The gut microbiome as a predictive biomarker for chimeric antigen receptor T cell therapy outcomes

Abstract

The present disclosure relates to methods and compositions related to adoptive cell therapy and its effectiveness in relation to gut microbiome.In certain cases, whether chimeric antigen receptor (CAR) T cell therapy is effective for an individual can be determined based on the individual's gut microbiome.In certain embodiments, based on the analysis of the individual's gut microbiome, the individual can be provided with a composition comprising one or more specific microbial compositions before administering CAR T cell therapy.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 143,665, filed January 29, 2021, which is incorporated by reference in its entirety.

[0002] Embodiments of the present disclosure relate to at least the fields of cell biology, molecular biology, immunology, microbiology, and medicine. [Background technology]

[0003] Recently, there has been considerable progress in cancer treatment with effective and less toxic targeted strategies. Immunotherapy and chimeric antigen receptor (CAR) T cells are increasingly being evaluated in a variety of tumors in relapsed / refractory and frontline disease settings, primarily in hematological malignancies. Despite impressive results in some patients, clinical responses to CAR T cells remain highly heterogeneous. The present disclosure provides a solution to such needs. Summary of the Invention

[0004] The present disclosure relates to systems, methods, and compositions at least related to making a determination of the outcome (or likelihood of outcome) of immunotherapy, such as adoptive cell transfer therapy. The present disclosure also relates to systems, methods, and compositions for making a determination of the toxicity (or likelihood of toxicity) of immunotherapy, such as adoptive cell transfer therapy. The present disclosure also relates to systems, methods, and compositions for immunotherapy, such as adoptive cell transfer therapy. Specific embodiments of the present disclosure allow medical personnel to make informed decisions regarding the likelihood of whether a treatment will be effective and / or toxic to an individual.

[0005] In certain embodiments, gut microbiome diversity metrics and compositions correlate with efficacy and / or toxicity associated with adoptive cell transfer therapy (e.g., cells expressing one or more engineered antigen receptors, regardless of the cell type expressed) directed at cancer. The present disclosure relates to compositions and methods for predicting a subject's response to adoptive cell transfer therapy (e.g., CAR T cell therapy), comprising analyzing the subject's gut microbiome. The present disclosure relates to compositions and methods for determining a subject's risk for ineffective CAR T cell therapy (including partial response, stable disease, or disease progression) and / or risk for toxicity of CAR T cell therapy, comprising analyzing the subject's gut microbiome. The present disclosure further provides therapeutic compositions and methods for treating a subject with cancer, including improving efficacy and / or reducing toxicity of CAR T cell therapy. In some cases, analysis of the gut microbiome of an individual in need of CAR T cell therapy provides information to determine that the individual requires a particular intervention that improves CAR T cell therapy for the individual and / or reduces toxicity of CAR T cell therapy for the individual. Such interventions include, by way of example only, one or more probiotic compositions and / or one or more fecal transplants.

[0006] An embodiment of the present disclosure includes a method of determining or predicting a therapeutic response of an individual, comprising analyzing a microbial composition from the gut microbiome of the individual, wherein

[0007] (a) a therapy for said individual is ineffective or at risk of being ineffective when compared to a standard or another individual, if the therapy comprises, consists of, or consists essentially of one or more microorganisms of the order Bacillales; and / or the species Phascolarctobacterium succinatutens; and / or Finegoldia magna; and / or the Streptococcus anginosus group; and / or Akkermansia muciniphila; and / or Escherichia coli; and / or Haemophilus parainfluenzae; and / or

[0008] (b) The gut microbiota of the individual includes the genera Varibaculum; Bifidobacterium animalis; Corynebacterium tuberculostearicum; Dialister succinatiphilus; Porphyromonas asaccharolytica; Porphyromonas endodontalis; Ruminococcaceae ge unclass; Varibaculum cambriense; Murdochiella; Levyella massiliensis; Porphyromonas bennonis; Peptoniphilus lacrimalis; Peptoniphilus harei; Anaerococcus vaginalis; Butyricicoccus pullicaecorum; Prevotella timonensis; Ruminiclostridium 1; Fenollaria massiliensis; Frisingicoccus caecimuris; Ruminococcaceae UCG 010; Hungateiclostridium cellulolyticum; Ruminococcaceae UCG 010 unclass; Prevotella; Ezakiella; Aminipila butyrica; Eisenbergiella; GCA 900066755; Bacteroides ovatus; Lachnospiraceae ge; Ruminococcaceae unclass; Ruminiclostridium 9; Bacteroides cellulosilyticus; Bacteroides vulgatus; Alistipes shahii; Eisenbergiella massiliensis; GCA 900066225; [Ruminococcus] torques; Longicatena caecimuris; Ruminococcaceae UCG 002; Anaerococcus; Barnesiella;[Clostridium] celerecrescens species; Barnesiella intestinihominis species; Desulfovibrio desulfuricans; Bacteroidaceae family; Barnesiellaceae family; Bacteroides genus; Bacteroides xylanisolvens species; Dialister propionicifaciens species; Fournierella genus; splanchnicus etc.); genus Peptoniphilus; genus Porphyromonas; spp. Blautia glucerasea; spp. GCA 900066575; spp. Lachnoclostridium; spp. Intestinimonas; spp. In a specific embodiment of (a), the individual has cancer and the response to the therapy for the individual is or is at risk of a partial response, stable disease, or progressive disease. In a specific embodiment of (b), the individual has cancer (such as a solid tumor or a hematological malignancy), the response to the therapy for the individual is or is at increased risk of a complete response, and the gut microbiome of the individual comprises Flavonifractor plautii;

[0009] The therapy referred to herein can be of any suitable type, including immunotherapy, such as adoptive cell therapy, which can be adoptive T cell therapy, adoptive NK cell therapy, etc. In a specific embodiment, the cells of the adoptive cell therapy are modified to include one or more engineered antigen receptors, e.g., the engineered antigen receptors include one or more chimeric antigen receptors (CARs) or one or more non-native T cell receptors, or the cells have one or more of both. Specifically, the adoptive cell therapy includes CAR T cell therapy.

[0010] In some embodiments related to element (b) above, the method further comprises administering to the individual a therapeutically effective amount of a therapy.

[0011] In some embodiments related to element (a) above, the therapy is a CAR T cell therapy, and the CAR T cell therapy is modified prior to administration to the individual to increase the efficacy of the CAR T cell therapy. The dosage of the CAR T cell therapy may be increased.

[0012] In any of the methods of the disclosure, one or more components of the CAR are altered, such as upon determination of the microbial composition from the gut microbiome of an individual in need of CAR therapy.

[0013] In certain embodiments, the individual is administered an effective amount of one or more probiotics and / or one or more fecal implants. In certain cases, the one or more probiotics and / or the one or more fecal transplants may be selected from the group consisting of: Varibaculum genus; Bifidobacterium animalis species; Corynebacterium tuberculostearicum species; Dialister succinatiphilus species; Porphyromonas asaccharolytica species; Porphyromonas endodontalis species; Ruminococcaceae ge unclass species; Varibaculum cambriense species; Murdochiella genus; Levyella massiliensis species; Porphyromonas bennonis species; Peptoniphilus lacrimalis species; Peptoniphilus harei species; Anaerococcus vaginalis species; Butyricicoccus pullicaecorum species; Prevotella timonensis species; Ruminiclostridium 1 species; Fenollaria massiliensis species; Frisingicoccus caecimuris species; Ruminococcaceae UCG species; Genus 010; Hungateiclostridium cellulolyticum species; Ruminococcaceae UCG 010 unclass species; Genus Prevotella; Genus Ezakiella; Genus Aminipila butyrica; Genus Eisenbergiella; Genus GCA 900066755; 9 genera; Bacteroides cellulosilyticus species; Bacteroides vulgatus species; Alistipes shahii species; Eisenbergiella massiliensis species; GCA 900066225 species; [Ruminococcus] torques species;Longicatena caecimuris species; Ruminococcaceae UCG 002; Anaerococcus species; Barnesiella species; [Clostridium] celerecrescens species; Barnesiella intestinihominis species; Desulfovibrio desulfuricans; propionicifaciens species; Fournierella genus; Lachnospiraceae unclass; Porphyromonadaceae family (such as Odoribacter splanchnicus); Peptoniphilus genus; Bacteroides thetaiotaomicron species; The present invention relates to a method for the preparation of a microbial organism comprising, consisting of, or consisting essentially of one or more microorganisms of the genus Flavonifractor; the species Agathobaculum desmolans; and the species Flavonifractor plautii.

[0014] In certain embodiments of the disclosed methods, the individual is provided with a therapeutically effective amount of a cancer therapy other than an adoptive cell therapy comprising cells expressing an engineered antigen receptor.

[0015]

[0010] Embodiments of the present disclosure include methods of determining or predicting toxicity of a therapy to an individual comprising analyzing a microbial composition from the individual's gut microbiome, wherein:

[0016] (a) the therapy is toxic or at risk of being toxic to the individual compared to a standard or another individual when the gut microbiome comprises, consists of, or consists essentially of one or more of the following: Lactobacillus rhamnosus species; Parabacteroides goldsteinii species; Olsenella uli species; Fusobacterium varium species; Porphyrobacter genus; Dialister succinatiphilus species; Faecalitalea cylindroides species; Porphyrobacter sanguineus species; Ruminiclostridium 9 unclass species; Sphingomonadaceae family; Sphingomonadales order; and Olsenella genus; and / or

[0017] (b) The intestinal microbiome is Corynebacterium durum species; Eubacterium sulci species; Ihubacter massiliensis species; Eubacteriaceae family; Bacteroides xylanisolvens species; Ruminococcus 2 genus; Ruminococcus bromii species; Blautia luti species; Turicibacter genus; Turicibacter sanguinis species; [Clostridium] celerecrescens species; Veillonella genus; Roseburia faecis species; Atopobium genus; Lactonifactor genus; Lactonifactor longoviformis species; Atopobium parvulum species; Peptostreptococcaceae family; Veillonella tobetsuensis species; and Veillonella When the cell comprises, consists of, or consists essentially of one or more of the genus Parvula, the likelihood that the therapy is non-toxic or non-toxic to the individual is increased compared to a standard or another individual. In certain embodiments, the toxicity comprises cytokine release syndrome (CRS). The determination of toxicity may be further defined as determining a grade of toxicity associated with CRS. The therapy may comprise an immunotherapy, such as adoptive cell therapy, including adoptive T cell therapy. In some cases, the cells of the adoptive cell therapy are modified to comprise one or more engineered antigen receptors, and the engineered antigen receptors may comprise one or more chimeric antigen receptors (CARs) or one or more non-native T cell receptors, or the cells may have one or more thereof. In certain embodiments, the adoptive cell therapy comprises CAR T cell therapy. In certain methods of the present disclosure, the method element (b) may further comprise administering a therapeutically effective amount of the therapy to the individual. In some embodiments of the method, in element (a), the therapy is a CAR T cell therapy, and the CAR T cell therapy is modified prior to administration to the individual to reduce toxicity of the CAR T cell therapy.The dosage of the CAR T cell therapy may be reduced and / or one or more components of the CAR may be altered.

[0018] In certain embodiments, the individual is administered an effective amount of one or more probiotics and / or one or more fecal implants. The one or more probiotics and / or one or more fecal implants comprise, consist of, or consist essentially of one or more microorganisms of the following species: Corynebacterium durum; Eubacterium sulci; Ihubacter massiliensis; Eubacteriaceae; Bacteroides xylanisolvens; Ruminococcus 2; Ruminococcus bromii; Blautia luti; Turicibacter; Turicibacter sanguinis; [Clostridium] celerecrescens; Veillonella; Roseburia faecis; Atopobium; Lactonifactor; Lactonifactor longoviformis; Atopobium parvulum; Peptostreptococcaceae; Veillonella tobetsuensis; and Veillonella parvula. In some cases, the individual is provided with a therapeutically effective amount of another cancer therapy.

[0019]

[0013] Embodiments of the present disclosure may include a method of determining the likelihood that an individual undergoing immunotherapy will have a particular grade of immune effector cell-associated neurotoxicity syndrome (ICANS) toxicity after receiving immunotherapy, comprising analyzing the individual's gut microbiome, wherein:

[0020] (a) the intestinal microbiome is [Clostridium] lavalense species; Cuneatibacter genus; Clostridiales vadin BB60 group family; Clostridiales vadin BB60 group genus; Clostridiales vadin BB60 group ge unclass species; [Clostridium] hylemonae species; Anaerotruncus rubiinfantis species; Eisenbergiella massiliensis species; Hydrogenoanaerobacterium species; Ruminococcaceae UCG 008 species; Intestinibacillus massiliensis species; Raoultibacter species; Monoglobus pectinilyticus species; Bacillaceae family; Pseudomonas aeruginosa species; Bacillus hisashii species; Caecibacter massiliensis species; and Prevotella multisaccharivorax species, the individual is likely to have or is at risk of having ICANS grade 3 or 4 toxicity; and / or

[0021] (b) if the gut microbiome comprises, consists of, or consists essentially of one or more of the following species: Corynebacterium genus; Lactobacillus sakei species; Veillonella dispar species; Streptococcus salivarius species; and Coprococcus eutactus species, the individual may have or is at risk of having grade 1 or 2 ICANS toxicity. The therapy may include an immunotherapy, such as an adoptive cell therapy, including an adoptive T cell therapy. The cells of the adoptive cell therapy may be modified to include one or more engineered antigen receptors, and the engineered antigen receptors may include one or more chimeric antigen receptors (CARs) or one or more non-native T cell receptors, and the cells may have one or more of them. The adoptive cell therapy may include a CAR T cell therapy.

[0022] In the method element (b), the method may further include administering a therapeutically effective amount of an immunotherapy to the individual. In the method element (a), after the analysis and prior to delivery to the individual, the immunotherapy may be modified to reduce the risk of ICANS. In the method element (a), the therapy is a CAR T cell therapy, and the CAR T cell therapy is modified prior to administration to the individual to reduce toxicity of the CAR T cell therapy. In some cases, the dosage of the CAR T cell therapy is reduced and / or one or more components of the CAR are altered. In certain embodiments of the method, the individual is administered an effective amount of one or more probiotics and / or one or more fecal transplants. The one or more probiotics and / or one or more fecal transplants may include one or more of the following species: Corynebacterium genus; Lactobacillus sakei species; Veillonella dispar species; Streptococcus salivarius species; and Coprococcus eutactus species. The individual may be provided with a therapeutically effective amount of another cancer therapy.

[0023]

[0013] Embodiments of the present disclosure include a method of treating cancer in an individual, the method comprising providing a therapeutically effective amount of an immunotherapy to the individual where:

[0024] (a) The gut microbiota of the individual consists of the genus Varibaculum; the species Bifidobacterium animalis; the species Corynebacterium tuberculostearicum; the species Dialister succinatiphilus; the species Porphyromonas asaccharolytica; the species Porphyromonas endodontalis; the unclassified genus Ruminococcaceae ge; the species Varibaculum cambriense; the genus Murdochiella; the species Levyella massiliensis; the species Porphyromonas bennonis; the species Peptoniphilus lacrimalis; the species Peptoniphilus harei; the species Anaerococcus vaginalis; the species Butyricicoccus pullicaecorum; the species Prevotella timonensis; the species Ruminiclostridium 1; the species Fenollaria massiliensis; the species Frisingicoccus caecimuris; the genus Ruminococcaceae UCG 010; the species Hungateiclostridium cellulolyticum; the unclassified genus Ruminococcaceae UCG 010 unclass; the genus Prevotella; the genus Ezakiella; the species Aminipila butyrica; the genus Eisenbergiella; the genus GCA 900066755; the species Bacteroides ovatus; the genus Lachnospiraceae ge; the unclassified genus Ruminococcaceae unclass; the genus Ruminiclostridium 9; the species Bacteroides cellulosilyticus; the species Bacteroides vulgatus; the species Alistipes shahii; the species Eisenbergiella massiliensis; the genus GCA 900066225; the species [Ruminococcus] torques; the species Longicatena caecimuris; the genus Ruminococcaceae UCG 002; the genus Anaerococcus; the genus Barnesiella;

[0023] The present invention relates to a method for treating a bacterial infection comprising, consisting of, or consisting essentially of one or more of the following microorganisms: [Clostridium] celerecrescens species; Barnesiella intestinihominis species; Desulfovibrio desulfuricans species; the family Bacteroidaceae; the family Barnesiellaceae; the genus Bacteroides; Bacteroides xylanisolvens species; Dialister propionicifaciens species; the genus Fournierella; the genus Lachnospiraceae unclass; the family Porphyromonadaceae; the genus Peptoniphilus; the genus Porphyromonas; the species Blautia glucerasea; the genus GCA 900066575; the genus Lachnoclostridium; the genus Intestinimonas; the species Anaerotignum lactatifermentans; the species Bacteroides thetaiotaomicron; the genus Flavonifractor; the species Agathobaculum desmolans; and the species Flavonifractor plautii;

[0025] (b) the individual's gut microbiome comprises, consists of, or consists essentially of one or more microorganisms of the following species: Corynebacterium durum; Eubacterium sulci; Ihubacter massiliensis; Eubacteriaceae; Bacteroides xylanisolvens; Ruminococcus 2; Ruminococcus bromii; Blautia luti; Turicibacter; Turicibacter sanguinis; [Clostridium] celerecrescens; Veillonella; Roseburia faecis; Atopobium; Lactonifactor; Lactonifactor longoviformis; Atopobium parvulum; Peptostreptococcaceae; Veillonella tobetsuensis; and Veillonella parvula; and / or

[0026] (c) the individual's gut microbiome comprises, consists of, or consists essentially of one or more of the following microorganisms: Corynebacterium genus; Lactobacillus sakei species; Veillonella dispar species; Streptococcus salivarius species; and Coprococcus eutactus species. In some embodiments, the immunotherapy comprises adoptive cell therapy, such as adoptive T cell therapy. The cells of the adoptive cell therapy may be modified to comprise one or more engineered antigen receptors, which may comprise one or more chimeric antigen receptors (CARs) or one or more non-native T cell receptors, or the cells may have one or more thereof. The adoptive cell therapy may comprise CAR T cell therapy. In some embodiments, the individual is administered an effective amount of one or more probiotics and / or one or more fecal transplants, which in some cases comprise, consist of, or consist essentially of any one or more microorganisms (a), (b), and / or (c):

