. 4 , 1×10 5 , 1×10 6 , 1×10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×1011 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 pieces, or 1 x 10 15 In some embodiments, the compositions or methods comprise administering at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 40, or 50 (or any derivable range therein) of different bacterial species, genera, or families.

[0168] Intratumoral injection or injection into the tumor vasculature is particularly contemplated for dispersed, solid, accessible tumors. Local, regional, or systemic administration may also be appropriate. For tumors >4 cm, the administered volume will be approximately 4-10 mL (especially 10 mL), while for tumors <4 cm, a volume of approximately 1-3 mL (especially 3 mL) is used. Multiple injections delivered as a single dose comprise a volume of approximately 0.1 to approximately 0.5 mL. For example, adenoviral particles can be advantageously contacted by administering multiple injections to the tumor.

[0169] Treatment regimens may also vary and often depend on tumor type, tumor location, disease progression, and the patient's health and age. Obviously, certain types of tumors require more aggressive treatment, but at the same time, certain patients cannot tolerate more burdensome protocols. Clinicians will be best suited to make such decisions based on the known efficacy and toxicity (if any) of treatment formulations.

[0170] In certain embodiments, the tumor being treated may not be resectable, at least initially. Treatment with a therapeutic viral construct can increase the resectability of the tumor due to margin reduction or elimination of certain particularly aggressive areas. After treatment, resection may become possible. Additional treatment after resection serves to eliminate minimal residual disease at the tumor site.

[0171] Treatments may include various "unit doses." A unit dose is defined as containing a predetermined amount of a treatment composition. The amount to be administered, as well as the specific route and formulation, are within the skill of those skilled in the clinical arts in their judgment. A unit dose need not be administered as a single injection, but may include continuous infusion over a period of time. In some aspects, a unit dose comprises a single administrable dose.

[0172] The amount to be administered depends on the desired therapeutic effect, depending on both the number of treatments and the unit dose. It is understood that an effective dose refers to the amount required to achieve a specific effect. In certain embodiments, it is contemplated that a dose ranging from 10 mg / kg to 200 mg / kg can affect the protective capacity of these agents. Thus, doses are contemplated to include doses of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 μg / kg, mg / kg, μg / day, or mg / day, or any derivable range therein. Furthermore, such doses can be administered multiple times during the day and / or on multiple days, weeks, or months.

[0173] In some embodiments, a therapeutically effective or sufficient amount of an immune checkpoint inhibitor, such as an antibody and / or microbial modulator, administered to a human, whether administered in a single dose or multiple doses, will be in the range of about 0.01 to about 50 mg / kg (of the patient's body weight). In some embodiments, the inhibitor used is, for example, about 0.01 to about 45 mg / kg, about 0.01 to about 40 mg / kg, about 0.01 to about 35 mg / kg, about 0.01 to about 30 mg / kg, about 0.01 to about 25 mg / kg, about 0.01 to about 20 mg / kg, about 0.01 to about 15 mg / kg, about 0.01 to about 10 mg / kg, about 0.01 to about 5 mg / kg, or about 0.01 to about 1 mg / kg, administered daily. In some embodiments, the inhibitor is administered at 15 mg / kg. However, other dosing regimens may be useful. In one embodiment, the inhibitor described herein is administered to subject at a dose of about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg or about 1400mg on the first day of a 21-day cycle.The dose can be administered as a single dose or as multiple doses (for example, two or three doses), such as by infusion.The progress of this therapy can be easily monitored by conventional techniques.

