Compositions for modulating gut microflora populations, enhancing drug potency and treating cancer, and methods for making and using same
Provided are compositions, including products of manufacture and kits, and methods, comprising combinations of microbes, such as non-pathogenic, live bacteria and/or bacterial spores, for the control, amelioration, prevention, and treatment of a disease or condition, for example, a cancer. In alternative embodiment, these non-pathogenic, live bacteria and/or bacterial spores are administered to an individual in need thereof, thereby resulting in a modification or modulation of the individual's gut microfloral population(s). In alternative embodiments, by modulating or modifying the individual's gut microbial population(s) using compositions, products of manufacture and methods as provided herein, the pharmacodynamics of a drug administered to the individual is altered, thereby controlling, ameliorating, preventing and/or treating of that cancer. Combinations of microbes are administered with chemotherapy, radiation therapy, an immune checkpoint inhibitor, a Chimeric Antigen Receptor T-cell therapy or other immunotherapy or cancer treatment.
1 . A formulation or a pharmaceutical composition comprising:
(a) a combination of microbes comprising:
(i) Thomasclavelia ramosa (deposited as ATCC 25582);
(ii) Blautia obeum (deposited as DSMZ 25238);
(iii) Dorea longicatena (deposited as DSMZ 13814); and
(iv) Faecalibacterium prausnitzii (deposited as ATCC 27768), or
(b) the combination of microbes of (a)
(b) the combination of (a), wherein the Thomasclavelia ramosa bacteria are in spore form, or the combination comprises Thomasclavelia ramose bacteria and Thomasclavelia ramosa spores.
2 . The formulation or a pharmaceutical composition of claim 1 , wherein the formulation comprises a combination of microbes consisting of:
(a)
(i) Thomasclavelia ramosa (deposited as ATCC 25582);
(ii) Blautia obeum (deposited as DSMZ 25238);
(iii) Dorea longicatena (deposited as DSMZ 13814); and
(iv) Faecalibacterium prausnitzii (deposited as ATCC 27768), or
(b) the combination of (a), wherein the Thomasclavelia ramosa bacteria are in spore form, or the combination comprises Thomasclavelia ramose bacteria and Thomasclavelia ramosa spores.
3 . The formulation or pharmaceutical composition of claim 1 , wherein the formulation comprises an inner core surrounded by an outer layer of polymeric material enveloping the inner core.
4 . The formulation or pharmaceutical composition of claim 1 , wherein the plurality of non-pathogenic colony forming live bacteria are substantially dormant colony forming live bacteria, or the plurality of non-pathogenic colony forming live bacteria or the plurality of non-pathogenic germinable bacterial spores are lyophilized.
5 . The formulation or pharmaceutical composition of claim 1 , wherein the formulation comprises at least 1×10 4 colony forming units (CFUs), or between about 1×10 2 and 1×10 8 CFUs, 1×10 3 and 1×10 7 CFUs, or 1×10 4 and 1×10 6 CFUs, of live non-pathogenic bacteria and/or non-pathogenic germinable bacterial spores.
6 . The formulation or pharmaceutical composition of claim 1 , wherein the formulation or pharmaceutical composition comprises water, saline, a pharmaceutically acceptable preservative, a carrier, a buffer, a diluent, an adjuvant or a combination thereof.
7 . A kit or product of manufacture comprising or having contained therein a formulation or pharmaceutical composition of claim 1 .
8 . The formulation or pharmaceutical composition of claim 3 , wherein the non-pathogenic bacteria or the non-pathogenic germinable bacterial spores are substantially in the inner core.
9 . The formulation or pharmaceutical composition of claim 3 , wherein the polymeric material comprises a natural polymeric material.
10 . The formulation or pharmaceutical composition of claim 4 , wherein the non-pathogenic dormant colony forming live bacteria comprise live vegetative bacterial cells that have been rendered dormant by lyophilization or freeze drying.
11 . The formulation or pharmaceutical composition of claim 1 , wherein the formulation or pharmaceutical composition is formulated for administration orally or rectally, or is formulated as a liquid, a food, a gel, a geltab, a candy, a lozenge, a tablet, pill or capsule, or a suppository.
12 . The formulation or pharmaceutical composition of claim 1 , further comprising a biofilm disrupting or dissolving agent, an antibiotic, an inhibitor of an inhibitory immune checkpoint molecule and/or a stimulatory immune checkpoint molecule or any composition for use in checkpoint blockade immunotherapy.
13 . The formulation or pharmaceutical composition of claim 12 , wherein the inhibitor of an inhibitory immune checkpoint molecule comprises a protein or polypeptide that binds to an inhibitory immune checkpoint protein.
14 . The formulation or pharmaceutical composition of claim 12 , wherein the inhibitor of the inhibitory immune checkpoint molecule is an antibody or an antigen binding fragment thereof that binds to an inhibitory immune checkpoint protein.
15 . The formulation or pharmaceutical composition of claim 12 , wherein the inhibitor of an inhibitory immune checkpoint molecule targets a compound or protein comprising: cytotoxic T-lymphocyte-associated protein 4; Programmed cell Death protein 1; Programmed Death-Ligand 1 (PD-L1); adenosine A 2A receptor; B7-H3; B7-H4; B- and T-lymphocyte attenuator protein; Killer-cell Immunoglobulin-like Receptor; Indoleamine-pyrrole 2,3-dioxygenase; Lymphocyte-Activation Gene 3 protein; TIM-3; V-domain Ig suppressor of T cell activation protein, or any combination thereof.
16 . The formulation or pharmaceutical composition of claim 12 , wherein the inhibitor of an inhibitory immune checkpoint molecule comprises: ipilimumab; pembrolizumab; nivolumab; atezolizumab; avelumab; durvalumab; AMP-224, AMP-514 anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb), PDR001 humanized mAb that targets PD-1, STI-A1110 or STI-A1010, BMS-936559, BMS-986016, TSR-042, JNJ-61610588, MSB-0020718C, AUR-012, enoblituzumab, MBG453, LAG525, BMS-986015, cemiplimab, or any combination thereof.
17 . The formulation or pharmaceutical composition of claim 12 , wherein the stimulatory immune checkpoint molecule comprises a member of the tumor necrosis factor (TNF) receptor superfamily.
18 . The formulation or pharmaceutical composition of claim 14 , wherein the inhibitor of the inhibitory immune checkpoint molecule comprises CD27, CD40, OX40, GITR glucocorticoid-Induced TNFR family Related gene protein or, CD137, or a CD28 or Inducible T-cell co-stimulator (ICOS).
19 . The kit or product of manufacture of claim 7 , wherein the product of manufacture is an implant.
20 . The formulation or the pharmaceutical composition of claim 1 , wherein the combination of microbes comprises:
(a)
(i) Thomasclavelia ramosa VPI 0427 (deposited as ATCC 25582);
(ii) Blautia obeum VPI B3-21 (deposited as DSMZ 25238);
(iii) Dorea longicatena 111-35 (deposited as DSMZ 13814); and
(iv) Faecalibacterium prausnitzii VPI C13-51 (deposited as ATCC 27768), or
(b) the combination of (a), wherein the Thomasclavelia ramosa bacteria are in spore form, or the combination comprises Thomasclavelia ramose bacteria and Thomasclavelia ramosa spores.