[0027] (a) Genus Varibaculum; Species Bifidobacterium animalis; Species Corynebacterium tuberculostearicum; Species Dialister succinatiphilus; Species Porphyromonas asaccharolytica; Species Porphyromonas endodontalis; Unclassified genus Ruminococcaceae; Species Varibaculum cambriense; Genus Murdochiella; Species Levyella massiliensis; Species Porphyromonas bennonis; Species Peptoniphilus lacrimalis; Species Peptoniphilus harei; Species Anaerococcus vaginalis; Species Butyricicoccus pullicaecorum; Species Prevotella timonensis; Species Ruminiclostridium 1; Species Fenollaria massiliensis; Species Frisingicoccus caecimuris; Genus Ruminococcaceae UCG 010; Species Hungateiclostridium cellulolyticum; Unclassified species Ruminococcaceae UCG 010; Genus Prevotella; Genus Ezakiella; Species Aminipila butyrica; Genus Eisenbergiella; Genus GCA 900066755; Species Bacteroides ovatus; Genus Lachnospiraceae ge; Unclassified genus Ruminococcaceae; Genus Ruminiclostridium 9; Species Bacteroides cellulosilyticus; Species Bacteroides vulgatus; Species Alistipes shahii; Species Eisenbergiella massiliensis; Genus GCA 900066225; [Ruminococcus] torques; Species Longicatena caecimuris; Genus Ruminococcaceae UCG 002; Genus Anaerococcus; Genus Barnesiella;[Clostridium] celerecrescens; Barnesiella intestinihominis; Desulfovibrio desulfuricans; Bacteroidaceae; Barnesiellaceae; Bacteroides; Bacteroides xylanisolvens; Dialister propionicifaciens; Fournierella; Lachnospiraceae unclass; Porphyromonadaceae; Peptoniphilus; Porphyromonas; Blautia glucerasea; GCA 900066575; Lachnoclostridium; Intestinimonas; Anaerotignum lactatifermentans; Bacteroides thetaiotaomicron; Flavonifractor; Agathobaculum desmolans; and at least one of the species Flavonifractor plautii;

[0028] (b) Corynebacterium durum; Eubacterium sulci; Ihubacter massiliensis; Eubacteriaceae; Bacteroides xylanisolvens; Ruminococcus 2; Ruminococcus bromii; Blautia luti; Turicibacter; Turicibacter sanguinis; [Clostridium] celerecrescens; Veillonella; Roseburia faecis; Atopobium; Lactonifactor; Lactonifactor longoviformis; Atopobium parvulum; Peptostreptococcaceae; Veillonella tobetsuensis; and one or more of the species Veillonella parvula; and / or,

[0029] (c) one or more of the following species: Corynebacterium genus; Lactobacillus sakei species; Veillonella dispar species; Streptococcus salivarius species; and Coprococcus eutactus species. In some embodiments, the individual is provided with a therapeutically effective amount of another cancer therapy.

[0030] An embodiment of the present disclosure includes a method of determining a treatment outcome of an individual in need of adoptive cell therapy, comprising analyzing the gut microbiome for microbial diversity therein, wherein if the individual's gut microbiome has high diversity, the individual has an increased likelihood of effective adoptive cell therapy compared to an individual lacking high gut microbiome diversity. In certain embodiments, if the individual's gut microbiome has low microbial diversity, the individual is provided with an effective amount of one or more fecal transplants and / or one or more probiotic compositions. The diversity of the gut microbiome may or may not be determined by the inverse Simpson index (ISI). In some cases, if the diversity of the individual's gut microbiome is in the highest tertile as determined by ISI, the individual has an increased chance of effective adoptive cell therapy. In some cases, the identity of one or more microorganisms in the microbiome is determined by shotgun sequencing of the genome of one or more microorganisms. The identity of one or more microorganisms in the microbiome may be determined by directed sequencing of the genome of one or more microorganisms, and the directed sequencing may be sequencing of the 16S rRNA of one or more microorganisms. In a specific embodiment, if the diversity of the individual's gut microbiome is in the highest tertile as determined by ISI, the individual is administered an effective amount of adoptive cell therapy, such as CAR T cell therapy. In some embodiments, if the diversity of the individual's gut microbiome is not in the highest tertile as determined by ISI, the individual is not administered an effective amount of adoptive cell therapy. In some cases, the adoptive cell therapy is a CAR T cell therapy, and if the diversity of the individual's gut microbiome is not in the highest tertile as determined by ISI, the CAR T cell therapy is modified, such as by reducing the dosage of the CAR T cell therapy and / or altering one or more components of the CAR. In certain embodiments, the individual is administered an effective amount of one or more probiotics and / or one or more fecal transplants. The one or more probiotics and / or one or more fecal transplants comprise, consist of, or consist essentially of any one or more of the following microorganisms: (a), (b), and / or (c):

[0031] (a)Genus Varibaculum; Species Bifidobacterium animalis; Species Corynebacterium tuberculostearicum; Species Dialister succinatiphilus; Species Porphyromonas asaccharolytica; Species Porphyromonas endodontalis; Unclassified genus Ruminococcaceae; Species Varibaculum cambriense; Genus Murdochiella; Species Levyella massiliensis; Species Porphyromonas bennonis; Species Peptoniphilus lacrimalis; Species Peptoniphilus harei; Species Anaerococcus vaginalis; Species Butyricicoccus pullicaecorum; Species Prevotella timonensis; Species Ruminiclostridium 1; Species Fenollaria massiliensis; Species Frisingicoccus caecimuris; Genus Ruminococcaceae UCG 010; Species Hungateiclostridium cellulolyticum; Unclassified species of Ruminococcaceae UCG 010; Genus Prevotella; Genus Ezakiella; Species Aminipila butyrica; Genus Eisenbergiella; Genus GCA 900066755; Species Bacteroides ovatus; Genus Lachnospiraceae ge; Unclassified genus Ruminococcaceae; Genus Ruminiclostridium 9; Species Bacteroides cellulosilyticus; Species Bacteroides vulgatus; Species Alistipes shahii; Species Eisenbergiella massiliensis; Genus GCA 900066225; [Ruminococcus] torques; Species Longicatena caecimuris; Genus Ruminococcaceae UCG 002; Genus Anaerococcus; Genus Barnesiella;[Clostridium] celerecrescens; Barnesiella intestinihominis; Desulfovibrio desulfuricans; Bacteroidaceae; Barnesiellaceae; Bacteroides; Bacteroides xylanisolvens; Dialister propionicifaciens; Fournierella; Lachnospiraceae unclass; Porphyromonadaceae; Peptoniphilus; Porphyromonas; Blautia glucerasea; GCA 900066575; Lachnoclostridium; Intestinimonas; Anaerotignum lactatifermentans; Bacteroides thetaiotaomicron; Flavonifractor; Agathobaculum desmolans; and at least one of the species Flavonifractor plautii;

[0032] (b) Corynebacterium durum; Eubacterium sulci; Ihubacter massiliensis; Eubacteriaceae; Bacteroides xylanisolvens; Ruminococcus 2; Ruminococcus bromii; Blautia luti; Turicibacter; Turicibacter sanguinis; [Clostridium] celerecrescens; Veillonella; Roseburia faecis; Atopobium; Lactonifactor; Lactonifactor longoviformis; Atopobium parvulum; Peptostreptococcaceae; Veillonella tobetsuensis; and one or more of the species Veillonella parvula; and / or,

[0033] (c) one or more of the genus Corynebacterium; the species Lactobacillus sakei; the species Veillonella dispar; the species Streptococcus salivarius; and the species Coprococcus eutactus.

[0034] Embodiments of the present disclosure include probiotic compositions and / or fecal transplant compositions comprising, consisting of, or consisting essentially of any one or more of the microorganisms (a), (b), and / or (c):

[0035] (a) Genus Varibaculum; Species Bifidobacterium animalis; Species Corynebacterium tuberculostearicum; Species Dialister succinatiphilus; Species Porphyromonas asaccharolytica; Species Porphyromonas endodontalis; Unclassified genus Ruminococcaceae; Species Varibaculum cambriense; Genus Murdochiella; Species Levyella massiliensis; Species Porphyromonas bennonis; Species Peptoniphilus lacrimalis; Species Peptoniphilus harei; Species Anaerococcus vaginalis; Species Butyricicoccus pullicaecorum; Species Prevotella timonensis; Genus Ruminiclostridium 1; Species Fenollaria massiliensis; Species Frisingicoccus caecimuris; Genus Ruminococcaceae UCG 010; Species Hungateiclostridium cellulolyticum; Unclassified species Ruminococcaceae UCG 010; Genus Prevotella; Genus Ezakiella; Species Aminipila butyrica; Genus Eisenbergiella; Genus GCA 900066755; Species Bacteroides ovatus; Unclassified genus Lachnospiraceae; Unclassified genus Ruminococcaceae; Genus Ruminiclostridium 9; Species Bacteroides cellulosilyticus; Species Bacteroides vulgatus; Species Alistipes shahii; Species Eisenbergiella massiliensis; Genus GCA 900066225; [Ruminococcus] torques; Species Longicatena caecimuris; Genus Ruminococcaceae UCG 002; Genus Anaerococcus; Genus Barnesiella;[Clostridium] celerecrescens; Barnesiella intestinihominis; Desulfovibrio desulfuricans; Bacteroidaceae; Barnesiellaceae; Bacteroides; Bacteroides xylanisolvens; Dialister propionicifaciens; Fournierella; Lachnospiraceae unclass; Porphyromonadaceae (including Odoribacter splanchnicus); Peptoniphilus; Porphyromonas; Blautia glucerasea; GCA 900066575; Lachnoclostridium; Intestinimonas; Anaerotignum lactatifermentans; Bacteroides thetaiotaomicron; Flavonifractor; Agathobaculum desmolans; and one or more microorganisms of the species Flavonifractor plautii;

[0036] (b) Corynebacterium durum species; Eubacterium sulci species; Ihubacter massiliensis species; Eubacteriaceae family; Bacteroides xylanisolvens species; Ruminococcus 2 genera; Ruminococcus bromii species; Blautia luti species; Turicibacter genus; Turicibacter sanguinis species; [Clostridium] celerecrescens species; one or more of the following: Veillonella sp.; Roseburia faecis sp.; Atopobium sp.; Lactonifactor sp.; Lactonifactor longoviformis sp.; Atopobium parvulum sp.; Peptostreptococcaceae family; Veillonella tobetsuensis sp.;

[0037] (c) one or more of the genus Corynebacterium; the species Lactobacillus sakei; the species Veillonella dispar; the species Streptococcus salivarius; and the species Coprococcus eutactus.

[0038] It is specifically contemplated that any limitations discussed with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Moreover, any composition of the invention may be used in any method of the invention, and any method of the invention may be used to make or utilize any composition of the invention. Aspects of the embodiments described in the examples are also embodiments that may be implemented in the context of different examples or embodiments discussed elsewhere in this application (e.g., in the brief summary, brief description of the figures, detailed description, and claims).

[0039] The features and technical advantages of the present disclosure have been outlined above, rather broadly, in order that the detailed description that follows may be better understood. Additional features and advantages will be described below which form the subject matter of the claims herein. It should be understood by those skilled in the art that the conception and specific embodiments disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present designs. It should also be understood by those skilled in the art that such equivalent constructions do not depart from the spirit and scope as defined by the appended claims. The novel features believed characteristic of the designs disclosed herein, both as to their organization and method of operation, together with further objects and advantages, will be better understood from the following description when considered in conjunction with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only, and is not intended as a definition of the limits of the present disclosure. [Brief description of the drawings]

[0040] For a more complete understanding of the present disclosure, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:

[0041] [Figure 1A-C] Association of gut microbiome with clinical outcomes in relapsed / refractory large B-cell lymphoma (r / r LBCL) patients receiving CAR T-cell therapy. Figure 1A: Inverse Simpson's index (α diversity; ISI) of gut microbiome in patients with ongoing complete response (CR) and no complete response (NoCR). Figure 1B: Kaplan-Meier plot of pFS by ISI tertiles (high n=11, middle n=11, low n=11). Figure 1C: Kaplan-Meier plot of OS by ISI tertile group.

[0042] [Diagram 2] Linear discriminant analysis showing differences in gut or microbiome species abundance associated with persistence of CR after 3 months.

[0043] [Diagram 3] Heatmap revealing differences in bacterial composition associated with response.

[0044] [Figure 4] Linear discriminant analysis showing differences in microbial composition associated with CRS toxicity (grade 0–1 vs. ≥2).

[0045] [Diagram 5] Heatmap revealing differences in bacterial composition associated with cytokine release syndrome (CRS) toxicity (grade 0–1 vs. ≥2).

[0046] [Figure 6] Linear discriminant analysis showing differences in microbial composition associated with immune effector cell-associated neurotoxicity syndrome (ICANS) toxicity (grades 0–2 vs. ≥3).

[0047] [Figure 7] Taxonomic results are shown that indicate whether the presence of bacteria supports disease progression or not.

[0048] While various embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the disclosed embodiments described herein may be employed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] [I. Definition Example] Following long-standing patent law practice, the words "a" and "an" when used in conjunction with the word comprising, herein, including in the claims, refer to one or more. As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a nucleic acid" includes a plurality of nucleic acids, including mixtures thereof. Some embodiments of the present disclosure may consist of, or consist essentially of, one or more elements, method steps, and / or methods of the present disclosure. Any method or composition described herein may be implemented with respect to any other method or composition described herein, and it is contemplated that different embodiments may be combined.

[0050] Throughout this specification, unless otherwise required by context, the words "comprise", "comprises" and "comprising" are understood to mean the inclusion of the stated steps or elements, or group of steps or elements, but not the exclusion of other steps or elements, or group of steps or elements. "Consist of" means including and limited to what follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the recited elements are required or mandatory, and that other elements must not be present. "Consisting essentially of" is meant to include the elements recited after the phrase, but is limited to other elements that do not interfere with or contribute to the activity or function specified in the disclosure for the recited elements. Thus, the phrase "consisting essentially of" indicates that the recited elements are necessary or essential, while other elements are optional and may or may not be present depending on whether they affect the activity or function of the recited elements.

[0051] As used herein, the terms "or" and "and / or" are used to describe multiple components in combination or mutually exclusive. 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.

[0052] Throughout this application, the term "about" is used according to its plain and ordinary meaning in the field of cell and molecular biology to indicate that the term "about" includes the standard deviation of error for the device or method being employed to determine the value.

[0053] Throughout this specification, reference to "one embodiment," "an embodiment," "a particular embodiment," "a related embodiment," "an embodiment," "an additional embodiment," or "a further embodiment," or any combination thereof, means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the aforementioned phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0054] As used herein, the term "intestine" refers to at least a portion of the digestive tract including at least the stomach, the small intestine, and the large intestine.

[0055] The term "microorganism" as used herein refers to a microorganism such as a bacterium, a fungus, a virus, a protozoan, an algae, an amoeba, a slime mold, or a combination thereof. For any bacterium encompassed in this disclosure, this disclosure includes any strain thereof. In this disclosure, when a genus is specifically mentioned, any species within that genus may also be incorporated by reference, such as by reference to the list. For example, when the genus Corynebacterium is mentioned, any species within the genus Corynebacterium is encompassed herein.

[0056] As used herein, the term "microbiome" generally refers to a collection of microorganisms (sometimes referred to as microbes), such as bacteria, fungi, viruses, protozoa, algae, amoebas, and / or slime molds, in a community within a host, including within a particular location and / or tissue and / or organ of the host, such as the gut.

[0057] As used herein, the term "probiotic" refers to one or more microorganisms introduced into the body for their beneficial qualities.

[0058] The term "sample" as used herein generally refers to a biological sample, including from any site in the body, such as the intestine. The sample may be taken from tissue or cells, or from the intestinal environment. In some examples, the sample may consist of or be derived from any part of the body tissue, including tissue biopsy, stool, blood, lung tissue, tumor, or a combination thereof. The sample may be separated from the source prior to collection. In some examples, the sample is separated from its primary source (cells, tissue, bodily fluids such as blood, environmental samples, etc.) during sample preparation. The sample may or may not be purified or concentrated from the primary source. In some embodiments, the primary source is homogenized before further processing. The sample may be filtered or centrifuged to remove undesired material. The sample may also be purified or enriched for a particular composition contained therein, such as a particular microorganism. The sample may include intact, fragmented, or partially degraded tissue or cells.

[0059] The term "subject" as used herein generally refers to an individual having a biological sample being processed or analyzed, and in some embodiments, a gut microbiome associated therewith. The subject may be an animal and may be a desired recipient of an immunotherapy, such as adoptive cell therapy. The subject may be any organism or animal subject that is the subject of a method or material, including mammals, e.g., humans, laboratory animals (e.g., primates, rats, mice, rabbits), livestock (e.g., cows, sheep, goats, pigs, turkeys, chickens), household pets (e.g., dogs, cats, rodents), horses, and transgenic non-human animals. The subject may be, for example, a patient who has or is suspected of having one or more diseases (sometimes referred to as medical conditions), such as cancer. The subject may be asymptomatic. The term "individual" may be used interchangeably, at least in some embodiments. As used herein, a "subject" or "individual" may or may not be housed in a medical facility, and may or may not be treated as an outpatient in a medical facility. An individual may receive one or more medical compositions via the internet. Individuals may include humans or non-human animals of any age, and thus include both adults and juveniles (e.g., children) and infants, including individuals in utero. Subjects may or may not have a need for medical treatment. Individuals may participate in trials, whether clinical or in support of basic science research, on a voluntary or involuntary basis. Individuals may be of any sex, race, or age.

[0060] [II. Disclosed Embodiments] The gut microbiome has emerged as one of the important host factors that may be related to the response to immunotherapy. Several recent human studies evaluating immunotherapy strategies, such as immune checkpoint inhibitor therapy, have found significantly better response and survival in patients with a more diverse gut microbiome. Currently, it is unclear whether the gut microbiome regulates antitumor responses to adoptive cell therapy, such as CAR T cells. In this disclosure, it is shown that the diversity of an individual's gut microbiome and the specific gut microbiome composition correlate with the efficacy and toxicity associated with CAR-T therapy (as an example of adoptive cell therapy) for cancer.