[0174] In certain embodiments, an effective dose of the pharmaceutical composition is one that can provide blood levels of about 1 μM to 150 μM. In other embodiments, an effective dose provides blood levels of about 4 μM to 100 μM; or about 1 μM to 100 μM; or about 1 μM to 50 μM; or about 1 μM to 40 μM; or about 1 μM to 30 μM; or about 1 μM to 20 μM; or about 1 μM to 10 μM; or about 10 μM to 150 μM; or about 10 μM to 100 μM; or about 10 μM to 50 μM; or about 25 μM to 150 μM; or about 25 μM to 100 μM; or about 25 μM to 50 μM; or about 50 μM to 150 μM; or about 50 μM to 100 μM (or any derivable range therein). In other embodiments, the dose can provide the following blood levels of the therapeutic agent as a result of administering the agent to a subject: about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 μM, or any derivable range therein. In certain embodiments, a therapeutic agent administered to a subject is metabolized in the body to a metabolic therapeutic agent, in which case blood levels can refer to the amount of that agent. Alternatively, to the extent that a therapeutic agent is not metabolized by the subject, blood levels discussed herein can refer to the unmetabolized therapeutic agent.

[0175] Precise amounts of the therapeutic composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dosage include the physical and clinical condition of the patient, the route of administration, the intended purpose of treatment (palliative versus curative), and the efficacy, stability, and toxicity of the particular therapeutic agent or other therapy the subject may be undergoing.

[0176] Those skilled in the art will understand and appreciate that dosage units of μg / kg or mg / kg (body weight) can be converted and expressed in comparable concentration units of μg / mL or mM (blood levels), e.g., 4 μM to 100 μM. It is also understood that uptake is species and organ / tissue dependent. Applicable conversion factors and physiological assumptions regarding uptake and concentration measurements are well known, allowing those skilled in the art to convert one concentration measurement to another and make reasonable comparisons and conclusions regarding the doses, efficacies, and results described herein.

[0177] VI. Treatment Methods Provided herein are methods for treating or slowing the progression of cancer in an individual, comprising administering to the individual an effective microbial modulator composition to a subject who has been or is currently receiving immune checkpoint therapy. Also provided herein are methods for selecting subjects who will respond favorably to immune checkpoint therapy by assessing the subject's microbial profile and administering an immune checkpoint inhibitor to subjects identified as having a favorable microbial profile.

[0178] In some embodiments, the treatment results in a sustained response in the individual even after the treatment is discontinued. The methods described herein can be used in the treatment of conditions in which improved immunogenicity is desired, such as increasing the immunogenicity of tumors to treat cancer. Also provided herein are methods for enhancing immune function in individuals, such as those with cancer, comprising administering to the individual an effective amount of an immune checkpoint inhibitor (e.g., a PD-1 inhibitor and / or a CTLA-4 inhibitor) and a microbial regulator. In some embodiments, the individual is a human.

[0179] In some embodiments, the individual has a cancer that is resistant (demonstrated to be resistant) to one or more anti-cancer therapies. In some embodiments, resistance to anti-cancer therapy includes recurrence of cancer or refractory cancer. Recurrence can refer to the recurrence of cancer at the original site or a new site after treatment. In some embodiments, resistance to anti-cancer therapy includes progression of cancer during treatment with anti-cancer therapy. In some embodiments, the cancer is in an early or late stage.

[0180] In some embodiments of the methods of the present disclosure, the cancer has a low level of T cell infiltration. In some embodiments, the cancer has no detectable T cell infiltration. In some embodiments, the cancer is a non-immunogenic cancer (e.g., non-immunogenic colorectal cancer and / or ovarian cancer). Without being bound by theory, the combination treatment may result in a higher T cell (e.g., CD4 + T cells, CD8 + It can increase the priming, activation, proliferation, and / or infiltration of T cells (e.g., T cells, memory T cells).

[0181] The cancer may be a solid tumor, a metastatic cancer, or a non-metastatic cancer. In certain aspects, the cancer may occur in the bladder, blood, bone, bone marrow, brain, breast, urinary tract, cervix, esophagus, duodenum, small intestine, large intestine, colon, rectum, anus, gums, head, kidney, liver, lung, nasopharynx, cervix, ovary, prostate, skin, stomach, testicles, tongue, or uterus.

