TREATMENT OF CANCER BY MANIPULATION OF COMMENSAL MICROFLORA

• US 20160354416A1
• Filed: 06/01/2016
• Published: 12/08/2016
• Est. Priority Date: 06/01/2015
• Status: Active Grant

• Current Assignee: University of Chicago
• Original Assignee: University of Chicago
• Inventors: Sivan, Ayelet, Gajewski, Thomas F., Corrales, Leticia
• Granted Patent: US 9,855,302 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/741 Probiotics probiotic yeast, e.g. saccharomyces A61K36/06
• CPC Class Codes: A61K 35/742 Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
• CPC Class Codes: A61K 35/745 Bifidobacteria
• CPC Class Codes: A61K 35/747 Lactobacilli, e.g. L. acidophilus or L. brevis
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

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×

10⁶ 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.

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 O11, 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.

9. The method of claim 9, wherein the administration of the two or more doses are separated by at least 1 week.

20. A method of treating cancer in a human subject comprising administering to the subject a bacterial formulation comprising at least 5×

10⁶ 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 O11, MPDL3280A, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010.