[0061] The present disclosure relates to methods and compositions for the treatment of cancer by modulating the microbiome to enhance the efficacy of CAR-T therapy. The present disclosure also relates to microbiome diversity indices and bacterial abundance as biomarkers for predicting efficacy and toxicity associated with CAR-T therapy.

[0062] The results contained herein relate to the specific composition of gut bacteria, which may be related to efficacy and toxicity. In certain embodiments, the gut microbiome is analyzed for individuals who require immunotherapy, and the analysis can be performed by any suitable method, including, for example, shotgun sequencing or standard 16S rRNA sequencing, which can provide detailed reads. In microbiome research, shotgun sequencing can simultaneously identify and profile bacteria, fungi, viruses, and many other types of microorganisms.

[0063] In some embodiments, probiotics or fecal microbiota transplants (and, in some cases, associated metabolites / proteins) may be utilized to modulate the response to CAR-T therapy to enhance its efficacy and / or safety. In such cases, prior analysis of the gut microbiome can determine which individuals require probiotics or fecal transplants, allowing for informed clinical decision-making.

[0064] (A. Example of usage) The disclosed method allows for the determination of the improvement or effectiveness (e.g., improvement of at least one symptom) of targeted treatment strategies, including immunotherapy such as adoptive cell transfer. The adoptive cell transfer can be of any type, but in certain embodiments, the adoptive cell transfer involves cells that have been engineered by the hand of man to express one or more engineered antibodies. The antigen receptor can be engineered to specifically target an antigen associated with an adverse medical condition, such as a cancer antigen associated with one or more specific cancers. The cancer can be relapsed or refractory, or not relapsed or refractory. The cancer can be a solid cancer or a hematological malignancy. The cancer can be of any stage, type, or tissue of origin. The cancer can be metastatic or not metastatic. The cancer can be resistant or not resistant to one or more types of therapy.

[0065] In certain embodiments, a sample taken from an individual is analyzed to determine the potential effectiveness of an immunotherapy such as adoptive cell transfer for the individual. The adoptive cell transfer may include cells expressing one or more engineered antigen receptors, in specific embodiments, the engineered antigen receptors are chimeric antigen receptors (CARs) and / or non-native T cell receptors. In certain aspects, the adoptive cell therapy includes adoptive cell therapy in which the cells express one or more CARs, and in certain aspects, the cells are T cells, NK cells, NKT cells, γδ T cells, macrophages, B cells, or mixtures thereof.

[0066] The disclosed method includes a method of enhancing the response to adoptive cell transfer therapy, so as to increase the likelihood that adoptive cell transfer will be effective.In some cases, the disclosed method is employed for an individual for whom it is unknown whether adoptive cell transfer will be effective, and in other cases, the disclosed method is employed for an individual for whom it is known that adoptive cell transfer may not be effective.In addition, the disclosed method may be employed as a matter of routine or for the general therapeutic benefit of the individual, even though it is determined that adoptive cell transfer should be effective for the individual.

[0067] The present disclosure encompasses methods and compositions relating to the gut microbiome of individuals having or suspected of having cancer and in need of immunotherapeutic intervention, including adoptive cell transfer.

[0068] In some embodiments, the potential toxicity of adoptive cell transfer to an individual is determined based on the gut microbiome, including before delivery of the adoptive cell transfer to the individual. In such cases, the result is that the adoptive cell transfer is not given to the individual, the adoptive cell transfer is modified to avoid toxicity to the individual, or one or more other agents are administered to the individual to reduce or eliminate the toxicity of the immunotherapy to the individual (whether the agent is administered simultaneously with, before, or after the immunotherapy). For example, an effective amount of an agent that activates a suicide gene in cells of the adoptive cell transfer can be administered to the individual. The one or more agents can include one or more probiotics and / or one or more fecal transplants. In some embodiments, the direct or indirect cause of toxicity of the adoptive cell transfer already given to the individual is determined based on the gut microbiome after delivery of the adoptive cell transfer.

[0069] The present disclosure encompasses methods and compositions for modulating an individual's gut microbiome to enhance the efficacy of adoptive cell transfer therapy. The modulation may or may not be the result of analyzing the gut microbiome prior to delivery of the adoptive cell transfer therapy to the individual. In some cases, the modulation is the result of analyzing the gut microbiome prior to administering the adoptive cell transfer therapy, with the results of the analysis determining the nature of the resulting gut microbiome modulation. For example, the modulation may include providing an effective amount of a composition including one or more microorganisms determined to be deficient in the individual's gut microbiome. In some cases, the modulation may include providing an effective amount of one or more antibiotics that will reduce the level of one or more microorganisms determined to be excess in the individual's gut microbiome. In some cases, both the gut microbiome deficiency and the gut microbiome excess are treated prior to delivery of the adoptive cell transfer therapy. In certain embodiments, such treatment improves the efficacy of the adoptive cell transfer therapy and / or reduces the toxicity of the adoptive cell transfer therapy.

[0070] In certain embodiments, the present disclosure relates to a method for predicting whether adoptive cell transfer therapy will be effective or toxic to an individual based on the analysis of one or more of the following biomarkers: (1) gut microbiome diversity; and / or (2) analysis of the level of one or more specific microorganisms in the gut microbiome. In some embodiments, the present disclosure relates to a method for determining the likelihood that adoptive cell transfer therapy will be effective or toxic in an individual, such as when compared to an individual with a normal or different microbiome. The results of the above (1) and / or (2) analysis can determine whether or how best to utilize adoptive cell transfer therapy. For example, if the results of the gut microbiome analysis indicate that adoptive cell transfer therapy will be effective (or likely to be effective) for the individual, the individual can receive a therapeutically effective amount of adoptive cell transfer therapy. If the analysis of the gut microbiome predicts that the adoptive cell transfer therapy will not be effective (or will be at high risk of being ineffective) for the individual, the individual may not receive the adoptive cell transfer therapy, the regimen and / or composition of the adoptive cell transfer therapy itself may be changed, or an effective amount of one or more microorganisms that change the gut microbiome may be administered to improve the effectiveness of the adoptive cell transfer therapy. If the analysis of the gut microbiome predicts that the adoptive cell transfer therapy will be toxic to the individual (or will likely be toxic compared to individuals with a different gut microbiome), the individual may not receive the adoptive cell transfer therapy, the regimen and / or composition of the adoptive cell transfer therapy itself may be changed, or an effective amount of one or more microorganisms that change the gut microbiome may be administered to reduce the toxicity of the adoptive cell transfer therapy. In any of these predicted cases or at-risk cases, an effective amount of one or more probiotics and / or one or more fecal transplants may be administered to increase the likelihood that the treatment will be effective and / or non-toxic to the individual.

[0071] In some embodiments, after analysis of the individual's gut microbiome, including before administering a particular therapy, such as an immunotherapy, including adoptive cell transfer therapy, it is determined that the individual needs modification of the gut microbiome. In some aspects, the modification includes administering to the individual an effective amount of one or more compositions that modify the gut microbiome such that the presence and / or level of one or more microorganisms is modified. In some embodiments, the individual is provided with a composition, such as a probiotic, that includes one or more microorganisms that the individual is believed to be deficient in, including based on the analysis of the gut microbiome. The composition may include one or more microorganisms that are deficient in the individual's gut microbiome, and following this administration (whether in a single administration or multiple administrations), the individual's gut microbiome is modified to a sufficient level such that the individual can be a recipient of a particular therapy, including a particular adoptive cell therapy. In certain embodiments, an individual is determined to be deficient in one or more microorganisms, and the individual is provided (in one or more administrations) with an effective amount of one or more compositions comprising the one or more microorganisms, whereby an effective amount of a particular adoptive cell therapy is provided such that (as a result of the modification of the gut microbiome) the adoptive cell therapy is more effective than if the individual had not received the composition(s). In some cases, alternatively or additionally, the individual is administered (in one or more administrations) one or more compositions comprising one or more microorganisms with reduced toxicity compared to if the individual had not received the composition(s).

[0072] The present disclosure encompasses determining or predicting whether an adoptive cell transfer therapy, such as CAR T cell therapy, will be therapeutic in an individual by analyzing the microbiome, and, if the analysis determines that the individual is in need of gut microbiome modification, providing the individual with an effective amount of a composition that addresses the microbiome deficiency. As an example, the individual may be provided with an effective amount of a composition that (1) includes one or more microorganisms present at insufficient levels in the individual's gut microbiome, (2) includes one or more agents (such as antibiotics) that reduce excess levels of one or more microorganisms in the gut microbiome, or (3) includes both. The composition in (1) may or may not be a probiotic, and may or may not be a fecal transplant.

[0073] In certain embodiments, the disclosure encompasses customizing one or more compositions such that an individual receives one or more microorganisms that are deficient in their gut microbiome compared to a control or standard or normal individual (such as an individual without cancer or an individual determined to have a highly diverse gut microbiome or an individual with a particular microorganism). Customization may be performed after analysis of the individual's gut microbiome, or the content of the composition may be standardized in comparison to deficiencies that are consistent in the general population, at least in some cases. In certain embodiments, compositions such as probiotics may be formulated after analysis of the individual's gut microbiome, while in other cases, probiotics may be administered to individuals whose gut microbiomes may have differences but have a common deficiency between them. The deficiency may be an insufficient level of one or more beneficial microorganisms in the gut, an excess of one or more non-beneficial microorganisms in the gut, a gut microbiome lacking a certain level of diversity, or a combination thereof.

[0074] (1. Overall microbial diversity) In certain embodiments, the gut microbiome of an individual is analyzed for its overall diversity of microorganisms, regardless of which microorganisms are actually present and / or absent. In certain cases, individuals with a highly diverse gut microbiome are more likely to receive an effective adoptive cell transfer therapy, such as improving one or more symptoms or showing a complete response. In certain cases, individuals with a low diversity gut microbiome are less likely to be effective with adoptive cell transfer therapy. In certain cases, individuals with a highly diverse gut microbiome are less likely to experience toxicity directly or indirectly associated with adoptive cell transfer therapy. In certain cases, individuals with a low diversity gut microbiome are more likely to experience toxicity directly or indirectly associated with adoptive cell transfer therapy. In at least some cases, individuals with a more diverse gut microbiome can expect progression-free survival after a certain period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 13, 14, 15, 16, 17, or 18 months or more after initial treatment with adoptive cell transfer therapy).

[0075] The overall diversity of the gut microbiome can be measured in any suitable manner. In certain aspects, there are multiple ways to quantify the microbiome, including microbial alpha diversity, such as the Shannon index, observed outcomes, and the like. Diversity measurements have historically relied on species as the basic unit of analysis. Diversity within a given community (alpha diversity) is typically characterized using an index that combines the total number of species (species richness), the relative abundance of species (species evenness), or these two dimensions. In some embodiments, diversity is measured as a function of the inverse Simpson index (ISI) to calculate microbial alpha diversity. Alternative indices include observed OUTs - the number of distinct species / OTUs in each sample, Chao1 index - estimated diversity from abundance data, Shannon diversity, and the like. Quantitative species-based indices such as ISI are often used to summarize and compare microbiome alpha diversity in different communities. The diversity of the gut microbiome in an individual can be compared to a standard value generated based on the ISI analysis, and if the individual's gut microbiome value is in the highest tertile (e.g., ISI cutoff value of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), the individual will receive an effective adoptive cell transfer therapy, for example, as measured by progression-free survival or complete response. In certain embodiments, if the individual's overall gut microbiome value is in the lowest tertile, the individual is at risk for a poor outcome from the adoptive cell transfer therapy, such as no response, poor response, partial response, stable disease, or progressive disease.

[0076] In certain embodiments, the standard generated based on ISI analysis is a function, in part, of the number of sequencing reads and / or the number of individuals analyzed for the standard. Standards can be generated based on known individuals and knowledge of which individuals have or have not had a complete response. Tertiles of ISI can be stratified based on the number of individuals with CR and those without CR after a certain time as a function of gut microbiome diversity. In a particular example, the higher tertile is considered to be 16 or higher and is identified as individuals expected to have at least a progression-free survival and a CR of 3 months. In a specific example, at 1.5 million reads, an ISI of 16 predicted high diversity and response. In a specific aspect, the average number of reads per sample is about 49,000, and the average ISI in this cohort is 13.8, while the median ISI is 13.4. Thus, in some embodiments, with an average 49,000 read response prediction, individuals with an ISI score of 16 will be more likely to obtain a response from CAR T cell therapy.

[0077] In embodiments in which an individual is determined to have a low diversity gut microbiome, the individual may or may not receive adoptive cell therapy. If an individual receives therapy despite having a low diversity gut microbiome, it may be because the individual has received an effective amount of one or more agents that improve gut microbiome diversity, such as a fecal transplant and / or a probiotic composition(s). If an individual is determined to have a high diversity gut microbiome, they may receive a therapeutically effective amount of adoptive cell therapy.

[0078] (2. No complete response) Certain embodiments of the present disclosure relate to the analysis of the gut microbiome in an individual in need of treatment with an immunotherapy, such as CAR T cell therapy. Specifically, an individual in need of CAR T cell therapy has their gut microbiome analyzed prior to treatment. In at least certain embodiments, the presence of one or more specific microorganisms, the absence of one or more specific microorganisms, or a combination thereof, identifies the type of response to treatment that the individual will have or is likely to have when compared to an individual with a different gut microbiome (e.g., an individual with a difference in the presence of one or more specific microorganisms and / or the absence of one or more specific microorganisms when compared to the individual in need of treatment).

[0079] As featured in Figure 2, individuals 3 months after treatment who showed a complete response to treatment had a different initial gut microbiome composition than individuals who showed a partial response (PR), stable disease (SD), or progressive disease (PD). In certain embodiments, individuals with microorganisms of the order Bacillales and / or individuals with the species Phascolarctobacterium succinatutens had or were at increased risk of having PR, SD, or PD. If an individual is at increased risk of having PR, SD, or PD, such risk of having PR, SD, or PD may be increased compared to individuals who did not have such microorganisms. In a specific embodiment, the individual's gut microbiome comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more microorganisms from any family of the order Bacillales, including any species of the genera Bacillus, Listeria, and Staphylococcus. If an individual is determined to have one or more bacteria from the order Bacillales and / or is determined to have Phascolarctobacterium succinatutens, the individual may or may not undergo CAR T-cell therapy. If the individual still undergoes CAR T-cell therapy despite having one or more of the aforementioned microorganisms, the individual may undergo one or more additional cancer therapies other than CAR T-cell therapy, such as surgery, chemotherapy, drug therapy, radiation therapy, hormone therapy, or a combination thereof. If an individual still receives CAR T cell therapy despite having one or more of the aforementioned microorganisms, the CAR T cell therapy may be administered at a different dose (e.g., higher) and / or modified to allow the individual to overcome the risk of having PR, SD, or PD.For example, the target antigen of the CAR may be altered; additional or different co-stimulatory domains may be utilized in the CAR; additional CARs targeting additional target antigens in the cells may be utilized; one or more cytokines (such as IL-15) may be utilized in the CAR T cell therapy, etc. In certain embodiments, additional hinge and transmembrane domains in the CAR-T therapy may be utilized. CAR-T secreted antibodies or any protein may also be utilized. The individual may be administered one or more antibiotics, including antibiotics that target one or more microorganisms that overcome deficiencies in the individual's gut microbiome, such as targeting one or more microorganisms of the order Bacillales and / or species Phascolarctobacterium succinatutens.

[0080] Representative families within the order Bacillales include Alicyclobacillaceae; Bacillaceae; Listeriaceae; Paenibacillaceae; Pasteuriaceae; Planococcaceae; Sporolactobacillaceae; Staphylococcaceae; and Thermoactinomycetaceae; while representative genera within the order Bacillales include Bacillus, Listeria, and Staphylococcus.

[0081] (3. Complete response) As highlighted in Figure 2, individuals who responded completely to treatment 3 months after treatment had a specific gut microbiome composition. Regarding the method of what database was used to generate OUTs by matching the sequencing results, the following was utilized: Amplicon pools were purified with QIAquick gel extraction kit (Qiagen) and sequenced on an Illumina Miseq sequencer platform using a 2 × 250 bp paired-end protocol. After sequencing, paired-end reads were de-multiplexed with QIIME, merged and de-replicated with VSEARCH by Chimera. Reads were de-noised using the UNOISE 3 command algorithm (RC Edgar. bioRxiv, 081257, 2016). Operational taxonomic units (OUTs) were classified using the Mothur method in the Silva database version 138. For differential taxon-based univariate analyses, abundant microbiome taxa at species, genus, family, class, and order levels were analyzed using the Mann-Whitney U test after logit transformation. The detailed computational pipeline of the analyses was described previously (Yinghong Wang et al. Nat Med. 2018). For exploratory analyses, p-values ​​were not adjusted for multiple comparisons.

[0082] In SILVA release 138, the Genome Taxonomic Database (GTDB) was adopted (Parks 2018). As a result of the effort, in certain cases, the following groups were amenable to significant adaptation: Archaea, Enterobacterales, Deltaproteobacteria, Firmicutes, and Clostridia. Betaproteobacteriales (previously called Betaproteobacteria) is now one order of Gammaproteobacteria, Burkholderiales. Epsilonproteobacteria disappeared into a new phylum, Campilobacterota. Tenericutes disappeared, all now part of Bacilli, and included in Firmicutes. In addition, all sequences in the SILVA dataset have an EMBL-EBI / ENA taxonomic assignment. When available, RDP and GTDB taxonomy have been added for comparison. Release <138 also added the greengenes taxonomy. We used SILVA for bacterial classification.