[0182] The cancer may be of the following specific histological types, but is not limited to: malignant neoplasm; carcinoma; undifferentiated, bladder, blood, bone, brain, breast, urinary, esophageal, thymoma, duodenum, colon, rectum, anus, gingiva, head, kidney, soft tissue, liver, lung, nasopharynx, cervix, ovary, prostate, skin, stomach, testis, tongue, uterus, thymus, cutaneous squamous cell, non-colorectal gastrointestinal, colorectal, melanoma, Merkel cell, renal cell, cervix, hepatocellular, urothelial, non-small cell lung, head and neck, endometrium, esophagogastric, small cell lung mesothelioma, ovary, esophagogastric, glioblastoma, adrenal cortex, uvea, pancreas, germ cell, giant cell, Cell and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; trichocarcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; malignant gastrinoma; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenocarcinomatous polyps; familial adenomatous polyposis coli; solid tumors; malignant carcinoid tumors; bronchoalveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; eosinophilic carcinoma; acidophilic gland; basophilic adenocarcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; non-encapsulating sclerosing carcinoma; adrenocortical carcinoma; endometrial carcinoma; skin adnexal carcinoma; apo Clinian adenocarcinoma; Sebaceous gland carcinoma; Adenocarcinoma of the auditory canal; Mucoepidermoid carcinoma; Cystadenocarcinoma; Papillary cystadenocarcinoma; Papillary serous cystadenocarcinoma; Mucinous cystadenocarcinoma; Mucinous adenocarcinoma; Signet ring cell carcinoma; Invasive ductal carcinoma; Medullary carcinoma; Lobular carcinoma; Inflammatory carcinoma; Paget's disease of the breast; Acinic cell carcinoma; Adenosquamous carcinoma; Adenocarcinoma with squamous metaplasia; Malignant thymoma; Malignant ovarian stromal tumor; Malignant thecal tumor; Malignant granulosa cell tumor; Malignant androblastoma; Sertoli cell carcinoma; Malignant Leydig cell tumor; Malignant lipid cell tumor; Malignant paraganglioma; Malignant extramammary paraganglioma; Pheochromocytoma; Hemangioangiosarcoma; Malignant melanoma; Amelanotic melanoma; Superficial spreading melanoma ;Malignant melanoma in giant pigmented nevus;Epithelioid cell melanoma;Cutaneous melanoma, malignant blue nevus;Sarcoma;Fibrosarcoma;Malignant fibrous histiocytoma;Myxosarcoma;Liposarcoma;Leiomyosarcoma;Rhabdomyosarcoma;Embryonic rhabdomyosarcoma;Alveolar rhabdomyosarcoma;Stromatous sarcoma;Malignant mixed tumor;Müllerian mixed tumor;Nephroblastoma;Hepatoblastoma;Carcinosarcoma;Malignant mesenchymoma;Malignant Brenner tumor;Malignant phyllodes tumor;Malignant synovial sarcoma;Dysgerminoma;Embryonal carcinoma;Malignant teratoma;Malignant ovarian goiter;Choriocarcinoma;Malignant mesonephroma;Angiosarcoma;Malignant hemangioendothelioma;Kaposi's sarcoma;Malignant hemangiopericytoma;Lymphangiosarcoma;Osteosarcoma;Parosteal osteosarcoma;Chondrosarcoma;Malignant chondroblastoma; Mesenchymal chondrosarcoma; Giant cell tumor of bone; Ewing's sarcoma; Malignant odontogenic tumor; Ameloblastic sarcoma; Malignant ameloblastoma; Ameloblastic fibrosarcoma; Malignant pinealoma; Chordoma; Malignant glioma; Ependymoma; Astrocytoma; Protoplasmic astrocytoma; Fibrous astrocytoma; Astroblastoma; Oligodendroglioma; Oligodendroglioma; Primitive neuroectodermal; Cerebellar sarcoma; Ganglioneuroblastoma; Neuroblastoma; Retinoblastoma; Olfactory neurogenic tumor; Malignant meningioma; Neurofibrosarcoma; Malignant neurilemmoma; Malignant granular cell tumor; Malignant riboma Lymphoma; Hodgkin's disease; Hodgkin's granuloma; small lymphocytic lymphoma; large cell, diffuse lymphoma; malignant follicular lymphoma; mycosis fungoides; other specified non-Hodgkin's lymphoma; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphocytic leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

[0183] In some aspects, the cancer comprises cutaneous squamous cell carcinoma, non-colorectal and colorectal gastrointestinal cancer, Merkel cell carcinoma, anal cancer, cervical cancer, hepatocellular carcinoma, urothelial carcinoma, melanoma, lung cancer, non-small cell lung cancer, small cell lung cancer, head and neck cancer, kidney cancer, bladder cancer, Hodgkin's lymphoma, pancreatic cancer, or skin cancer.

