Treatment of cancer by manipulation of commensal microflora

Abstract

Provided herein are methods of treatment and/or prevention of cancer by manipulation of commensal microflora. In particular, the amount, identity, presence, and/or ratio of microflora (e.g., gut microflora) in a subject is manipulated to facilitate one or more co-treatments.

We claim: 
     
         1 . A method of treating cancer in a human subject comprising administering to the subject an immune checkpoint inhibitor and a bacterial formulation comprising bacteria of the genera  Bifidobacterium.    
     
     
         2 . The method of  claim 1 , wherein at least 50% of the bacteria in the bacterial formulation are of the genera  Bifidobacterium.    
     
     
         3 . The method of  claim 1 , wherein at least 90% of the bacteria in the bacterial formulation are of the genera  Bifidobacterium.    
     
     
         4 . The method of  claim 1 , wherein the bacteria of the genus  Bifidobacterium  comprise bacteria of the species  Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium catenulatum, Bifidobacterium pseudocatenulatum, Bifidobacterium adolescentis, Bifidobacterium angulatum, Bifidobacterium asteroides, Bifidobacterium boum, Bifidobacterium choerinum, Bifidobacterium coryneforme, Bifidobacterium cuniculi, Bifidobacterium denticolens, Bifidobacterium dentium, Bifidobacterium gallicum, Bifidobacterium gallinarum, Bifidobacterium indicum, Bifidobacterium inopinatum, Bifidobacterium magnum, Bifidobacterium merycicum, Bifidobacterium minimum, Bifidobacterium pseudolongum, Bifidobacterium pullorum, Bifidobacterium psychraerophilum, Bifidobacterium ruminantium, Bifidobacterium saeculare, Bifidobacterium scardovii, Bifidobacterium simiae, Bifidobacterium subtile, Bifidobacterium therammcidophilum, Bifidobacterium thermophilum, Bifidobacterium tsurumiense, Bifidobacterium urinalis  or  Bifidobacterium  sp. 
     
     
         5 . The method of  claim 1 , wherein the bacterial formulation is administered by oral administration or rectal administration. 
     
     
         6 . The method of  claim 5 , wherein the bacterial formulation is administered by oral administration. 
     
     
         7 . The method of  claim 1 , wherein the bacterial formulation comprises at least 5×10 6  CFU of bacteria of the genera  Bifidobacterium.    
     
     
         8 . The method of  claim 1 , wherein the bacterial formulation is administered to the subject in two or more doses. 
     
     
         9 . The method of  claim 9 , wherein the administration of the two or more doses are separated by at least 1 week. 
     
     
         10 . The method of  claim 1 , further comprising administering to the subject an antibiotic prior to the administration of the bacterial formulation. 
     
     
         11 . The method of  claim 10 , wherein the antibiotic is administered to the subject at least 1 day before the bacterial formulation is administered to the subject. 
     
     
         12 . The method of  claim 1 , wherein the immune checkpoint inhibitor is a protein or polypeptide that binds to an immune checkpoint protein. 
     
     
         13 . The method of  claim 12 , wherein the immune checkpoint protein is CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA. 
     
     
         14 . The method of  claim 13 , wherein the immune checkpoint protein is PD-1 or PD-L1. 
     
     
         15 . The method of  claim 1 , wherein the immune checkpoint inhibitor is an antibody or antigen binding fragment thereof that binds to an immune checkpoint protein. 
     
     
         16 . The method of  claim 15 , wherein the immune checkpoint protein is CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA. 
     
     
         17 . The method of  claim 16 , wherein the immune checkpoint protein is PD-1 or PD-L1. 
     
     
         18 . The method of  claim 1 , wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1110, TSR-042, RG-7446, BMS-936559, BMS-936558, MK-3475, CT Ol l, MPDL3280A, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010. 
     
     
         19 . The method of  claim 1 , wherein the immune checkpoint inhibitor is administered by intravenous injection, intramuscular injection, intratumoral injection or subcutaneous injection. 
     
     
         20 . A method of treating cancer in a human subject comprising administering to the subject a bacterial formulation comprising at least 5×10 6  CFU of bacteria of the genera  Bifidobacterium , wherein at least 50% of the bacteria in the bacterial formulation are of the genera  Bifidobacterium.    
     
     
         21 . The method of  claim 20 , wherein at least 90% of the bacteria in the bacterial formulation are of the genera  Bifidobacterium.    
     
     
         22 . The method of  claim 20 , wherein the bacteria of the genus  Bifidobacterium  comprise bacteria of the species  Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium catenulatum, Bifidobacterium pseudocatenulatum, Bifidobacterium adolescentis, Bifidobacterium angulatum, Bifidobacterium asteroides, Bifidobacterium boum, Bifidobacterium choerinum, Bifidobacterium coryneforme, Bifidobacterium cuniculi, Bifidobacterium denticolens, Bifidobacterium dentium, Bifidobacterium gallicum, Bifidobacterium gallinarum, Bifidobacterium indicum, Bifidobacterium inopinatum, Bifidobacterium magnum, Bifidobacterium merycicum, Bifidobacterium minimum, Bifidobacterium pseudolongum, Bifidobacterium pullorum, Bifidobacterium psychraerophilum, Bifidobacterium ruminantium, Bifidobacterium saeculare, Bifidobacterium scardovii, Bifidobacterium simiae, Bifidobacterium subtile, Bifidobacterium therammcidophilum, Bifidobacterium thermophilum, Bifidobacterium tsurumiense, Bifidobacterium urinalis  or  Bifidobacterium  sp. 
     
     
         23 . The method of  claim 20 , wherein the bacterial formulation is administered by oral administration or rectal administration. 
     
     
         24 . The method of  claim 23 , wherein the bacterial formulation is administered by oral administration. 
     
     
         25 . The method of  claim 20 , wherein the bacterial formulation is administered to the subject in two or more doses. 
     
     
         26 . The method of  claim 20 , further comprising administering to the subject an antibiotic before the bacterial formulation is administered to the subject. 
     
     
         27 . The method of  claim 20 , further comprising administering to the subject an immune checkpoint inhibitor. 
     
     
         28 . The method of  claim 27 , wherein the immune checkpoint inhibitor is an antibody or antigen binding fragment thereof that binds to CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA. 
     
     
         29 . The method of  claim 27 , wherein the immune checkpoint inhibitor is an antibody or antigen binding fragment thereof that binds to PD-1 or PD-L1. 
     
     
         30 . The method of  claim 27 , wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1110, TSR-042, RG-7446, BMS-936559, BMS-936558, MK-3475, CT Ol l, MPDL3280A, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010.