[0083] In specific embodiments, individuals who had one or more microorganisms from the following list had an increased likelihood of having a complete response, including an increased likelihood, compared to individuals who did not have one or more microorganisms from the following list:

[0084] Genus Varibaculum; Species Bifidobacterium animalis; Species Corynebacterium tuberculostearicum; Species Dialister succinatiphilus; Species Porphyromonas asaccharolytica; Species Porphyromonas endodontalis; Unclassified genus Ruminococcaceae; Species Varibaculum cambriense; Genus Murdochiella; Species Levyella massiliensis; Species Porphyromonas bennonis; Species Peptoniphilus lacrimalis; Species Peptoniphilus harei; Species Anaerococcus vaginalis; Species Butyricicoccus pullicaecorum; Species Prevotella timonensis; Genus Ruminiclostridium 1; Species Fenollaria massiliensis; Species Frisingicoccus caecimuris; Genus Ruminococcaceae UCG 010; Species Hungateiclostridium cellulolyticum; Unclassified species Ruminococcaceae UCG 010; Genus Prevotella; Genus Ezakiella; Species Aminipila butyrica; Genus Eisenbergiella; Genus GCA 900066755; Species Bacteroides ovatus; Unclassified genus Lachnospiraceae; Unclassified genus Ruminococcaceae; Genus Ruminiclostridium 9; Species Bacteroides cellulosilyticus; Species Bacteroides vulgatus; Species Alistipes shahii; Species Eisenbergiella massiliensis; Genus GCA 900066225; [Ruminococcus] torques; Species Longicatena caecimuris; Genus Ruminococcaceae UCG 002; Genus Anaerococcus; Genus Barnesiella;Clostridium celerecrescens species; Barnesiella intestinihominis species; Desulfovibrio desulfuricans; Bacteroidaceae family; Barnesiellaceae family; Bacteroides genus; Bacteroides xylanisolvens species; Dialister propionicifaciens species; Fournierella genus; Genus Peptoniphilus; Genus Porphyromonas; Genus Blautia glucerasea; Genus GCA 900066575; Genus Lachnoclostridium; Genus Intestinimonas; Genus Anaerotignum lactatifermentans; In certain embodiments, the individual's gut microbiome comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more of the aforementioned microorganisms;

[0085] In certain embodiments, if an individual is determined to have one or more of the aforementioned microorganisms (and in some cases most or all of the microorganisms), the individual will have a complete response or an increased likelihood of a complete response compared to an individual who does not have the corresponding microorganism. In specific embodiments, if an individual is determined to have at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95% of a particular number of the aforementioned microorganisms, the individual will have a complete response or an increased likelihood of a complete response compared to an individual who does not have the same or a similar number of the corresponding microorganisms.

[0086] In certain embodiments, if an individual is determined to have one or more of the aforementioned microorganisms in the complete response list (possibly most or all of the microorganisms, or a percentage as described above), the individual may be administered a therapeutically effective amount of CAR T cell therapy. The individual may or may not be administered additional cancer therapy. Despite the fact that the individual may receive effective CAR T cell therapy based on the gut composition, the individual may be administered one or more probiotic compositions comprising one or more microorganisms that enhance the individual's gut microbiome.

[0087] Below, specific species are presented from the families and genera mentioned in the complete response list above.

[0088] Bacillus is also a species of B. acid cells; B. acidicola; B. acidiproducens; B. acidocaldarius; B. acidoterrestris; B. aeolius; B. aerius; B. aerophilus; B. agaradhaerens; B. agree; B. aidingensis; B. akibai; B. alkalophilus; B. algicola; B. alginolyticus; B. alkalidiazotrophicus; B. alkalinitrile; B. alkalisediminis; B. alkalitelluris; B. altitude; B. alveayuensis; B. alvei; B. amyloliquefaciens; B. aminovorans; B. amylolyticus; B. andresen;;B. aneurinilyticus; B. anthracis; B. aquimaris; B. arenosi; B. arsenicselenatis; B. arsenicus; B. aurantiacus; B. arvi; B. aryabhattai; B. asahi; B. atrophaeus; B. axarchiensis ; B. nitrofixans; B. nitroformans; B. badius; B. barbaricus; B. bataviensis; B. beijingensis; B. benzoevorans; B. beringensis; B. berkeley; B. beveridgei; B. bogoriensis; B. boroniphilus; B. borstelensis; B. brevis Buy; B. butanolivorans; B. canavelius; B. carboniphilus; B. cecembensis; B. cellulolyticus; B. centrosporus; B. cereus; B. chagannorensis; B.chitinolyticus; B. chondroitinus; B. choshinensis; B. chungangensis; B. cibi; B. circulans; B. clarkia; B. clausii;B; coagulans;;B. coahuilensis; B. cohnii; B. composti; B. curdlanolyticus; B. cycloheptanicus; B. cytotoxicus; B. daliensis; B. decisifrondis; B. decolorationis; B. deserti; B. dipsosauri; B. drentensis; B. edaphicus; B. ehimensis; B. eiseniae; B. enclensis; B. endophyticus; B. endoradicis; B. farraginis; B. fastidiosus; B. fengqiuensis; B. firmus; B. flexus; B. foraminis; B. fordii; B. formosus; B. fortis; B. fumarioli; B. funiculus; B. fusiformis; B. galactophilus; B. galactosidilyticus; B. galliciensis; B. gelatini; B. gibsonii; B. ginseng; B. ginsengihumi; B. ginsengisoli; B. glucanolyticus; B. gordonae; B. gottheilii; B. graminis; B. halmapalus; B. haloalkaliphilus; B. halochares; B. halodenitrificans; B. halodurans; B. halophilus; B. halosaccharovorans; B. hemicellulosilyticus; B. hemicentroti; B. herbersteinensis; B. horikoshii; B. horneckiae; B. horti; B.huizhouensis; B. humi; B. hwajinpoensis; B. idriensis; B. indicus; B. infantis; B. infernus; B. insolitus; B. invictae; B. iranensis; B. isabeliae; B. isronensis; B. jeotgali; B. kaustophilus; B. kobensis; B. kochii; B. kokeshiiformis; B. koreensis; B. korlensis; B. kribbensis; B. krulwichiae; B. laevolacticus; B. larvae; B. laterosporus; B. lautus; B. lehensis; B. lentimorbus; B. lentus; B. licheniformis; B. ligniniphilus; B. litoralis; B. locisalis; B. luciferensis; B. luteolus; B. luteus; B. macauensis; B. macerans; B. macquariensis; B. macyae; B. malacitensis; B. mannanilyticus; B. marisflavi; B. died at sea; B. marmarensis; B. massiliensis; B. megatherium; B. mesons; B. methanolic; B. methylotrophicus; B. migulanus; B. mojavensis; B. mucilaginous; B. mural; B. murimartini; B. mycoides; B. naganoensis; B. nanhaiensis; B. nanhaiisediminis; B. nealsonii; B. Neidei; B. neizhouensis; B. niabensis; B. niacin; B. novalis; B. oceanization; B. odysseyi; B. okhensis; B.okuhidensis; B. oleronius; B. oryzaecorticis; B. oshimensis; B. pabuli; B. pakistanensis; B. pallidus; B. pallidus; B. panacisoli; B. panaciterrae; B. pantothenticus; B. parabrevis; B. paraflexus; B. pasteurii; B. patagoniensis; B. peoriae; B. persepolensis; B. persicus; B. pervagus; B. plakortidis; B. pocheonensis; B. polygoni; B. polymyxa; B. popilliae; B. pseudalcalophilus; B. pseudofirmus; B. pseudomycoides; B. psychrodurans; B. psychrophilus; B. psychrosaccharolyticus; B. psychrotolerans; B. pulvifaciens; B. pumilus; B. purgationiresistens; B. pycnus; B. qingdaonensis; B. qingshengii; B. reuszeri; B. rhizosphaerae; B. rigui; B. ruris; B. safensis; B. salaries; B. salexigens; B. saliphilus; B. schlegelii; B. sediminis; B. selenatarsenatis; B. selenitireducens; B. seohaeanensis; B. shacheensis; B. shackletonii; B. siamensis; B. silvestris; B. simplex; B. spiralis; B. smithii; B. soli; B. solimangrovi; B. solisalsi; B. songklensis; B. sonorensis; B. sphaericus; B.sporothermodurans; B. stearothermophilus; B. stratosphericus; B. subterraneus; B. subtilis; B. taeanensis; B. tequilensis; B. thermanarcticus; B. thermoaerophilus; B. thermoamylovorans; B. thermocatenulatus; B. thermocloacae; B. thermocopriae; B. thermodenitrificans; B. thermoglucosidasius; B. thermolactis; B. thermoleovorans; B. thermophiles; B. thermoruber; B. thermosphaericus; B. thiaminolyticus; B. thioparans; B. thuringiensis; B. tianshenii; B. trypoxylicola; B. tusciae; B. validus; B. vallismortis; B. vedderi; B. velezensis; B. vietnamensis; B. vireti; B. vulcani; B. wakoensis; B. xiamenensis; B. xiaoxiensis; B. zanthoxyli; and B. zhanjiangensis can be mentioned.

[0089] Representative species of the genus Listeria include Listeria monocytogenes, Listeria seeligeri, Listeria ivanovii, Listeria welshimeri, Listeria marthii, Listeria innocua, Listeria grayi, Listeria fleischmannii, Listeria floridensis, Listeria aquatica, Listeria newyorkensis, Listeria cornellensis, Listeria rocourtiae, Listeria weihenstephanensis, Listeria grandensis, Listeria riparia, and Listeria booriae.

[0090] In the genus Staphylococcus, representative species include S. argenteus; S. arlettae; S. agnetis; S. aureus; S. auricularis; S. caeli; S. capitis; S. caprae; S. carnosus; S. caseolyticus; S. chromogenes; S. cohnii; S. cornubiensis; S. condiment; S. debuckii; S. delphini; S. devriesei; S. edaphicus; S. epidermidis; S. equorum; S. felis; S. fleurettii; S. gallinarum; S. haemolyticus; S. hominis; S. hyicus; S. intermedius; S. jettensis; S. kloosii; S. leei; S. lentus; S. lugdunensis; S. lutrae; S. lyticans; S. massiliensis; S. microti; S. muscae; S. nepalensis; S. pasteuri; S. petrasii; S. pettenkoferi; S. piscifermentans; S. pseudintermedius; S. pseudolugdunensis; S. pulvereri; S. rostri; S. saccharolyticus; S. saprophyticus; S. schleiferi; S. schweitzeri; S. sciuri; S. simiae; S. simulans; S. stepanovicii; S. succinus; S. vitulinus; S. warneri; and S. xylosus.

[0091] With respect to the Genus Varibaculum, representative species include V. anthropic; V. cambriense; V. massiliense; and V. timonense.

[0092] In the genus Murdochiella, representative species include Murdochella alacer; Murdochella Antarctica; Murdochella crispate; Murdochella levifoliata; Murdochella lobate; Murdochella macrina; Murdochella superlata (synonymous with Papuliscala superlata); and Murdochella tertia.

[0093] Representative species in the genus Ruminiclostridium include Ruminiclostridium cellobioparum; Ruminiclostridium cellulolyticum; Ruminiclostridium hungatei; Ruminiclostridium josui; Ruminiclostridium papyrosolvens; Ruminiclostridium sufflavum; and Ruminiclostridium sp. MA18.

[0094] In the genus Prevotella, representative species are Prevotella albensis; Prevotella amnii; Prevotella bergensis; Prevotella bivia; Prevotella brevis; Prevotella bryantii; Prevotella buccae; Prevotella buccalis; Prevotella copri; Prevotella dentalis; Prevotella denticola; Prevotella intermedia; Prevotella maculosa; Prevotella marshii; Prevotella melaninogenica; Prevotella micans; Prevotella multiformis; Prevotella nigrescens; Prevotella oralis; Prevotella oris;

[0095] In the genus Ezakiella, representative species include Ezakiella coagulans; Ezakiella massiliensis; Ezakiella peruensis; and Ezakiella massiliensis.

[0096] With respect to the Genus Eisenbergiella, representative species include E. massiliensis; and E. tayi.

[0097] In the genus Anaerococcus, representative species include Anaerococcus hydrogenalis; Anaerococcus lactolyticus; Anaerococcus octavius; Anaerococcus prevotii; Anaerococcus tetradius; Anaerococcus vaginalis; Anaerococcus murdochii; Anaerococcus degenerii; Anaerococcus provencensis; Anaerococcus senegalensis; Anaerococcus rubiinfantis; Anaerococcus marasmi; Anaerococcus urinomassiliensis; and Anaerococcus nagyae.

[0098] Representative species in the genus Barnesiella include B. intestinihominis and B. viscericola.

[0099] In the family Bacteroidaceae, representative genera include Acetofilamentum; Acetomicrobium; Acetothermus; Anaerorhabdus; Bacteroides; and Capsularis.

[0100] In the family Barnesiellaceae, representative genera include Barnesiella and Coprobacter.

[0101] In the genus Bacteroides, representative species include B. acidifaciens; B. barnesiaes; B. caccae; B. caecicola; B. caecigallinarum; B. cellulosilyticus; B. cellulosolvens; B. clarus; B. coagulans; B. coprocola; B. coprophilus; B. coprosuis; B. distasonis (which may be considered Parabacteroides distasonis); B. dorei; B. eggerthii; B. gracilis; B. faecichinchillae; B. faecis; B. finegoldii; B. fluxus; B. fragilis; B. galacturonicus; B. gallinaceum; B. gallinarum; B. goldsteinii; B. graminisolvens; B. helcogene; B. intestinalis; B. luti; B. massiliensis; B. melaninogenicus; B. nordii; B. oleiciplenus; B. oris; B. ovatus; B. paurosaccharolyticus; B. plebeius; B. polypragmatus; B. propionicifaciens; B. putredinis; B. pyogenes; B. reticulotermitis; B. rodentium; B. salanitronis; B. salyersiae; B. sartorii; B. sediment; B. stercoris; B. suis; B. tectus; B. thetaiotaomicronl B. uniformis; B. vulgatus; B. xylanisolvens; and B. xylanolyticus.

[0102] In the genus Fournierella, a representative species is Fournierella massiliensis.

[0103] In the family Porphyromonadaceae, representative genera include Barnesiella; Candidatus Vestibaculum; Coprobacter; Dysgonomonas; Falsiporphyromonas; Fermentimonas; Gabonia; Gabonibacter; Lascolabacillus; Macellibacteroides; Microbacter; Muribaculum; Parabacteroides; Porphyromonas; Proteiniphilum; Sanguibacteroides; and Tannerella.

[0104] In the genus Peptoniphilus, representative species include P. asaccharolyticus; P. catoniae; P. coxii; P. duerdenii; P. gorbachii; P. harei; P. ivorii; P. koenoeneniae; P. lacrimalis; P. lacydonensis; P. methioninivorax; P. olsenii; P. senegalensis; P. stercorisuis; P. timonensis; P. tyrrelliae; and P. urinimassiliensis.

[0105] In the genus Porphyromonas, representative species include P. asaccharolytica; P. bennonis; P. cangingivalis; P. canoris; P. catoniae; P. circumdentaria; P. crevioricanis; P. endodontalis; P. gingivalis; P. gingivicanis; P. gulae; P. levii; P. macacae; P. pasteri; P. pogonae; P. somerae; and P. uenonis.

[0106] In the genus GCA-900066575, representative species include sp002160765; sp002160825; sp900066385; and sp900553635.

[0107] In the genus Lachnoclostridium, representative species include Lachnoclostridium pacaense; Lachnoclostridium touaregense; Lachnoclostridium bouchesdurhonense; Lachnoclostridium phytofermentans; Lachnoclostridium sp. YL32; and Lachnoclostridium massiliosenegalense.

[0108] Representative species of the genus Intestinimonas include Intestinimonas butyriciproducens and Intestinimonas massiliensis.

[0109] In the genus Flavonifractor, the representative species is Flavonifractor plautii.

[0110] (4. Risk of Cytokine Release Syndrome) In certain embodiments, the composition of the gut microbiome acts as a biomarker for whether immunotherapy, such as cells expressing one or more engineered antigen receptors (including CAR T cell therapy), will be toxic to an individual. In certain embodiments, the composition of the gut microbiome serves as a biomarker for the risk of an individual developing cytokine release syndrome (CRS) as a result of CAR T cell therapy. An individual's gut microbiome may allow the grade of CRS to be determined, and such information may influence whether an individual will undergo CAR T cell therapy or whether an adjustment in the treatment regimen is warranted.

[0111] In certain embodiments, gut microbiome analysis of the individual determines that the individual has a CRS grade of 0, 1, 2, 3, or 4.

[0112] In certain embodiments, an individual has a CRS grade of 2, 3, or 4 if the individual has one or more of the following microorganisms: Lactobacillus rhamnosus species; Parabacteroides goldsteinii species; Olsenella uli species; Fusobacterium varium species; the genus Porphyrobacter; Dialister succinatiphilus species; Faecalitalea cylindroides species; Porphyrobacter sanguineus species; Ruminiclostridium 9 unclass species; the family Sphingomonadaceae; the order Sphingomonadales; and the genus Olsenella.

[0113] In certain embodiments, if an individual has a certain number of the aforementioned microorganisms, e.g., at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95%, or more than 95% of the microorganisms, they have a CRS grade of 2, 3, or 4, or are more likely to have a CRS grade of 2, 3, or 4, compared to individuals who do not have the relevant microorganisms.

[0114] In such cases, as a result of the analysis, the individual may or may not be provided with a therapeutically effective amount of CAR T cell therapy. In certain embodiments, the treatment regimen can be modified to further reduce the individual's risk of CRS, such as by modifying (e.g., decreasing) the CAR T cells and / or their dosage. For example, the target antigen of the CAR may be changed, one or more additional or different co-stimulatory domains may be utilized in the CAR, additional CARs that target additional target antigens in the cells may be utilized, one or more cytokines may be avoided in the CAR T cell therapy, etc. The individual may or may not receive additional cancer therapy. The individual may be administered one or more probiotic compositions and / or one or more fecal transplants that include one or more microbes that overcome deficiencies in the individual's gut microbiome.

[0115] In other embodiments, gut microbiome analysis of an individual determines that the individual will have a CRS grade of 0 or 1 in the future, or is more likely to have a CRS grade of 0 or 1 compared to individuals without the corresponding microbe. In certain embodiments, an individual has a CRS grade of 0 or 1 (or is at risk of having, compared to an individual lacking these microorganisms) if the individual has one or more of the following microorganisms: Eubacterium sulci species; Ihubacter massiliensis species; Eubacteriaceae family; Bacteroides xylanisolvens species; Ruminococcus 2 genus; Ruminococcus bromii species; Blautia luti species; Turicibacter genus; Turicibacter sanguinis species; Clostridium celerecrescens species; Veillonella genus; Roseburia faecis species; Atopobium genus; Lactonifactor genus; Lactonifactor longoviformis species; Atopobium parvulum species; Peptostreptococcaceae family; Veillonella tobetsuensis species; Veillonella parvula species.