[0184] In some aspects, the cancer comprises lung cancer, pancreatic cancer, metastatic melanoma, kidney cancer, bladder cancer, head and neck cancer, or Hodgkin's lymphoma.

[0185] The methods can involve determining, administering, or selecting an appropriate cancer "management regimen" and predicting its outcome. As used herein, the phrase "management regimen" refers to a management plan that specifies the types of tests, screenings, diagnosis, monitoring, care, and treatments (such as dosage, schedule, and / or duration of treatment) to be provided to a subject in need thereof (e.g., a subject diagnosed with cancer).

[0186] The term "treatment" or "treating" refers to any treatment of a disease in a mammal, including: (i) preventing the disease, i.e., preventing the onset of clinical symptoms of the disease by administering a protective composition prior to the induction of the disease; (ii) suppressing the disease, i.e., preventing the onset of clinical symptoms of the disease by administering a protective composition after an inducing event but prior to the clinical appearance or reappearance of the disease; (iii) inhibiting the disease, i.e., preventing the onset of clinical symptoms by administering a protective composition after their initial appearance; and / or (iv) ameliorating the disease, i.e., reversing clinical symptoms by administering a protective composition after their initial appearance. In some embodiments, treatment may exclude prevention of the disease.

[0187] In certain aspects, to detect cancer or cancer metastasis in patients determined to have a particular gut microbiome composition, further cancer or metastasis testing or screening, or further diagnostics such as contrast-enhanced computed tomography (CT), positron emission tomography-CT (PET-CT), and magnetic resonance imaging (MRI) may be performed.

[0188] VII. Methods for Determining Microbiome Composition In some embodiments, the method relates to obtaining a microbiome profile. In some embodiments, obtaining a microbiome profile includes, or includes the following steps in this order: i) obtaining a sample from a subject (e.g., a human subject); ii) isolating one or more bacterial species from the sample; iii) isolating one or more nucleic acids from at least one bacterial species; iv) sequencing the isolated nucleic acids; and v) comparing the sequenced nucleic acids with a reference nucleic acid sequence. When performing a method requiring genotyping, any genotyping assay can be used. For example, this can be performed by sequencing 16S or 23S ribosomal subunits, or by metagenomics shotgun sequencing associated with metatranscriptomics.

[0189] Methods for determining the composition of the microbiome may include one or more microbiological methods such as sequencing, next generation sequencing, wester blotting, comparative genomic hybridization, PCR, ELISA, etc.

[0190] VIII. Kit Certain aspects of the present disclosure also encompass kits for carrying out the disclosed methods, such as cancer detection, diagnosis, or treatment, and / or the detection and qualitative or quantitative characterization of microorganisms. Such kits can be prepared from readily available materials and reagents. For example, such kits may include any one or more of the following materials: enzymes, reaction tubes, buffers, detergents, primers, probes, and antibodies. In preferred embodiments, these kits enable practitioners to obtain samples of neoplastic cells in blood, tears, semen, saliva, urine, tissue, serum, feces, sputum, cerebrospinal fluid, and supernatants from cell lysates. In another preferred embodiment, these kits include the equipment necessary to perform RNA extraction, RT-PCR, and gel electrophoresis. Instructions for carrying out the assays may also be included in the kits.

