SELECTIVELY ALTERING MICROBIOTA FOR IMMUNE MODULATION

• US 20190321469A1
• Filed: 06/26/2019
• Published: 10/24/2019
• Est. Priority Date: 06/05/2016
• Status: Active Grant

• Current Assignee: Snipr Technologies Limited
• Original Assignee: Snipr Technologies Limited
• Inventors: CLUBE, Jasper, GRONDAHL, Christian, SOMMER, Morten
• Granted Patent: US 10,953,090 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 35/15 Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/50 Methods for regulating/modulating their activity

Abstract

The invention relates to methods of modulating immune cells in a patient by altering microbiota of the patient. The invention also relates to methods of modulating treatments or therapies in a subject organism by altering microbiota of the subject. The invention also relates to cell populations, systems, arrays, cells, RNA, kits and other means for effecting this. In an example, advantageously selective targeting of a particular species in a human gut microbiota using guided nucleic acid modification is carried out to effect the alteration.

Claims

1. A method for treating a disease or condition in a patient, wherein the method comprises:

(a) exposing a microbiota in the patient to an antibacterial agent to selectively kill cells of a first species in the microbiota, wherein the first species is a bacterial or archaeal species; and

(b) simultaneously or sequentially administering to the patient an effective amount of a therapy to treat the disease or condition,

wherein;

the therapy is selected from the group consisting of an immunotherapy, antibody therapy, adoptive cell therapy, radiation therapy, chemotherapy, and vaccine therapy;

the selective killing is carried out by avoiding killing second cells comprised by the microbiota, wherein the second cells are of a different strain or a different species from the first cells; and

the proportion of the first cells in the microbiota is thereby reduced to modulate CD8⁺ immune cells in the patient, whereby the efficacy of the therapy is enhanced for treatment of the disease or condition in the patient.

2. The method of claim 1, wherein the therapy is an immunotherapy.

3. The method of claim 1, wherein the immunotherapy comprises administration of an immune checkpoint modulator.

4. The method of claim 1, wherein the CD8⁺ immune cells are upregulated or expanded in the patient.

5. The method of claim 1, wherein and the CD8⁺ immune cells comprise cells selected from tumor infiltrating lymphocytes (TILs), T_reg cells, memory cells, central memory T-cells (T_CM), effector memory T-cells (T_EM), stem cell memory cells (T_SCM), and memory effector T-cells (Teff).

6. The method of claim 1, wherein the CD8⁺ immune cells comprise memory cells selected from the group consisting of CD45RO⁺CD62L⁺ and CD25⁺ CD45RA⁻

CD45RO⁺ CD127⁺ cells.

7. The method of claim 1, wherein the CD8⁺ immune cells are CD8⁺ cells of the patient.

8. The method of claim 1, wherein the CD8⁺ immune cells are CD8⁺ cells of an adoptive cell therapy that has been administered to the patient.

9. The method of claim 3, wherein the immune checkpoint modulator is a PD-1 (programmed death-1) inhibitor, PD-L1 (programmed death-ligand 1) inhibitor, or CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) inhibitor.

10. The method of claim 3, wherein the immune checkpoint modulator is selected from the group consisting of ipilimumab, tremelimumab, nivolumab, pembrolizumab, pidilizumab, BMS-936559, durvalumab, and atezolizumab.

11. The method of claim 1, wherein the first cells are Fusobacterium, Mycoplasma, or Lactobacillus cells.

12. The method of claim 11, wherein the first cells are Fusobacterium nucleatum, Lactobacillus iners, or Lactobacillus crispatus cells.

13. The method of claim 1, wherein the second cells are of a human gut commensal strain and/or a human gut probiotic strain.

14. The method of claim 1, wherein the second cells are Akkermansia, Faecalibacterium, Ruminococcus, or Clostridium cells.

15. The method of claim 14, wherein the second cells are Akkermansia muciniphila or Faecalibacterium prausnitzi cells.

16. The method of claim 1, wherein the disease or condition is a cancer, or an autoimmune, inflammatory, neurodegenerative, central nervous system, or infectious disease or condition.

17. The method of claim 16, wherein the disease or condition is a cancer selected from the group consisting of lung cancer, melanoma, breast cancer, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, neuroblastoma, rhabdomyosarcoma, leukaemia, lymphoma melanoma, non-small cell lung cancer (NSCLC), bladder carcinoma and pancreatic cancer.

18. The method of claim 1, wherein the microbiota is a gut microbiota of the patient.

19. The method of claim 1, wherein step (a) is carried out by administering to the patient a guided nuclease to selectively target the genome of cells of the first species or strain in the microbiota and allowing the guided nuclease to cut one or more target nucleotide sequences comprised by the first cells, thereby killing the first cells, whereby the proportion of the first cells comprised by the microbiota is reduced.

20. The method of claim 19, wherein the guided nuclease is a Cas, TALEN, meganuclease, or zinc finger nuclease.