[0116] In certain embodiments, if an individual is determined to have at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95%, or more than 95% of the aforementioned microorganisms, the individual has a CRS score of 0 or 1 or has an increased likelihood of having a CRS score of 0 or 1 compared to individuals who do not have the corresponding microorganisms.

[0117] In such cases, the analysis results in the individual being provided with a therapeutically effective amount of CAR T cell therapy. However, in certain embodiments, the treatment regimen can be modified to further reduce the individual's risk of CRS, such as by modifying the CAR T cells and / or modifying (e.g., reducing) their dosage. For example, the target antigen of the CAR can be modified; one or more additional or different co-stimulatory domains can be utilized in the CAR; additional CARs that target additional target antigens can be utilized in the cells; one or more cytokines can be avoided in the CAR T cell therapy, etc. The individual may or may not receive additional cancer therapy. The individual may be administered one or more probiotic compositions and / or one or more fecal transplants that include one or more microbes that overcome deficiencies in the individual's gut microbiome.

[0118] Below are specific species from the orders, families, and genera mentioned in the list of cytokine release syndrome risks above.

[0119] In the genus Porphyrobacter, representative species include P. colymbi; P. cryptus; P. dokdonensis; P. donghaensis; P. neustonensis; P. sanguineus; and P. tepidarius.

[0120] In the family Sphingomonadaceae, representative genera include Blastomonas; Citrimicrobium; Citromicrobium; Hankyongella; Hephaestia; Lutibacterium; Novosphingobium; Pacificimonas; Parablastomonas; Parasphingopyxis; Polymorphobacter; Rhizorhabdus; Rhizorhapis; Sandaracinobacter; Sandarakinorhabdus; Sphingoaurantiacus; Sphingobium; Sphingomicrobium; Sphingomonas; Sphingopyxis; Sphingorhabdus; Sphingosinicella; Stakelama; and Zymomonas.

[0121] In the order Sphingomonadales, representative genera include Altererythrobacter; Blastomonas (a representative species is Blastomonas aquatic); Citrimicrobium; Citromicrobium; croceicoccus; Erythrobacter; Porphyrobacter; Sphingobium; Sphingomonadaceae; Sphingomonadales; Sphingomonas; Sphingopyxis; and Zymomonas (a representative species is Zymomonas mobilis).

[0122] In the genus Altererythrobacter, representative species are Altererythrobacter aerius; Altererythrobacter aestiaquae; Altererythrobacter aestuarii; Altererythrobacter aquaemixtae; Altererythrobacter aquiaggeris; Altererythrobacter atlanticus; Altererythrobacter aurantiacus; Altererythrobacter buctensis; Altererythrobacter confluentis; Altererythrobacter deserti; Altererythrobacter dongtanensis; Altererythrobacter endophyticus; Altererythrobacter epoxidivorans; Altererythrobacter flavus; Altererythrobacter fulvus; Altererythrobacter gangjinensis; Altererythrobacter indicus; Altererythrobacter ishigakiensis; Altererythrobacter lauratis; Altererythrobacter luteolus; Altererythrobacter mangrove; Altererythrobacter marensis; Altererythrobacter marinus; Altererythrobacter namhicola; Altererythrobacter oceanensis; Altererythrobacter rigui; Altererythrobacter salegens; Altererythrobacter sediminis; Altererythrobacter soli; Altererythrobacter troitsensis; Altererythrobacter xiamenensis; Altererythrobacter xinjiangensis;and Altererythrobacter xixiisoli.

[0123] In the genus Erythrobacter, representative species include Erythrobacter aquimaris; Erythrobacter aquimixticola; Erythrobacter arachoides; Erythrobacter atlanticus; Erythrobacter citreus; Erythrobacter flavus; Erythrobacter gaetbuli; Erythrobacter gangjinensis; Erythrobacter jejuensis; Erythrobacter litoralis; Erythrobacter longus; Erythrobacter luteus; Erythrobacter lutimaris; Erythrobacter marinus; Erythrobacter nanhaisediminis; Erythrobacter odishensis; Erythrobacter pelagi; Erythrobacter seohaensis; Erythrobacter vulgaris; Erythrobacter xanthus; Erythrobacteraceae; Erythromicrobium; Erythromicrobium ramosum; and Erythrobacter aquimaris.

[0124] In the genus Novosphingobium, representative species include Novosphingobium acidiphilum; Novosphingobium aquaticum; Novosphingobium aquiterrae; Novosphingobium arabidopsis; Novosphingobium barchaimii; Novosphingobium chloroacetimidivorans; Novosphingobium endophyticum; Novosphingobium fluoreni; Novosphingobium fuchskuhlense; Novosphingobium gossypii; Novosphingobium hassiacum; Novosphingobium indicum; Novosphingobium kunmingense; Novosphingobium lentum; Novosphingobium lindaniclasticum; Novosphingobium malaysiense; Novosphingobium marinum; Novosphingobium mathurense; Novosphingobium naphthalenivorans; Novosphingobium nitrogenifigens; Novosphingobium oryzae; Novosphingobium panipatense; Novosphingobium rhizosphaerae; Novosphingobium sediminicola; Novosphingobium soli; Novosphingobium taihuense; and Novosphingobium tardaugens.

[0125] In the genus Porphyrobacter, representative species include Porphyrobacter colymbi; Porphyrobacter cryptus; Porphyrobacter dokdonensis; Porphyrobacter donghaensis; Porphyrobacter neustonensis; and Porphyrobacter tepidarius.

[0126] In the genus Sphingobium, representative species include Sphingobium chlorophenolicum; Sphingobium francense; Sphingobium indicum; and Sphingobium japonicum.

[0127] In the genus Sphingopyxis, representative species are Sphingopyxis alaskensis; Sphingopyxis baekryungensis; Sphingopyxis bauzanensis; Sphingopyxis chilensis; Sphingopyxis flava; Sphingopyxis flavimaris; Sphingopyxis fribergensis; Sphingopyxis ginsengisoli; Sphingopyxis granuli; Sphingopyxis indica; Sphingopyxis italic; Sphingopyxis nepalensis; Sphingopyxis panaciterrae; Sphingopyxis panaciterrulae; Sphingopyxis soli; Sphingopyxis solisilvae; ummariensis; Sphingopyxis witflariensis; and Sphingosinicella humi.

[0128] In the genus Olsenella, representative species include O. profuse; O. scatoligenes; O. uli; and O. umbonata.

[0129] In the family Eubacteriaceae, representative genera include Acetobacterium; Alkalibacter; Alkalibaculum; Aminicella; Anaerofustis; Eubacterium; Garciella; Intestinibacillus; Irregularibacter; Pseudoramibacter; and Rhabdanaerobium.

[0130] In the genus Acetobacterium, representative species include Acetobacterium bakii; Acetobacterium carbinolicum; Acetobacterium fimetarium; Acetobacterium malicum; Acetobacterium paludpsum; Acetobacterium tundra; Acetobacterium wieringae; and Acetobacterium woodii.

[0131] In the genus Alkalibacter, a representative species is A. saccharofermentans.

[0132] In the genus Alkalibaculum, the representative species is A. bacchi.

[0133] In the genus Aminicella, a representative species is Aminicella lysinilytica.

[0134] In the genus Anaerofustis, the representative species is A. stercorihominis.

[0135] In the genus Eubacterium, representative species include Eubacterium aggregans; Eubacterium angustum; Eubacterium barkeri; Eubacterium brachy; Eubacterium budayi; Eubacterium callanderi; Eubacterium cellulosolvens; Eubacterium combesii; Eubacterium coprostanoligenes; Eubacterium dolichum; Eubacterium eligens; Eubacterium hallii; Eubacterium infirmum; Eubacterium limosum; Eubacterium minutum; Eubacterium multiforme; Eubacterium nitritogenes; Eubacterium nodatum; Eubacterium oxidoreducens; Eubacterium plexicaudatum; Eubacterium pyruvativorans; Eubacterium ramulus; Eubacterium rectale; Eubacterium ruminantium; Eubacterium saphenum; Eubacterium siraeum; Eubacterium sulci; Eubacterium tarantellae; Eubacterium tenue; Eubacterium tortuosum; Eubacterium uniforme; Eubacterium ventriosum; Eubacterium xylanophilum; and Eubacterium yurii.

[0136] In the genus Garciella, the representative species is G. nitratireducens.

[0137] In the genus Intestinibacillus, the representative species is Intestinibacillus massiliensis.

[0138] In the genus Irregularibacter, a representative species is Irregularibacter muris.

[0139] In the genus Pseudoramibacter, a representative species is P. alactolyticus.

[0140] Regarding the genus Rhabdanaerobium, a representative species is Rhabdanaerobium thermarum.

[0141] In the genus Ruminococcus, representative species include Ruminococcus albus; Ruminococcus bromii; Ruminococcus callidus; Ruminococcus flavefaciens; Ruminococcus gauvreauii; Ruminococcus gnavus; Ruminococcus lactaris; Ruminococcus obeum; and Ruminococcus torques.

[0142] In the genus Turicibacter, the representative species is Turicibacter sanguinis.

[0143] In the genus Veillonella, representative species include V. tobetsuensis; V. magna; V. criceti; V. ratti; V. montpellierensis; V. caviae; V. dispar; V. parvula; V. rogosae; V. atypica; V. denticariosi; and V. rodentium.

[0144] In the genus Atopobium, representative species include A. deltae; A. fossor; A. minutum; A. parvulum; A. rimae; and A. vaginae.

[0145] In the genus Lactonifactor, the representative species is Lactonifactor longoviformis.

[0146] In the family Peptostreptococcaceae, representative genera include Acetoanaerobium; Asaccharospora; Clostridioides; Cribacterium; Filifactor; Intestinibacter; Paeniclostridium; Paraclostridium; Peptoanaerobacter; Peptoclostridium; Peptostreptococcus; Proteocatella; Romboutsia; Sporacetigenium; Tepidibacter; and Terrisporobacter.

[0147] In the genus Acetoanaerobium, a representative species is A. noterae.

[0148] In the genus Asaccharospora, the representative species is Asaccharospora irregularis.

[0149] In the genus Clostridioides, representative species include Clostridioides difficile and Clostridioides mangenotii.

[0150] In the genus Criibacterium, a representative species is Criibacterium bergeronii.

[0151] In the genus Filifactor, representative species include Filifactor villosus and Filifactor alocis.

[0152] In the genus Intestinibacter, a representative species is Intestinibacter bartlettii.

[0153] In the genus Paeniclostridium, representative species include Paeniclostridium sordellii and Paeniclostridium ghonii.

[0154] In the genus Paraclostridium, representative species include Paraclostridium bifermentans and Paraclostridium benzoelyticum.

[0155] In the genus Peptoanaerobacter, a representative species is Peptoanaerobacter stomatis.

[0156] In the genus Peptoclostridium, a representative species is Peptoclostridium difficile.

[0157] In the genus Peptostreptococcus, the representative species are Peptostreptococcus anaerobius; Peptostreptococcus asaccharolyticus; Peptostreptococcus canis; Peptostreptococcus harei; Peptostreptococcus hydrogenalis; Peptostreptococcus indoliticus; Peptostreptococcus ivorii; Peptostreptococcus lactolyticus; Peptostreptococcus magnus; Peptostreptococcus micros; Peptostreptococcus octavius; Peptostreptococcus prevotii; Peptostreptococcus tetradius; vaginalis.

[0158] In the genus Proteocatella, a representative species is Proteocatella sphenisci.

[0159] In the genus Romboutsia, representative species include Romboutsia timonensis; Romboutsia hominis; Romboutsia lituseburensis; and Romboutsia ilealis.

[0160] In the genus Sporacetigenium, representative species include S. poracetigenium and Sporacetigenium mesophilum.

[0161] In the genus Tepidibacter, representative species include T. formicigenes; T. mesophilus; and T. thalassicus.

[0162] In the genus Terrisporobacter, representative species include Terrisporobacter glycolicus; Terrisporobacter mayombei; and Terrisporobacter petrolearius.

[0163] (5. Risk of immune effector cell-associated neurotoxicity syndrome) In certain embodiments, the gut microbiome of an individual in need of immunotherapy, such as CAR T cell therapy, is analyzed prior to therapy to determine the individual's risk of having immune effector cell-associated neurotoxicity syndrome (ICANS). In certain embodiments, the individual's gut microbiome is analyzed prior to CAR T cell therapy to determine the grade of ICANS (0, 1, 2, 3, or 4) to which the individual is predisposed compared to individuals who do not have the same microbes.

[0164] In certain embodiments, an individual is at risk of having an ICANS grade of 3 or 4 if their gut microbiome contains one or more of the following microorganisms: [Clostridium] lavalense species; Cuneatibacter genus; Clostridiales vadin BB60 group family; Clostridiales vadin BB60 group genus; Clostridiales vadin BB60 group ge unclass species; [Clostridium] hylemonae species; Anaerotruncus rubiinfantis species; Ruminococcaceae UCG 004 species; Eisenbergiella massiliensis species; Hydrogenoanaerobacterium genus; Ruminococcaceae UCG 008 species; Intestinibacillus massiliensis species; Raoultibacter genus; Monoglobus pectinilyticus species; Bacillaceae family; Pseudomonas aeruginosa species; Bacillus hisashii species; Caecibacter massiliensis species; and Prevotella multisaccharivorax species. In certain embodiments, if the gut microbiome has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more microorganisms, the individual is at risk for ICANS grade 3 or 4. In at least some cases, if the gut microbiome has at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95%, or more than 95% of the aforementioned microorganisms, the individual is at risk for ICANS grade 3 or 4.

[0165] If an individual is determined to have ICANS grade 3 or 4 based on the gut microbiome, the individual may or may not receive CAR T cell therapy. If the individual still receives CAR T cell therapy despite having one or more of the aforementioned microorganisms, the CAR T cell therapy may be administered at a different (e.g., lower) dose and / or modified to overcome the risk of having ICANS. For example, the target antigen of the CAR may be changed; additional or different costimulatory domains may be utilized in the CAR; additional CARs that target additional target antigens in the cells may be utilized; one or more cytokines may be avoided in the CAR T cell therapy, etc.

[0166] In some embodiments, the gut microbiome of an individual is analyzed to determine that the individual has an ICANS grade of 0, 1, or 2, or is at risk of having an ICANS grade of 0, 1, or 2, compared to an individual who does not have the corresponding one or more microorganisms. In certain embodiments, the gut microbiome of an individual has one or more of the following: Corynebacterium genus; Lactobacillus sakei species; Veillonella dispar species; Streptococcus salivarius species; Coprococcus eutactus species. In some cases, the gut microbiome has most or all of the aforementioned list. An individual may have 1, 2, 3, 4, 5 microorganisms from the aforementioned list.

[0167] In certain embodiments, the individual after this determination is administered a therapeutically effective amount of CAR T cell therapy. In some cases, the CAR T cell therapy may be administered at a different (e.g., lower) dose to further reduce the risk of ICANS and / or may be modified to allow the individual to overcome the risk of having ICANS. For example, the target antigen of the CAR may be changed; additional or different co-stimulatory domains may be utilized in the CAR; additional CARs that target additional target antigens may be utilized in the cells; one or more cytokines may be avoided in the CAR T cell therapy, etc. The individual may be administered one or more probiotic compositions or one or more fecal transplants that include one or more microbes that overcome the deficiencies in the individual's gut microbiome.

[0168] Below are specific species from the orders, families, and genera mentioned in the ICANS risk list above.

[0169] In the genus Cuneatibacter, the representative species is C. caecimuris.

[0170] In the genus Hydrogenoanaerobacterium, a representative species is Hydrogenoanaerobacterium saccharovorans.

[0171] In the genus Raoultibacter, representative species include Raoultibacter timonensis and Raoultibacter massiliensis.

[0172] In the Bacillaceae family, representative genera are Aeribacillus; Aliibacillus; Alkalibacillus; Alkalicoccus; Alkalilactibacillus; Allobacillus; Alteribacillus; Amphibacillus; Amylobacillus; Anaerobacillus; Anoxybacillus; Aquibacillus; Aquisalibacillus; Aureibacillus; Bacillus; Caldalkalibacillus; Caldibacillus; Calditerricola; Cerasibacillus; Compostibacillus; Desertibacillus; Domibacillus; Edaphobacillus; Falsibacillus; Fermentibacillus; Fictibacillus; Filobacillus; Geobacillus; Geomicrobium; Gracilibacillus; Halalkalibacillus; Halobacillus; Halolactibacillus; Hydrogenibacillus; Lentibacillus; Lysinibacillus; Marinococcus; Massilibacterium; Melghiribacillus; Microaerobacter; Natribacillus; Natronobacillus; Numidum; Oceanobacillus; Ornithinibacillus; Parageobacillus; Paraliobacillus; Paralkalibacillus; Paucisalibacillus; Pelagirhabdus; Piscibacillus; Polygonibacillus; Pontibacillus; Pradoshia; Pseudobacillus; Pseudogracilibacillus; Psychrobacillus; Pueribacillus; Quasibacillus; Rubeoparvulum; Saccharococcus;Salibacterium; Salimicrobium; Salinibacillus; Salipaludibacillus; Salirhabdus; Salisediminibacterium; Saliterribacillus; Salsuginibacillus; Sediminibacillus; Thalassobacillus; Thalassorhabdus; Thermolongibacillus; Virgibacillus; and Vulcanibacillus. ;

[0173] In the genus Aeribacillus, a representative species is A. pallidus.

[0174] In the genus Aliibacillus, a representative species is Aliibacillus thermotolerans.

[0175] In the genus Alkalibacillus, representative species include A. almallahensis; A. filiformis; A. flavidus; A. haloalkaliphilus; A. halophilus; A. salilacus; and A. silvisoli.

[0176] In the genus Alkalilactibacillus, a representative species is Alkalilactibacillus ikkensis.

[0177] In the genus Alkalicoccus, representative species include Alkalicoccus saliphilus and Alkalicoccus halolimnae.

[0178] In the genus Allobacillus, a representative species is A. halotolerans.

[0179] In the genus Alteribacillus, representative species include A. alkaliphilus; A. bidgolensis; A. iranensis; and A. persepolensis.

[0180] In the genus Amphibacillus, representative species include A. cookii; A. fermentum; A. iburiensis; A. indicireducens; A. jilinensis; A. marinus; A. sediminis; A. tropicus; and A. xylanus.

[0181] In the genus Amylobacillus, a representative species is A. thermophiles.