[0191] In certain aspects, these kits may include multiple agents for evaluating or identifying microorganisms, the kits being housed in a container. The kits may further include instructions for using the kit to evaluate sequences and means for converting and / or analyzing sequence data to determine a prognosis. The agents in the kit for measuring biomarker expression may include multiple PCR probes and / or primers for qRT-PCR and / or multiple antibodies or fragments thereof for assessing biomarker expression. In another embodiment, the agents in the kit for measuring biomarker expression may include multiple polynucleotides complementary to the mRNAs of the biomarkers of the invention. Possible means for converting expression data into expression values ​​and analyzing the expression values ​​to generate scores predictive of survival or prognosis may also be included.

[0192] The kit may include a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a composition containing a probe useful for a prognostic or non-prognostic application, such as those described above. The label on the container may indicate that the composition is to be used for a particular prognostic or non-prognostic application and may also indicate instructions for either in vivo or in vitro use, such as those described above. The kit may include the container described above and one or more other containers containing materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts containing instructions for use.

[0193] Further kit embodiments relate to kits that include the therapeutic compositions of the present disclosure. The kits may be useful in the therapeutic methods of the present disclosure and may include instructions for use. [Example]

[0194] IX. Working Example The following examples are included to illustrate preferred embodiments of the invention. It should be understood by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to work well in the practice of the invention, and therefore can be considered to constitute preferred modes for its practice. However, those skilled in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0195] Example 1 - Molecular, immune, and microbial drivers of response and toxicity to combined CTLA-4 and PD-1 blockade Cancer treatment paradigms are rapidly evolving, fueled by parallel advances in our ability to understand and characterize tumors at the genomic and immune levels. Checkpoint blockade immunotherapy, which targets negative regulatory pathways that contribute to the abrogation of antitumor immune responses in patients, is now a practical and effective strategy in widespread clinical use. Multiple novel agents designed to block immunosuppressive or activate immunostimulatory molecular targets are under development. Attempts to improve response rates to checkpoint blockade are currently dominated by combination drug strategies, exemplified by the combination of inhibitors of CTLA-4 and PD-1 (combined immune checkpoint blockade, CICB). Although more effective at inducing objective responses (Larkin et al., 2015), this combination is associated with serious immune-related adverse events (irAEs) (Hammers et al., 2017; Sznol et al., 2017) and may not be necessary or appropriate for up to 40% of unselected patients predicted to respond to PD-1 blockade alone, who have a low attendant risk of severe irAEs (Robert et al., 2015a; Robert et al., 2015b). Reliable pretreatment predictors of toxicity have yet to be identified despite recent attempts and are greatly needed.

[0196] We sought to identify potential tumor-derived and systemic molecular, immune, and gut bacterial biomarkers of both response and immune-related toxicity in melanoma patients receiving CICB. We constructed a cohort of patients with advanced melanoma who were concurrently treated with the anti-CTLA-4 antibody ipilimumab and either the anti-PD-1 antibody nivolumab or pembrolizumab. Patients were classified for response and toxicity using objective radiographic assessments to determine response and the occurrence of high-grade (grade 3 or higher) irAEs to determine toxicity.

[0197] Lower toxicity was associated with a lower diversity of the peripheral T cell repertoire and an immune phenotype indicative of greater antigen experience. Surprisingly, this phenotype was also associated with prior immunotherapy, which predicted lower-grade toxicity. Median fecal microbial alpha diversity was numerically higher in responders, and differential abundance of Bacteroides stercolis, Ackermansia muciniphila, Prevotella copri, and Bacteroides fragilis correlated with response and toxicity. The causal role of the gut microbiota in promoting CICB-mediated subclinical ileitis and colitis was investigated in two tumor-bearing mouse models, demonstrating that distinctive symbiotic ecosystems driving immunostimulatory or inhibitory effects are shared across mammalian species.

[0198] A. Results 1. Study Scheme and Biospecimen Collection We constructed a cohort of patients with metastatic melanoma who received CICB either in a clinical trial or as standard of care (SOC) therapy between January 1, 2014, and August 31, 2017 (Figure 1, Table 1). Patients were excluded from the primary study cohort if they had mucosal or uveal melanoma subtypes, lacked adequate biospecimens related to treatment duration, or had insufficient data available to determine radiographic response and toxicity data.

[0199] Patients were classified as "responders" (R) or "non-responders" (NR) based on best overall response (BOR) to CICB as measured by RECIST v1.1, and as patients with any grade 3 or higher irAEs versus patients with grade <3 irAEs. Available pre- and intra-treatment tumor and peripheral blood samples were collected for molecular and immunological correlation analyses, while pre- or early-treatment fecal specimens were collected using the OMNIgene-GUT kit and frozen prior to microbiome profiling by 16S rDNA sequencing (Table 1).

[0200] 2. Patient characteristics, clinical efficacy and toxicity of CICB The cohort consisted of 53 patients, primarily with stage IV disease (n = 45, 85%), and the majority of patients had not received prior systemic therapy for advanced disease (n = 39, 74%) (Table 2). One-fifth of patients (n = 11, 20.8%) had received some form of prior immunotherapy: ipilimumab or anti-PD-1, anti-PD-L1 agents, alone or as part of an adjuvant or palliative biochemotherapy regimen (Table 2).

[0201] The median number of doses of the combined ipilimumab and anti-PD-1 agent was 3 (range 1-4) (Table 3), and the median number of doses of anti-PD-1 monotherapy after the first combination was 1 (range 0-44). The overall response rate was 77.4% (41 / 53 patients), and progression occurred in 21 patients after a median follow-up period of 15.6 months (overall median PFS was not reached, median progression-free time in progressers was 3.0 months; Figure 1). Nearly all patients (n=51, 96.2%) experienced treatment-related (probably, almost certainly, or definitely) adverse events (AEs) of any grade, and 28 (52.8%) of the patients experienced high-grade treatment-related immune-related AEs (irAEs) (≥grade 3), with diarrhea / colitis, transaminitis, hypothyroidism / hyperthyroidism, other endocrine disorders, and cutaneous toxicities (rash, pruritus) being the most common (Table 3). Treatment-related toxicities led to treatment discontinuation in 21 (39.6%) patients, but there were no treatment-related deaths.

[0202] 3. Molecular and immunological determinants of response and resistance to CICB Because mutational burden varies significantly across tumor types and has been shown to influence objective responses to CTLA-4 or PD-1 blockade monotherapy (Hugo et al., 2016; Snyder et al., 2014; Van Allen et al., 2015), and some evidence has also been reported in the setting of CICB treatment in non-small cell lung cancer (NSCLC) (Hellmann et al., 2018), we first investigated the relationship between mutational burden and response to CICB. We performed whole-exome sequencing on available pretreatment tumor samples (n = 26, Table 1). All cases showed a predominant UV damage signature characterized by a C-to-T transition, as expected for cutaneous melanoma (data not shown). There were no statistically significant differences between whole-exon mutations or nonsynonymous polymorphisms (NSVs) between responders (R, n = 20) and nonresponders (NR, n = 6) to CICB ( Figure 2A ), although there was significant overlap in the low mutation burden range (<1000 NSVs), suggesting that a high mutation burden may be tolerated but not required for response.

[0203] Next, we investigated whether specific mutational drivers or immune-related signaling pathways in melanoma were associated with CICB response. Common melanoma driver mutations were uniformly distributed across patient-derived tumors, regardless of response status. When grouped into melanoma driver, IFN-γ pathway, and antigen processing pathway gene sets, there was no clear pattern based on mutation type (e.g., missense, nonsense, indel), affected gene, or gene group (Figure 8A). BRAF V600 Mutations were significantly associated with a lower overall somatic mutation load (p<0.001) (Fig. 8B), as expected, but not with response.