[0182] In the genus Anaerobacillus, representative species include A. alkalidiazotrophicus; A. alkalilacustris; and A. arseniciselenatis.

[0183] In the genus Anoxybacillus, A. amylolyticus; A. ayderensis; A. bogrovensis; A. caldiproteolyticus; A. calidus; A. contaminans; A. eryuanensis; A. flavithermus; A. gonensis; A. kamchatkensis; pushchinoensis; A. rupiensis; A. salavatliensis; A. tengchongensis; A. tepidamans; A. thermarum; A. vitaminiphilus; and voinovskiensis.

[0184] In the genus Aquibacillus, representative species include A. albus; A. halophilus; A. koreensis; and A. salifodinae.

[0185] In the genus Aquisalibacillus, a representative species is A. elongates.

[0186] In the genus Aureibacillus, a representative species is Aureibacillus halotolerans.

[0187] In the genus Caldalkalibacillus, representative species include C. thermarum and C. uzonensis.

[0188] In the genus Caldibacillus, a representative species is C. debilis.

[0189] In the genus Calditerricola, representative species include C. satsumensis and C. yamamurae.

[0190] In the genus Cerasibacillus, a representative species is C. quisquiliarum.

[0191] In the genus Compostibacillus, a representative species is C. humi.

[0192] In the genus Desertibacillus, a representative species is Desertibacillus haloalkaliphilus.

[0193] In the genus Domibacillus, representative species include D. antri; D. enclensis; D. indicus; D. iocasae; D. robiginosus; and D. tundra.

[0194] In the genus Edaphobacillus, a representative species is E. lindanitolerans.

[0195] In the genus Falsibacillus, a representative species is F. pallidus.

[0196] In the genus Fermentibacillus, a representative species is F. polygoni.

[0197] In the genus Fictibacillus, representative species include F. arsenicus; F. barbaricus; F. enclensis; F. gelatini; F. halophilus; F. acauensis; F. nanhaiensis; F. phosphorivorans; F. rigui; and F. solisalsi.

[0198] In the genus Filobacillus, a representative species is F. milensis.

[0199] In the genus Geobacillus, representative species include G. caldoxylosilyticus; G. galactosidasius; G. icigianus; G. jurassicus; G. kaustophilus; G. lituanicus; G. stearothermophilus; G. subterraneus; G. thermantarcticus; G. thermocatenulatus; G. thermodenitrificans; G. thermoglucosidasius; G. thermoleovorans; G. toebii; G.uzenensis; and G. vulcani.

[0200] Representative species in the genus Geomicrobium include Geomicrobium halophilum and Geomicrobium sediminis.

[0201] In the genus Gracilibacillus, representative species include G. alcaliphilus; G. boraciitolerans; G. bigeumensis; G. dipsosauri; G. halophilus; G. halotolerans; G. kekensis; G. lacisalsi; G. massiliensis; G. orientalis; G. quinghaiensis; G. saliphilus; G. thailandensis; and G. ureilyticus.

[0202] In the genus Halalkalibacillus, a representative species is H. halophilus.

[0203] In the genus Halobacillus, the representative species are H. aidingensis; H. alkaliphilus; H. andaensis; H. campisalis; H. dabanensis; H. faecis; H. halophilus; H. karajensis; H. kuroshimensis; H. litoralis; H. locisalis; salsuginis; H. seohaensis; H. trueperi; and H. yeomjeoni.

[0204] In the genus Halolactibacillus, representative species include H. alkaliphilus; H. halophilus; and H. miurensis.

[0205] In the genus Hydrogenibacillus, a representative species is H. schlegelii.

[0206] In the genus Lentibacillus, representative species include L. garicola; L. halodurans; L. halophilus; L. jeotgali; L. juripiscarius; L. kapialis; L. lacisalsi; L. persicus; L. salaries; L. salicampi; L. salinarum; and L. salis.

[0207] In the genus Lysinibacillus, representative species include L. sphaericus and L. fusiformis.

[0208] In the genus Marinococcus, representative species are M. halophilus; M. halotolerans; M. luteus; M. salis; and M. tarijensis.

[0209] In the genus Massilibacterium, a representative species is Massilibacterium senegalense.

[0210] In the genus Melghiribacillus, a representative species is M. thermohalophilus.

[0211] In the genus Microaerobacter, the representative species is M. geothermalis.

[0212] In the genus Natribacillus, a representative species is N. halophilus.

[0213] In the genus Natronobacillus, a representative species is N. azotifigens.

[0214] In the genus Numidum, the representative species is Numidum massiliense.

[0215] In the genus Oceanobacillus, O. arenosus; O. bengalensis; O. caeni; O. chironomi; O. chungangensis; O. damuensis; O. iheyensis; O. indicireducens; O. kapialis; pacificus; O. picturae; O. polygoni; O. profundus; O. rekensis; and O. sojae.

[0216] In the genus Ornithinibacillus, representative species include O. bavariensis; O. californiensis; O. contaminans; O. halophilus; O. heyuanensis; and O. scapharcae.

[0217] In the genus Parageobacillus, representative species include Parageobacillus caldoxylosilyticus; Parageobacillus genomospecies 1; Parageobacillus thermantarcticus; Parageobacillus thermoglucosidasius; and Parageobacillus toebii.

[0218] In the genus Paraliobacillus, representative species include P. quinghaiensis; P. ryukyuensis; and P. sediminis.

[0219] A representative species of the genus Paralkalibacillus is Paralkalibacillus indicireducens.

[0220] In the genus Paucisalibacillus, representative species include P. algeriensis and P. globulus.

[0221] In the genus Pelagirhabdus, representative species include P. alkalitolerans and P. fermentum.

[0222] In the genus Piscibacillus, representative species include P. halophilus and P. salipiscarius.

[0223] In the genus Polygonibacillus, a representative species is P. indicireducens.

[0224] In the genus Pontiabacillus, representative species include P. chungwhensis; P. halophilus; P. litoralis; P. marinus; P. salicampi; P. salipaludis; and P. yanchengensis.

[0225] In the genus Pradoshia, the representative species is Pradoshia eiseniae.

[0226] In the genus Pseudobacillus, a representative species is Pseudobacillus badius.

[0227] In the genus Pseudogracilibacillus, representative species include P. marinus; P. endophyticus; and P. auburnensis.

[0228] In the genus Psychrobacillus, representative species include P. insolitus; P. psychrodurans; P. psychrotolerans; and P. soli.

[0229] In the genus Pueribacillus, a representative species is Pueribacillus theae.

[0230] In the genus Quasibacillus, a representative species is Quasibacillus thermotolerans.

[0231] In the genus Rubeoparvulum, the representative species is Rubeoparvulum massiliense.

[0232] In the genus Saccharococcus, a representative species is S. thermophiles.

[0233] In the genus Salibacterium, representative species include S. halochares; S. halotolerans; S. qingdaonense; and S. lacus.

[0234] In the genus Salimicrobium, representative species include S. album; S. flavidum; S. halophilum; S. jeotgali; S. luteum; and S. salexigens.

[0235] In the genus Salinibacillus, representative species include S. aidingensis; S. kushneri; and S. xinjiangensis.

[0236] In the genus Salipaludibacillus, representative species include S. agaradhaerens; S. aurantiacus; and S. neizhouensis.

[0237] In the genus Salirhabdus, representative species include S. euzebyi and S. salicampi.

[0238] In the genus Salisediminibacterium, representative species include S. haloalkalitolerans; S. halotolerans; and S. locisalis.

[0239] In the genus Saliterribacillus, a representative species is S. persicus.

[0240] In the genus Salsuginibacillus, representative species include S. halophilus and S. kocurii.

[0241] In the genus Sediminibacillus, representative species include S. albus; S. halophilus; and S. massiliensis.

[0242] In the genus Sinibacillus, a representative species is S. soli.

[0243] In the genus Streptohalobacillus, a representative species is S. salinus.

[0244] In the genus Swionibacillus, a representative species is Swionibacillus sediminis.

[0245] Representative species of the genus Tenuibacillus include Tenuibacillus multivorans and Tenuibacillus halotolerans.

[0246] In the genus Tepidibacillus, representative species include T. decaturensis; T. fermentans; and T. infernus.

[0247] In the genus Terribacillus, representative species include T. aidingensis; T. goriensis; T. halophilus; and T. saccharophilus.

[0248] In the genus Terrilactibacillus, a representative species is T. laevilacticus.

[0249] In the genus Texcoconibacillus, a representative species is T. texcoconensis.

[0250] In the genus Thalassobacillus, representative species include T. cyri; T. devorans; T. hwangdonensis; and T. pellis.

[0251] In the genus Thalassorhabdus, the representative species is Thalassorhabdus alkalitolerans.

[0252] In the genus Thermolongibacillus, representative species include T. altinsuensis and T. kozakliensis.

[0253] In the genus Virgibacillus, V. alimentarius; V. arcticus; V. byunsanensis; V. campisalis; V. carmonensis; V. chiguensis; V. dokdonensis; V. flavescens; V. halodenitrificans; V. natechei; V. necropolis; V. oceani; V. olivae; V. pantothenticus; V. phasianinus; V. picturae; V. profundi; V. proomii; V. salaries; xinjiangensis.

[0254] In the genus Vulcanibacillus, a representative species is V. modesticaldus.

[0255] In the genus Corynebacterium, representative species are Corynebacterium accolens; Corynebacterium acetoacidophilum; Corynebacterium afermentans; Corynebacterium alimapuense; Corynebacterium alkanolyticum; Corynebacterium ammoniagenes; Corynebacterium amycolatum; Corynebacterium appendicis; Corynebacterium aquatimens; Corynebacterium aquilae; Corynebacterium argentoratense; Corynebacterium atrinae; Corynebacterium atypicum; Corynebacterium aurimucosum; Corynebacterium auris; Corynebacterium auriscanis; Corynebacterium bouchesdurhonense; Corynebacterium bovis; Corynebacterium callunae; Corynebacterium camporealensis; Corynebacterium canis; Corynebacterium capitovis; Corynebacterium casei; Corynebacterium caspium; Corynebacterium cervicis; Corynebacterium choanis; Corynebacterium ciconiae; Corynebacterium confusum; Corynebacterium coyleae; Corynebacterium crenatum; Corynebacterium crudilactis; Corynebacterium cyclohexanicum; Corynebacterium cystitidis; Corynebacterium defluvii; Corynebacterium deserti;Corynebacterium diphtheria; Corynebacterium doosanense; Corynebacterium durum; Corynebacterium efficiens; Corynebacterium epidermidicanis; Corynebacterium faecale; Corynebacterium falsenii; Corynebacterium fastidiosum; Corynebacterium felinum; Corynebacterium flavescens; Corynebacterium fournierii; Corynebacterium frankenforstense; Corynebacterium freiburgense; Corynebacterium freneyi; Corynebacterium genitalium; Corynebacterium geronticis; Corynebacterium glaucum; Corynebacterium glucuronolyticum; Corynebacterium glutamicum; Corynebacterium glyciniphilum; Corynebacterium godavarianum; Corynebacterium gottingense; Corynebacterium guangdongense; Corynebacterium hadale; Corynebacterium halotolerans; Corynebacterium hansenii; Corynebacterium heidelbergense; Corynebacterium humireducens; Corynebacterium ihumii; Corynebacterium imitans; Corynebacterium jeddahense; Corynebacterium jeikeium; Corynebacterium kefirresidentii; Corynebacterium kroppenstedtii; Corynebacterium kutscheri;Corynebacterium lactis; Corynebacterium lipophiloflavum; Corynebacterium lowii; Corynebacterium lubricantis; Corynebacterium macginleyi; Corynebacterium marinum; Corynebacterium maris; Corynebacterium massiliense; Corynebacterium mastitidis; Corynebacterium matruchotii; Corynebacterium melassecola; Corynebacterium minutissimum; Corynebacterium mucifaciens; Corynebacterium mustelae; Corynebacterium mycetoides; Corynebacterium nasicanis; Corynebacterium nephridii; Corynebacterium nuruki; Corynebacterium oculi; Corynebacterium otitidis; Corynebacterium pekinense; Corynebacterium pelargi; Corynebacterium phocae; Corynebacterium phoceense; Corynebacterium pilbarense; Corynebacterium pilosum; Corynebacterium pollutisoli; Corynebacterium propinquum; Corynebacterium provencense; Corynebacterium pseudodiphtheriticum; Corynebacterium pseudogenitalium; Corynebacterium pseudopelargi; Corynebacterium pseudotuberculosis; Corynebacterium pyruviciproducens; Corynebacterium renale;Corynebacterium resistens; Corynebacterium riegelii; Corynebacterium sanguinis; Corynebacterium segmentosum; Corynebacterium simulans; Corynebacterium singular; Corynebacterium sphenisci; Corynebacterium spheniscorum; Corynebacterium sputi; Corynebacterium stationis; Corynebacterium striatum; Corynebacterium suicordis; Corynebacterium sundsvallense; Corynebacterium tapiri; Corynebacterium terpenotabidum; Corynebacterium testudinoris; Corynebacterium thermoaminogenes; Corynebacterium thomssenii; Corynebacterium timonense; Corynebacterium tracheae; Corynebacterium tuberculostearicum; Corynebacterium tuscaniense; Corynebacterium ulcerans; Corynebacterium ulceribovis; Corynebacterium urealyticum; Corynebacterium ureicelerivorans; Corynebacterium urinapleomorphum; Corynebacterium uropygiale; Corynebacterium uterequi; Corynebacterium variabile; Corynebacterium vitaeruminis; and Corynebacterium xerosis.

[0256] (B. Example of the composition of the disclosure) (1) Embodiments of the present disclosure include fecal transplants to individuals in need of adoptive cell therapy but with an inadequate gut microbiome that poses a lack of efficacy and / or a risk of toxicity to the individual.

[0257] In certain embodiments, the gut microbiome of an individual who is not in need of CAR T cell therapy is a donor for fecal transplantation to an individual who is in need of CAR T cell therapy. In such cases, the donor individual who is not in need of CAR T cell therapy is screened to determine whether its gut microbiome has a suitable composition based on the parameters contained herein. That is, the individual does not need adoptive cell therapy itself, but the gut microbiome of the individual may be of a suitable composition (based on the parameters contained herein) to be a donor. An effective amount of feces from this individual can be transplanted to an individual who is in need of CAR T cell therapy. In certain embodiments, the feces of this individual (or a combination of other suitable donor individuals) can be stored in a ready-made manner so that it can be used later by the individual in need. In other cases, it is not stored before use.

[0258] Fecal transplants are performed by colonoscopy or nasoduodenal tube feeding. During colonoscopy, a colonoscope is advanced through the entire colon. As the colonoscope is withdrawn, the fecal transplant composition is delivered through the colonoscope into the colon. Methods for preparing fecal transplants are known in the art, such as U.S. Pat. No. 10,736,849.

[0259] In certain embodiments, one or more customized fecal transplant compositions are included herein. The composition of one or more fecal transplant compositions may or may not be adjusted to address the deficiencies of the individual's gut microbiome or to enhance the individual's gut microbiome. In some cases, the fecal transplant is considered to be off-the-shelf and includes one or more standard microorganisms for enhancing any type of immunotherapy, including CAR T cell therapy. Such fecal transplants can be administered to an individual without prior analysis of the gut microbiome. In certain embodiments, the fecal transplant composition is adjusted to the specific deficiencies of the individual's gut microbiome. In some cases, such customized fecal transplants may or may not include all of the microorganisms that are considered to be deficient in the individual.

[0260] 2. Probiotic Compositions In certain embodiments, one or more probiotic compositions are included herein. The composition of one or more probiotic compositions may or may not be adjusted to address any deficiency in the gut microbiome of an individual or to enhance the gut microbiome of an individual. In some cases, probiotics are considered to be off-the-shelf and include one or more standard microorganisms for enhancing any type of immunotherapy, including CAR T cell therapy. Such probiotics can be administered to an individual without prior analysis of the gut microbiome. Probiotics may include any one or more microorganisms listed herein as being associated with effective CAR T cell therapy and / or not associated with toxicity.

[0261] In certain embodiments, the probiotic composition is tailored to a particular deficiency in an individual's gut microbiome. In some cases, such customized probiotics may or may not include all of the microorganisms believed to be deficient in the individual.

[0262] An individual may be administered one or more probiotic compositions comprising one or more microorganisms that overcome deficiencies in the individual's gut microbiome. The probiotics may be administered to enhance CAR T cell therapy and / or to reduce toxicity of CAR T cell therapy to the individual.

[0263] In certain embodiments, probiotics include live microorganisms that, when administered in appropriate amounts, can enhance CAR T cell therapy and / or reduce the toxicity of CAR T cell therapy to an individual. Probiotics are available in foods and dietary supplements, including, but not limited to, capsules, tablets, and powders. Non-limiting examples of foods that contain probiotics include dairy products, such as yogurt, fermented milk, unfermented milk, smoothies, butter, cream, hummus, kombucha, salad dressings, miso, tempeh, nutritional bars, some juices and soy drinks, and the like.

[0264] When multiple microorganisms are included in probiotics, the ratio of multiple microorganisms may be substantially the same or not.For example, in some cases, two specific microorganisms in a composition may be in a ratio of 1:1, 1:2, 1:5, 1:10, 1:20, 1:50, 1:100, etc. In one embodiment, a probiotic composition comprises bacteria from at least two different bacterial species disclosed herein.In a given composition, different bacterial strains may be contained in equal amounts (equal combination) or in various ratios (unequal combination) required to achieve maximum biological activity. For example, in a bacterial composition having two bacterial strains, the strains may be present in a ratio of 1:10,000 to 1:1, a ratio of 1:10,000 to 1:1,000, a ratio of 1:1,000 to 1:100, a ratio of 1:100 to 1:50, a ratio of 1:50 to 1:20, a ratio of 1:20 to 1:10, a ratio of 1:10 to 1:1. In the case of a bacterial composition comprising at least three bacterial strains, the ratio of the strains may be selected pairwise from the ratios of the bacterial composition having two strains. For example, in a bacterial composition comprising bacterial strains A, B, and C, at least one of the ratio between strain A and strain B, the ratio between strain B and strain C, and the ratio between strain A and strain C may be independently selected from the above pairwise combinations. In one particular embodiment, the present invention encompasses administering two or more bacteria-containing compositions to the same subject. Such compositions may be administered simultaneously or sequentially.