[0204] Given that neoantigen burden-related immunogenicity is predicted to be proportional to the underlying nonsynonymous mutation load, we performed in silico neoantigen prediction using the netMHCpan algorithm (Nielsen et al., 2007) and found no significant differences in the number of total or high-affinity predicted neoantigens between the two response groups (n = 26, Figure 8C). Given the lack of correlation between mutation or predicted neoantigen load and response, we next investigated whether genomic copy number alterations (CNAs) influence response. Unlike mutation load, copy number loss load showed a statistically significant association with response (p = 0.04, Figure 2B), driven by a higher chromosomal copy number loss burden in NRs, primarily affecting chromosomes 5, 15, and particularly 10 (Figure 2C, Figures 8D-E). Several genes previously implicated in resistance to immune checkpoint blockade monotherapy appear to be exclusively (CD74) or disproportionately (PDIA3, B2M, PTEN) affected by copy number loss in NR tumors ( Figure 2D ), suggesting potential immunogenomic mechanisms of resistance to CICB ( Ekmekcioglu et al., 2016 ; Peng et al., 2016 ; Roh et al., 2017 ; Tanese et al., 2015 ; Zaretsky et al., 2016 ).

[0205] To further elucidate the complex microenvironmental interactions between tumors and infiltrating immune cells that shape outcomes to CICB, we next examined intratumoral and systemic immune populations to identify potential markers of response. As expected, we observed numerically higher CD8+ density in baseline tumor immune infiltrates in R compared with NR tumors, but this did not reach statistical significance (n = 19 R, n = 6 NR; p = 0.052, one-sided Mann-Whitney test, Figure 2E), likely due to the limited cohort size and relatively small proportion of non-responders. Furthermore, the density of CD8+ T cells tended to increase after CICB treatment, regardless of treatment response (Figure 9A). Analysis of the intratumoral T cell repertoire by T cell receptor (TCR) sequencing (n = 25, Table 1) revealed a strong tendency for higher entropy in tumor T cell infiltrates in R (Figure 2F). TCR sequencing of baseline tumors demonstrated no significant difference in clonality between R and NR (p=0.28, Figure 2G), but this was also limited by cohort size and the R / NR ratio (n=19 R, n=6 NR).

[0206] 4. Antigen-experienced T cell repertoire and prior immunotherapy are associated with the absence of grade 3-4 irAEs Severe irAEs are particularly common in patients receiving CICB, and the occurrence of grade 3 or higher irAEs often leads to therapy interruption despite clinical response. The precise immune mechanisms and reliable predictive biomarkers for irAEs caused by CICB are lacking (Carlino and Long, 2016). We investigated the association between systemic immune parameters and toxicity and hypothesized that the systemic circulation would be the most easily accessible compartment for sampling potentially autoreactive immune cells and thereby identifying immune signatures of patient susceptibility to CICB-induced irAEs. We performed comprehensive immune profiling of peripheral blood leukocytes using multiparameter flow cytometry and assessed the circulating T cell repertoire using TCR sequencing. Consistent with previously reported findings that treatment-induced expansion of circulating CD8+ T cell clones after ipilimumab therapy predicts toxicity in prostate cancer patients (Subudhi et al., 2016), TCR sequencing analysis (n = 16) also demonstrated that a cutoff of 55 expanded clones in peripheral blood was associated with high-grade toxicity, but that TCR repertoires with fewer expanded clones lacked meaningful negative predictive value (overall p = 0.22, Figure 9B). Patients experiencing toxicity also had higher Ki67 proliferation indices in effector and central memory CD8+ T lymphocytes early during treatment (p = 0.0044, n = 14; Figure 3A, Figure 9C), consistent with accelerated expansion of cytotoxic T cells contributing to immune-related toxicity. Furthermore, peripheral blood lymphocytes (n = 24) collected before the initiation of CICB revealed that patients who subsequently experienced high-grade irAEs had significantly higher T cell repertoire diversity (p = 0.028, Figure 3B) and entropy (p = 0.0068, Figure 3C). Collectively, these results suggest that a less focused T cell repertoire with a greater number of potentially autoreactive clones may be responsible for toxicity to CICB.

[0207] To gain further insight into the phenotype of these circulating lymphocytes, we performed multiparameter flow cytometry on baseline peripheral blood samples (n = 14–18). We found that circulating CD4+ and CD8+ T lymphocytes from patients who did not develop severe irAEs had significantly lower surface expression of CD28 and CD27 (CD27 in CD4 T cells, p = 0.0022; CD28 in CD4 T cells, p = 0.014; CD27 in CD...