[0265] Probiotic compositions of the present disclosure may include, but are not limited to, for example, live bacterial cells, conditionally lethal bacterial cells, inactivated bacterial cells, killed bacterial cells, spores (e.g., germination competent spores), recombinant carrier strains, cell extracts, and bacterial derived products (e.g., natural or synthetic bacterial derived products such as bacterial antigens or bacterial metabolic products). In a particular embodiment, the probiotic composition includes an excipient or carrier that optimizes the seeding of one or more bacterial strains included in the probiotic composition.

[0266] In one embodiment of any of the methods involving administration of a probiotic composition, the probiotic composition is reconstituted from a lyophilized preparation. In one embodiment of any of the methods involving administration of a probiotic composition, the probiotic composition includes a buffer to adjust the pH to an appropriate value, for example 7.0.

[0267] The bacterial strains administered in the probiotic composition according to the method of the present disclosure may comprise live bacteria. One or several different bacterial inocula may be administered simultaneously or sequentially (including at different times). Such bacteria may be isolated from the gastrointestinal (GI) microbiota and grown in culture. The present disclosure also includes administering "bacterial analogs" such as recombinant carrier strains expressing one or more heterologous genes from related bacterial species. The use of such recombinant bacteria may allow the use of smaller therapeutic doses due to higher protein expression.

[0268] In one embodiment of any of the above methods involving administration of a probiotic composition, the probiotic composition comprises (i) a carrier and / or excipient, and / or (ii) one or more prebiotic agents that stimulate the growth and / or activity of one or more bacteria present in the composition. In a particular embodiment, the probiotic composition comprises an excipient or carrier that optimizes the inoculation of one or more bacterial strains included in the probiotic composition.

[0269] In one embodiment of any of the above methods including administration of a probiotic composition, the probiotic composition is delivered directly or indirectly to the subject's digestive tract. In one embodiment, the probiotic composition is administered to the subject by a route selected from the group consisting of oral, topical, rectal (e.g., fecal microbiota transplant (FMT), enema), mucosal, sublingual, nasal, and naso-orogastric tube. In one embodiment, the probiotic composition is delivered to the subject in the form of a liquid, foam, cream, spray, powder, or gel. In one embodiment, the probiotic composition comprises a buffer (e.g., sodium bicarbonate), infant formula or sterile human milk, or other agents that allow the bacteria to survive and grow (e.g., survive in the acidic environment of the stomach and grow in the intestine), as well as preservatives, stabilizers, binders, compression agents, lubricants, dispersion enhancers, disintegrants, antioxidants, flavoring agents, sweetening agents, and coloring agents.

[0270] In one embodiment of any of the above methods including administration of a probiotic composition, the probiotic composition is administered together with a prebiotic that stimulates the growth and / or activity of the bacteria contained in the probiotic composition.Non-limiting examples of useful prebiotics include, for example, fructooligosaccharides (FOS), galactooligosaccharides (GOS), human milk oligosaccharides (HMO), lacto-N-neotetraose, D-tagatose, xylooligosaccharides (XOS), arabinoxylan oligosaccharides (AXOS), N-acetylglucosamine, N-acetylgalactosamine, glucose, arabinose, maltose, lactose, sucrose, cellobiose, amino acids, alcohol, resistant starch (RS), and any mixture thereof.In a particular embodiment, the probiotics and prebiotics are administered in one composition, or administered simultaneously as two separate compositions, or administered sequentially.

[0271] In some embodiments, the dosage for an individual includes a predetermined amount of microorganisms calculated in an amount sufficient to produce the desired effect. The actual form of administration depends on the particular bacteria employed and the effect to be achieved. The composition containing the desired microorganisms can be administered alone or in combination with one or more additional probiotic agents, nutritional supplements, or therapeutic agents. Administration "in combination with" one or more additional probiotic agents, nutritional supplements, or therapeutic agents includes both simultaneous (concurrent) administration and sequential administration in any order. Administration can be chronic or intermittent, as deemed appropriate by the supervising practitioner, such as taking into account changes in undesirable side effects.

[0272] The composition can be formulated for storage and / or transportation, for example, as a flash-frozen, dried or lyophilized frozen composition. Additionally, the composition can be administered alone or in combination with a carrier, such as a pharma- ceutically acceptable carrier or a biocompatible scaffold. The compositions of the present disclosure can be conventionally administered rectally as a suppository, parenterally, or by injection, for example, intravenously, subcutaneously, or intramuscularly. Additional formulations suitable for other modes of administration include oral formulations. Oral formulations include commonly used excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suppositories, suspensions, tablets, pills, capsules, sustained-release formulations, or powders, and contain about 10% to about 95%, preferably about 25% to about 70%, of the active ingredient.

[0273] Typically, the compositions are administered in a manner compatible with the dosage formulation, and in an amount that will be therapeutically effective for the individual being treated. The dosage will depend on the individual being treated. The exact amount of the composition to be administered will depend on the judgment of the skilled artisan. Suitable dosage regimes for initial and booster administrations are also various, but typically represent an initial administration followed by subsequent administrations.

[0274] In many embodiments, it may be desirable to administer multiple doses of the composition, at most or at least about 3, 4, 5, 6, 7, 8, 9, 10 days or more. In certain cases, administration occurs before, during, and / or after CAR T cell therapy. Administration usually occurs at intervals of 2 days to 12 weeks, more usually at intervals of 1 week to 2 weeks. It may also be desirable to administer boosters periodically at certain intervals to maintain the status of the immune system.

[0275] Probiotics are pharma- ceutically acceptable or pharmacologically acceptable. The phrases "pharmacologically acceptable" or "pharmacologically acceptable" refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans. As used herein, "pharmaceutically acceptable carriers" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the immunogenic or therapeutic compositions is contemplated.

[0276] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of undesirable microbial action can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonicity agents, for example, sugars and sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0277] The effective amount of the probiotic composition can be determined based on the intended purpose. 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 the composition calculated to produce the desired response as described above in connection with its administration, i.e., the appropriate route and regimen. The amount administered depends on the desired outcome and / or protection, both according to the number of treatments and the unit dose. The precise amount of the composition also depends on the judgment of the practitioner and is peculiar to each individual. Factors influencing the dosage include the physical and clinical condition of the subject, the route of administration, the intended therapeutic goal (alleviation of symptoms versus cure), and the potency, stability, and toxicity of the particular composition. The formulated solution is administered in a manner compatible with the dosage form and in a therapeutically or prophylactically effective amount. The formulation is easily administered in a variety of dosage forms, such as the above-mentioned injection solutions.

[0278] (3. Adoptive Cell Therapy and Chimeric Antigen Receptors) In certain embodiments of the present disclosure, an individual is in need of adoptive cell therapy, including CAR T cell therapy. In certain embodiments, the individual has cancer and is in need of adoptive cell therapy that targets one or more antigens on cancer cells in the individual's body. The individual is subject to gut microbiome analysis as part of routine health care, and such analysis is applied to cancer treatment as needed, or the individual is subject to gut microbiome analysis after cancer diagnosis and treatment is required. The individual may be screened for suitability for adoptive cell therapy by screening the composition of the gut microbiome. In some cases, the analysis of the individual's gut microbiome provides a determination of treatment outcome, including whether the individual can receive adoptive cell therapy with or without therapeutic intervention, at least in some cases. For example, the analysis of the gut microbiome determines whether adoptive cell therapy is effective for the individual. If the adoptive cell therapy is deemed toxic and / or ineffective to the individual, the adoptive cell therapy may be omitted from the individual, modified for the individual, or one or more additional agents may be included in the treatment regimen to enhance and / or make the adoptive cell therapy safer.

[0279] In certain embodiments, the gut microbiome is analyzed for suitability for adoptive cell transfer therapy with specific immune cells expressing one or more engineered antigen receptors. In certain cases, the immune cells are T cells, NK cells, NKT cells, γδT cells, macrophages, B cells, or mixtures thereof.

[0280] While the adoptive cell therapy can be of any type, in specific embodiments, the adoptive cell therapy includes a plurality of immune cells that are engineered, for example, because they are engineered to express one or more non-natural artificial antigen receptors. The engineered antigen receptor can be one or more chimeric antigen receptors (CARs), one or more engineered T cell receptors, or both, but in specific embodiments, the engineered antigen receptor includes a CAR that is engineered to include an antigen binding domain (such as an scFv) that targets a specific cancer antigen on the individual's cancer cells. That is, in specific embodiments, the CAR is specifically tailored or selected to target an antigen on the individual's cancer cells. In specific embodiments, the CAR includes two or more antigen binding domains that allow it to target two or more corresponding cancer antigens.

[0281] In some embodiments, the CAR comprises a) one or more intracellular signaling domains, b) a transmembrane domain, and c) an extracellular domain comprising one or more antigen binding regions. In some embodiments, the CAR comprises a transmembrane domain and one or more costimulatory domains, such as one or more of CD28, CD27, OX-40 (CD134), DAP10, DAP12, and 4-1BB (CD137). The CAR may also comprise CD3zeta in certain embodiments.

[0282] In some embodiments, the CAR is constructed to have specificity for a particular antigen (or marker, ligand), such as an antigen expressed on a particular cell type targeted in adoptive therapy, e.g., a cancer marker. Thus, the CAR typically comprises one or more antigen-binding molecules, such as one or more antigen-binding fragments, domains, or portions, or one or more antibody variable domains, and / or antibody molecules, in its extracellular portion. In some embodiments, the CAR comprises an antigen-binding portion or portion of an antibody molecule, such as a single-chain antibody fragment (scFv) derived from the variable heavy (VH) and variable light (VL) chains of a monoclonal antibody (mAb). Any suitable antigen can be targeted in the present method. An antigen may, in some cases, be associated with certain cancer cells but not with non-cancerous cells. Exemplary antigens include, but are not limited to, tumor / cancer-associated antigens, tumor neoantigens, antigenic molecules of infectious agents, or self / autoantigens.

[0283] In alternative embodiments, the adoptive cell therapy involves an engineered antigen receptor that is not a CAR, but instead is a non-natural T cell receptor. Thus, in some embodiments, the engineered heterologous antigen receptor includes a recombinant TCR and / or a TCR cloned from a naturally occurring T cell. "T cell receptor" or "TCR" refers to a molecule that includes variable α and β chains (also known as TCRα and TCRβ, respectively), or variable γ and δ chains (also known as TCRγ and TCRδ, respectively), and can specifically bind to an antigenic peptide bound to an MHC receptor. In some embodiments, the TCR is of the αβ type.

[0284] In some embodiments, the TCR chain can include a transmembrane domain. In some embodiments, the transmembrane domain is positively charged. In some cases, the TCR chain includes a cytoplasmic tail. In some cases, this structure allows the TCR to associate with other molecules, such as CD3. For example, a TCR that includes a constant domain with a transmembrane region can anchor the protein to the cell membrane and associate with the invariant subunit of the CD3 signaling apparatus or complex. In some embodiments, the TCR can be a heterodimer of two chains, α and β (or optionally γ and δ), or a single chain TCR construct. In some embodiments, the TCR is a heterodimer that includes two separate chains (α and β, or γ and δ) linked by disulfide bonds or disulfide bonds, etc.

[0285] In some embodiments, adoptive cell transfer therapies including CAR T cells include one or more safety switches that allow the adoptive cells to be killed if they are toxic to the individual. In certain embodiments, the cells include a vector that includes a suicide gene that allows the adoptive cells to be killed upon delivery of the drug. One example of a suicide gene is EGFRt, which is targeted by the antibody cetuximab. Another example is iCaspase9+ and AP1903. Other suicide switches include the switch HSV-TK and the switch CD20.

[0286] (C. Examples of methods for analyzing the gut microbiome) Analysis of the gut microbiome to determine its contents can be performed by any suitable method. Analysis can begin with collection of a suitable sample, such as stool, tissue biopsy, or a combination thereof. If stool is selected as the sample, the entire stool can be collected and immediately homogenized (e.g., using a blender or tissue homogenizer), the homogenate can be flash frozen in liquid nitrogen or in a dry ice / ethanol slurry, and aliquots can be stored in a percentage of glycerol in a medium suitable for culture. The analysis may or may not be performed by the person who collected the sample. The sample may or may not be stored prior to analysis.

[0287] In certain embodiments, the gut microbiome is analyzed based on shotgun sequencing of microbial nucleic acids, including shotgun metagenomics sequencing, to provide a more detailed read. In certain embodiments, most or substantially all of the genomic DNA of the microorganism is analyzed, rather than specific regions of DNA. However, in certain embodiments, analysis of specific regions of DNA, such as 16S rRNA sequencing, is utilized.

[0288] Other analytical methods can be used alone or in combination with other methods. As an example, for known organisms with well-characterized selective culture conditions, culture can be used as a detection method. Assay panels targeting a set of known microorganisms or their genes can be used. After nucleic acid extraction, stool samples undergo complementary DNA synthesis and are amplified using a mixture of primers specific for a range of organisms. Either genomic DNA or PCR products can then be qualified and quantified, such as by hybridization arrays using fluorescence-based measurements or melt curve analysis. In specific embodiments, quantitative PCR and reverse transcription quantitative PCR can be used.

[0289] In certain embodiments, amplicon analysis is employed, where specific regions of DNA are amplified by orders of magnitude using a variety of methods, including PCR. In certain cases, PCR primers match specific regions, such as the bacterial 16S rRNA. The bacterial 16S rRNA gene has nine hypervariable regions (V1-V9) that display sequence diversity and can be used as a barcode-like method to distinguish many bacterial taxa, including to the species level. In some cases, the sequence is read using a next-generation sequencer. In other cases, rather than using a single gene such as 16S rRNA, shotgun metagenomics is used, where all the DNA in a sample is finely fragmented and the fragments are sequenced, and the sequenced fragments are aligned to provide the information required for microbial identification on a larger scale.

[0290] Specifically, fecal baseline samples were collected from lymphoma patients. Briefly, genomic DNA was isolated using the QIAamp DNA stool mini kit (Qiagen) according to the manufacturer's protocol, modified to include an intensive bead-beat lysis step. The V4 region of the 16S rRNA gene was amplified by PCR from 10 ng of each extracted and purified genomic DNA using 515 forward and 806 reverse primer pairs (Caporaso, JG et al. ISME J. 6, 1621-1624 2012). Amplicon pools were purified with the QIAquick gel extraction kit (Qiagen) and sequenced on an Illumina Miseq sequencer platform using a 2 × 250 bp paired-end protocol. EXAMPLES

[0291] The following examples are included to demonstrate preferred embodiments of the invention. Those skilled in the art should understand that the techniques disclosed in the following examples 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 understand in light of this disclosure that many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the subject matter of this disclosure.

[0292] [Example 1. The gut microbiome as a biomarker predicting outcomes after CAR T cell therapy and how it can be modulated to enhance CAR-T efficacy and reduce toxicity] Baseline stool samples were collected from patients with relapsed / refractory large B-cell lymphoma treated with anti-CD19 CAR-T therapy. All samples were taxonomically profiled using targeted ribosomal 16S RNA gene sequencing of the V4 region, and various microbiome diversity indices were calculated to examine associations with response, survival outcomes, and toxicity.

[0293] Patients with higher microbial diversity, as measured by the inverse Simpson index (ISI), were significantly correlated with progression-free survival and overall survival, as shown in the figure below. Because ongoing response at 3 months was previously shown to be associated with long-term durability (Locke et al, Lancet Oncol 2019), we analyzed differences in baseline gut microbiome markers in patients with or without ongoing complete response (CR) at 3 months after CAR-T infusion. As shown in Figure 1A, patients with ongoing complete response at 3 months had significantly higher ISI compared to those without. We also stratified patients by ISI tertiles to analyze the impact of gut bacterial diversity on progression-free survival (PFS) and overall survival (OS). PFS was significantly higher in patients in the highest tertile of ISI (n=11, median PFS not reached) compared with patients in the intermediate (n=11, median PFS 2.82 months, HR 12.7, 95% CI 3.61-44.77, log-rank, p=0.001) or low (n=11, median PFS 2.43 months, HR 12.9, 95% CI 3.68-45.75, log-rank, p=0.001) ISI (Figure 1B). High ISI also showed a significant positive correlation with OS (Figure 1C).

[0294] The relative abundance of several bacterial families was increased in patients with and without ongoing CR (partial response (PR), stable disease (SD), and progressive disease (PD)). Examples of these species include Falvonifractor, Intestimonas, Lachnoclostridium, and peptoniphilus. A list of bacteria associated with response is shown in Figures 2 and 3.

[0295] As shown in the figures below, there were differences in the microbial composition associated with CAR-T therapy-related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). For example, species Veillonella parvula, genera Lactonifactor, Atopobium, and Ruminococcus are associated with low-grade CRS, as shown in Figures 4 and 5.

[0296] Similarly, a few species of bacteria such as Cuneatibacter, Clostridiales, and Raolutibacter are associated with high grade ICAN, as shown in Figure 6. Figure 7 analyzes various bacteria and shows whether their presence promotes disease progression or not. The five non-effective bacterial groups included Finegoldia magna, Streptococcus anginosus group, Akkermansia muciniphila, Escherichia coli, and Haemophilus parainfluenzae. One bacterium was effective in preventing disease progression: Odribacter splanchnicus.

[0297] In certain embodiments, gut microbiome diversity index is a strong predictor of response durability and survival after CAR T cell therapy. Furthermore, differences in gut bacterial composition and abundance affect the response and toxicity associated with CAR-T therapy. Modulation of gut microbiome may have a significant impact on the efficacy and toxicity of CAR T cell therapy.

[0298] Although the present disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the design as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the processes, machines, manufacture, compositions of matter, means, methods and steps described herein. As will be readily understood by those skilled in the art from the present disclosure, any currently existing or later developed processes, machines, manufacture, compositions of matter, means, methods or steps that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein can be utilized in accordance with the present disclosure. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods or steps.

Claims

1. 1. A method of determining or predicting a response to a therapy in an individual, comprising analyzing a microbial composition from the gut microbiome of the individual: (a) a therapy in said individual is ineffective or at risk of being ineffective compared to a standard or another individual if said individual's gut microbiome comprises, consists of, or consists essentially of one or more microorganisms of the order Bacillales; and / or the species Phascolarctobacterium succinatutens; and / or Finegoldia magna; and / or the Streptococcus anginosus group; and / or Akkermansia muciniphila; and / or Escherichia coli; and / or Haemophilus parainfluenzae; and / or (b) Intestinal microbiota of the individuals mentioned above: Varibaculum spp.; Bifidobacterium animalis spp.; Corynebacterium tuberculostearicum spp.; Dialister succinatiphilus spp.; Porphyromonas asaccharolytica spp.; Porphyromonas endodontalis spp.; Ruminococcaceae ge unclass spp.; Varibaculum cambriense spp.; Murdochiella spp.; Levyella massiliensis spp.; Porphyromonas bennonis spp.; Peptoniphilus lacrimalis spp.; Peptoniphilus harei spp.; Anaerococcus vaginalis spp.; Butyricicoccus pullicaecorum spp.; Prevotella timonensis spp.; Ruminiclostridium 1 spp.; Fenollaria massiliensis spp.; Frisingicoccus caecimuris spp.; Ruminococcaceae UCG 010 genus; Hungateiclostridium cellulolyticum species; Ruminococcaceae UCG 010 unclass species; Prevotella genus; Ezakiella genus; Aminipila butyrica species; Eisenbergiella genus; GCA 900066755 genus; Bacteroides ovatus species; Lachnospiraceae ge genus; Ruminococcaceae unclass genus; Ruminiclostridium 9 genus; Bacteroides cellulosilyticus species; Bacteroides vulgatus species; Alistipes shahii species; Eisenbergiella massiliensis species; GCA 900066225 genus; [Ruminococcus] torques species; Longicatena caecimuris species; Ruminococcaceae UCG 002 genus; Anaerococcus genus; Barnesiella genus;[Clostridium] celerecrescens species; Barnesiella intestinihominis species; Desulfovibrio desulfuricans species; Bacteroidaceae family; Barnesiellaceae family; Bacteroides genus; Bacteroides xylanisolvens species; Dialister propionicifaciens species; Fournierella genus; Genus Porphyromonas; Blautia glucerasea species; Genus GCA 900066575; Genus Lachnoclostridium; Genus Intestinimonas; Species Anaerotignum lactatifermentans; Species Bacteroides thetaiotaomicron; Genus Flavonifractor; plautii genus microorganism, the therapy in said individual is effective or has an increased likelihood of being effective when compared to a standard or another individual;

2. 2. The method of claim 1(a), wherein the individual has cancer and the response to therapy for the individual is a partial response, stable disease, or progressive disease, or is at risk of a partial response, stable disease, or progressive disease.

3. 2. The method of claim 1(b), wherein the individual has cancer and the individual's response to the therapy is a complete response, or an increased likelihood of a complete response.

4. 2. The method of claim 1(b), wherein the individual's gut microbiome comprises Flavonifractor plautii.

5. The method of any one of claims 1 to 4, wherein the therapy comprises immunotherapy.

6. The method of claim 5 , wherein the immunotherapy comprises adoptive cellular therapy.

7. The method of claim 6 , wherein the adoptive cell therapy comprises adoptive T cell therapy.

8. 8. The method of claim 6 or 7, wherein the adoptive cell therapy cells are modified to contain one or more engineered antigen receptors.

9. 9. The method of claim 8, wherein the engineered antigen receptor comprises, or the cell comprises, one or more of, one or more chimeric antigen receptors (CARs) or one or more non-native T cell receptors.

10. The method of any one of claims 6 to 9, wherein the adoptive cell therapy comprises CAR T cell therapy.

11. 2. The method of claim 1(b), further comprising administering a therapeutically effective amount of said therapy to said individual.

12. 2. The method of claim 1 (a), wherein the therapy is a CAR T cell therapy, and the CAR T cell therapy is modified prior to administration to the individual to increase efficacy of the CAR T cell therapy.

13. 13. The method of claim 12, wherein the dose of the CAR T cell therapy is escalated.

14. 14. The method of claim 12 or 13, wherein one or more components of the CAR are altered.

15. The method according to any one of claims 1 to 14, wherein the individual is administered an effective amount of one or more probiotics and / or one or more fecal transplants.

16. Preface: 1 or more probiotechnics and / or 1 or more fecal transplants, Varibaculum spp.; Bifidobacterium animalis spp.; Corynebacterium tuberculostearicum spp.; Dialister succinatiphilus spp.; Porphyromonas asaccharolytica spp.; Porphyromonas endodontalis spp.; Ruminococcaceae ge unclass spp.; Varibaculum cambriense spp.; Murdochiella spp.; Levyella massiliensis spp.; Porphyromonas bennonis spp.; Peptoniphilus lacrimalis spp.; Peptoniphilus harei spp.; Anaerococcus vaginalis spp.; Butyricicoccus pullicaecorum spp.; Prevotella timonensis spp.; Ruminiclostridium 1 spp.; Fenollaria massiliensis; Frisingicoccus caecimuris; Ruminococcaceae UCG 010; Hungateiclostridium cellulolyticum; Ruminococcaceae UCG 010 unclass; Prevotella; Ezakiella; Aminipila butyrica; Eisenbergiella; GCA 900066755; Bacteroides ovatus; Lachnospiraceae ge; Ruminococcaceae unclass; Ruminiclostridium 9; Bacteroides cellulosilyticus; Bacteroides vulgatus; Alistipes shahii; Eisenbergiella massiliensis; GCA 900066225; [Ruminococcus] torques; Longicatena caecimuris; Ruminococcaceae UCG 002; Anaerococcus genus;Genus Barnesiella; [Clostridium] celerecrescens species; Barnesiella intestinihominis species; Desulfovibrio desulfuricans species; Family Bacteroidaceae; Family Barnesiellaceae; Genus Bacteroides; Peptoniphilus sp.; Porphyromonas sp.; Blautia glucerasea sp.; GCA 900066575 sp.; Lachnoclostridium sp.; Intestinimonas sp.; Anaerotignum lactatifermentans sp.; Bacteroides thetaiotaomicron sp.; 16. The method of claim 15, comprising, consisting of, or consisting essentially of one or more microorganisms of the species plautii.

17. 1. A method for determining or predicting toxicity of a therapy in an individual, comprising analyzing a microbial composition from the gut microbiome of said individual: (a) the gut microbiome is selected from the group consisting of Lactobacillus rhamnosus species; Parabacteroides the therapy is toxic, or at risk of being toxic, to the individual compared to a standard or another individual if the therapy comprises, consists of, or consists essentially of one or more microorganisms of the following groups: S. goldsteinii spp.; S. Olsenella uli spp.; S. Fusobacterium varium spp.; S. genus Porphyrobacter; S. Dialister succinatiphilus spp.; S. Faecalitalea cylindroides spp.; S. Porphyrobacter sanguineus spp.; S. Ruminiclostridium 9 unclass spp.; S. family Sphingomonadaceae; S. order Sphingomonadales; and S. Olsenella spp.; and / or (b) The intestinal microbiome is Corynebacterium durum species; Eubacterium sulci species; Ihubacter massiliensis species; Eubacteriaceae family; Bacteroides xylanisolvens species; Ruminococcus 2 genus; Ruminococcus bromii species; Blautia luti species; Turicibacter genus; Turicibacter sanguinis species; [Clostridium] celerecrescens species; Veillonella genus; Roseburia faecis species; Atopobium genus; Lactonifactor genus; Lactonifactor longoviformis species; Atopobium parvulum species; Peptostreptococcaceae family; Veillonella tobetsuensis species; and Veillonella The method of claim 1, wherein the therapy is non-toxic or has an increased likelihood of being non-toxic to the individual when the therapy comprises, consists of, or consists essentially of one or more microorganisms of the parvula species.

18. 18. The method of claim 17, wherein the toxicity comprises cytokine release syndrome (CRS).

19. 20. The method of claim 18, wherein assessing the toxicity is further defined as assessing a grade of toxicity associated with CRS.

20. 1. A method of determining the likelihood that an individual undergoing immunotherapy will have a particular grade of immune effector cell-associated neurotoxicity syndrome (ICANS) toxicity after receiving immunotherapy, comprising analyzing the individual's gut microbiome: (a) the intestinal microbiome is [Clostridium] lavalense species; Cuneatibacter genus; Clostridiales vadin BB60 group family; Clostridiales vadin BB60 group genus; Clostridiales vadin BB60 group ge unclass species; [Clostridium] hylemonae species; Anaerotruncus rubiinfantis species; Eisenbergiella massiliensis species; Hydrogenoanaerobacterium species; Ruminococcaceae UCG 008 species; Intestinibacillus massiliensis species; Raoultibacter species; Monoglobus pectinilyticus species; Bacillaceae family; Pseudomonas aeruginosa species; Bacillus hisashii species; Caecibacter massiliensis species; and Prevotella multisaccharivorax species, the individual is likely to have or is at risk of having ICANS toxicity grade 3 or 4; and / or (b) the individual is likely to have or is at risk of having ICANS toxicity grade 1 or 2 if the gut microbiome comprises, consists of, or consists essentially of one or more of the following species: Corynebacterium genus; Lactobacillus sakei species; Veillonella dispar species; Streptococcus salivarius species; and Coprococcus eutactus species.

21. 21. The method of claim 20(a), wherein after said analysis and prior to delivery to said individual, the immunotherapy is modified to reduce the risk of ICANS.

22. 1. A method of treating cancer in an individual, comprising providing a therapeutically effective amount of an immunotherapy to the individual: (a) The intestinal microbiota of the individuals mentioned above were: Varibaculum spp.; Bifidobacterium animalis spp.; Corynebacterium tuberculostearicum spp.; Dialister succinatiphilus spp.; Porphyromonas asaccharolytica spp.; Porphyromonas endodontalis spp.; Ruminococcaceae ge unclass spp.; Varibaculum cambriense spp.; Murdochiella spp.; Levyella massiliensis spp.; Porphyromonas bennonis spp.; Peptoniphilus lacrimalis spp.; Peptoniphilus harei spp.; Anaerococcus vaginalis spp.; Butyricicoccus pullicaecorum spp.; Prevotella timonensis spp.; Ruminiclostridium 1 spp.; Fenollaria massiliensis spp.; Frisingicoccus caecimuris spp.; Ruminococcaceae UCG 010 genus; Hungateiclostridium cellulolyticum species; Ruminococcaceae UCG 010 unclass species; Prevotella genus; Ezakiella genus; Aminipila butyrica species; Eisenbergiella genus; GCA 900066755 genus; Bacteroides ovatus species; Lachnospiraceae ge genus; Ruminococcaceae unclass genus; Ruminiclostridium 9 genus; Bacteroides cellulosilyticus species; Bacteroides vulgatus species; Alistipes shahii species; Eisenbergiella massiliensis species; GCA 900066225 genus; [Ruminococcus] torques species; Longicatena caecimuris species; Ruminococcaceae UCG 002 genus; Anaerococcus genus; Barnesiella genus;[0023] The present invention relates to a method for treating a bacterial infection comprising the steps of: (a) comprising or consisting essentially of one or more of the following microorganisms: [Clostridium] celerecrescens species; Barnesiella intestinihominis species; Desulfovibrio desulfuricans species; the family Bacteroidaceae; the family Barnesiellaceae; the genus Bacteroides; Bacteroides xylanisolvens species; Dialister propionicifaciens species; the genus Fournierella; the genus Lachnospiraceae unclass; the family Porphyromonadaceae; the genus Peptoniphilus; the genus Porphyromonas; the species Blautia glucerasea; the genus GCA 900066575; the genus Lachnoclostridium; the genus Intestinimonas; the species Anaerotignum lactatifermentans; the species Bacteroides thetaiotaomicron; the genus Flavonifractor; the species Agathobaculum desmolans; and the species Flavonifractor plautii; (b) the individual's gut microbiome is characterized by the presence of: Corynebacterium durum species; Eubacterium sulci species; Ihubacter massiliensis species; the family Eubacteriaceae; Bacteroides xylanisolvens species; the genus Ruminococcus 2; the species Ruminococcus bromii; the species Blautia luti; the genus Turicibacter; the species Turicibacter sanguinis; the species [Clostridium] celerecrescens; the genus Veillonella; the species Roseburia faecis; the genus Atopobium; the genus Lactonifactor; the species Lactonifactor longoviformis; the species Atopobium parvulum; the family Peptostreptococcaceae; the species Veillonella tobetsuensis; and the species Veillonella parvula; and / or (c) the individual's gut microbiome comprises, consists of, or consists essentially of one or more microorganisms of the genus Corynebacterium; Lactobacillus sakei; Veillonella dispar; Streptococcus salivarius; and Coprococcus eutactus.

23. 1. A method for determining a treatment outcome of an individual in need of adoptive cell therapy, comprising analyzing the gut microbiome for microbial diversity therein, wherein if the individual's gut microbiome has high diversity, then the individual is more likely to benefit from adoptive cell therapy compared to individuals lacking high diversity in their gut microbiome.

24. 24. The method of claim 23, wherein the individual is provided with an effective amount of one or more fecal transplants and / or one or more probiotic compositions if the individual has low microbial diversity in their gut microbiome.

25. 25. The method of claim 23 or 24, wherein the diversity of the gut microbiome is determined by the Inverse Simpson Index (ISI).

26. 26. The method of claim 25, wherein the likelihood that the individual will benefit from adoptive cell therapy is increased if the diversity of the individual's gut microbiome is in the highest tertile as determined by ISI.

27. 27. The method of any one of claims 23 to 26, wherein the attribution of one or more microorganisms in the microbiome is determined by shotgun sequencing of the genome of one or more microorganisms.

28. 27. The method of any one of claims 23 to 26, wherein the attribution of one or more microorganisms in the microbiome is determined by directed sequencing of the genome of one or more microorganisms.

29. 30. The method of claim 28, wherein the directed sequencing is sequencing of 16S rRNA of the one or more microorganisms.

30. 30. The method of any one of claims 26-29, wherein the individual is administered an effective amount of adoptive cellular therapy if the individual's gut microbiome diversity is in the highest tertile as determined by ISI.

31. 30. The method of any one of claims 26-29, wherein an effective amount of adoptive cellular therapy is not administered to the individual if the diversity of the individual's gut microbiome is not in the highest tertile as determined by ISI.

32. 30. The method of any one of claims 26-29, wherein the adoptive cell therapy is a CAR T cell therapy, and if the individual's gut microbiome diversity is not in the highest tertile as determined by ISI, then CAR T cell therapy is altered.

33. A probiotic composition and / or fecal transplant composition comprising, consisting of, or consisting essentially of any one or more of (a), (b), (c) and / or (d) microorganisms: (a) Genus Varibaculum; Species Bifidobacterium animalis; Species Corynebacterium tuberculostearicum; Species Dialister succinatiphilus; Species Porphyromonas asaccharolytica; Species Porphyromonas endodontalis; Unclassified genus Ruminococcaceae; Species Varibaculum cambriense; Genus Murdochiella; Species Levyella massiliensis; Species Porphyromonas bennonis; Species Peptoniphilus lacrimalis; Species Peptoniphilus harei; Species Anaerococcus vaginalis; Species Butyricicoccus pullicaecorum; Species Prevotella timonensis; Species Ruminiclostridium 1; Species Fenollaria massiliensis; Species Frisingicoccus caecimuris; Genus Ruminococcaceae UCG 010; Species Hungateiclostridium cellulolyticum; Unclassified species Ruminococcaceae UCG 010; Genus Prevotella; Genus Ezakiella; Species Aminipila butyrica; Genus Eisenbergiella; Genus GCA 900066755; Species Bacteroides ovatus; Genus Lachnospiraceae ge; Unclassified genus Ruminococcaceae; Genus Ruminiclostridium 9; Species Bacteroides cellulosilyticus; Species Bacteroides vulgatus; Species Alistipes shahii; Species Eisenbergiella massiliensis; Genus GCA 900066225; [Ruminococcus] torques; Species Longicatena caecimuris; Genus Ruminococcaceae UCG 002; Genus Anaerococcus; Genus Barnesiella;[Clostridium] celerecrescens; Barnesiella intestinihominis; Desulfovibrio desulfuricans; Bacteroidaceae; Barnesiellaceae; Bacteroides; Bacteroides xylanisolvens; Dialister propionicifaciens; Fournierella; Lachnospiraceae unclass; Porphyromonadaceae; Peptoniphilus; Porphyromonas; Blautia glucerasea; GCA 900066575; Lachnoclostridium; Intestinimonas; Anaerotignum lactatifermentans; Bacteroides thetaiotaomicron; Flavonifractor; Agathobaculum desmolans; and at least one of the species Flavonifractor plautii; (b) Corynebacterium durum species; Eubacterium sulci species; Ihubacter massiliensis species; Eubacteriaceae family; Bacteroides xylanisolvens species; Ruminococcus 2 genera; Ruminococcus bromii species; Blautia luti species; Turicibacter genus; Turicibacter sanguinis species; [Clostridium] celerecrescens species; one or more of the following: Veillonella sp.; Roseburia faecis sp.; Atopobium sp.; Lactonifactor sp.; Lactonifactor longoviformis sp.; Atopobium parvulum sp.; Peptostreptococcaceae family; Veillonella tobetsuensis sp.; (c) one or more of the genus Corynebacterium; Lactobacillus sakei; Veillonella dispar; Streptococcus salivarius; and Coprococcus eutactus; and / or (d) Odoribacter splanchnicus.

34. 1. A method for determining or predicting an individual's response to a therapy, comprising analyzing a microbial composition from the individual's gut microbiome: (a) treatment for said individual will be ineffective or at risk of being ineffective when compared to a standard individual or another individual if said individual's gut microbiome comprises, consists of, or consists essentially of one or more of the following microorganisms: Finegoldia magna; and / or Streptococcus anginosus group; and / or Akkermansia muciniphila; and / or Escherichia coli; and / or Haemophilus parainfluenzae; and / or (b) if the individual's gut microbiome comprises, consists of, or consists essentially of Odoribacter splanchnicus, then a therapy for said individual is effective or has an increased likelihood of being effective compared to a normal individual or another individual.

35. 34. The method of claim 34(a), wherein the individual has cancer and the individual's response to the therapy is, or is at risk of, a partial response, stable disease, or progressive disease.

36. 34(b). The method of claim 34(b), wherein the individual has cancer and the individual's response to the therapy is a complete response or the likelihood of a complete response is increased.

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