Claims

1. A composition for treating cancer in a subject, comprising at least one isolated or purified population of bacteria belonging to the genus Flavonifractor, wherein the composition is administered to the subject in combination with (i) an inhibitor of PD-1, PDL1, or PDL2, and (ii) an inhibitor of CTLA-4, B7-1, or B7-2.

2. The following genera or species: Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzerellales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secariphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactifermentans.

10. The composition of claim 1, further comprising at least one isolated or purified population of bacteria belonging to one or more of the following:

3. The following genera or species:

10. The composition of claim 1, further comprising at least one isolated or purified population of bacteria belonging to one or more of the following orders: Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercolis, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, Fungatei, Clostridium thermocellum.

4. at least one isolated or purified population of bacteria belonging to the genus Flavonifractor; The following genera or species: and at least one isolated or purified population of bacteria belonging to one or more of the following genus: Dielma, Ackermansia, Alistipes, Bacteroides, Butyricimonas, Vampirovibrio, Tyzerella, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Eisenberghiella tai, Tyzerellales, Fungatei, Clostridium thermocellum, Dorea formisigenerans, Carolacter kurhaasi, Muricomes, Geosporiobacter, Prevotella parsibivens, Lactobacillus secaliphilus, Bacteroides finegoldii, Lactobacillus johnsonii, Parapedobacter compostii, and Anaerotignum lactatifermentans.

1. A composition for treating cancer in a subject, comprising: The composition is administered to a subject in combination with (i) an inhibitor of PD-1, PDL1, or PDL2 and (ii) an inhibitor of CTLA-4, B7-1, or B7-2.

5. at least one isolated or purified population of bacteria belonging to the genus Flavonifractor; The following genera or species: and at least one isolated or purified population of bacteria belonging to one or more of the following orders: Bacteroides, Butyricimonas, Dielma, Ackermansia, Alistipes, Bacteroides stercolis, Parabacteroides distasonis, Fournierera, Fournierera massiliensis, Bacteroides coprophilus, Eisenberghiella tai, Tissierrales, Fungatei, Clostridium thermocellum.

1. A composition for treating cancer in a subject, comprising: The composition is administered to a subject in combination with (i) an inhibitor of PD-1, PDL1, or PDL2 and (ii) an inhibitor of CTLA-4, B7-1, or B7-2.

6. Bacterial populations each contain at least 1 × 10 3 The composition of any one of claims 1 to 5, wherein the composition is present in a concentration of CFU.

7. 10. The composition of claim 4 or 6, which is a live bacterial product.

8. The composition of any one of claims 1 to 7, wherein the bacteria is lyophilized, freeze-dried, or frozen.

9. 9. The composition of any one of claims 1 to 8, formulated for oral delivery.

10. 10. The composition of claim 9, wherein the composition formulated for oral delivery is a tablet or capsule.

11. 11. The composition of claim 10, wherein the tablet or capsule comprises an acid-resistant enteric coating.

12. 8. The composition of any one of claims 1 to 7, wherein the composition comprising at least one isolated or purified population of bacteria, or at least two isolated or purified populations of bacteria, is formulated for rectal administration via colonoscopy, nasogastric sigmoidoscopy, or enema.

13. 8. The composition of any one of claims 1 to 7, which can be reconstituted for ultimate delivery as a liquid, suspension, gel, geltabs, semisolid, tablet, sachet, lozenge, capsule, or as an enteral formulation.

14. 14. The composition of any one of claims 1 to 13, formulated for multiple administration.

15. 15. The composition of any one of claims 1 to 14, further comprising a pharmaceutically acceptable excipient.

16. 16. The composition of any one of claims 1 to 15, wherein the purified population of bacteria comprises bacteria from at least two genera or species, and the ratio of the two bacteria is 1:

1.

17. 17. The composition of any one of claims 1 to 16, comprising bacteria of at least two different species or genera.

18. 18. The composition of any one of claims 1 to 17, which provides an alpha diversity that is at least 5 after administration to a subject.

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