WO2018112364A1 - Polythérapies pour le traitement d'un mélanome - Google Patents

Polythérapies pour le traitement d'un mélanome Download PDF

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WO2018112364A1
WO2018112364A1 PCT/US2017/066711 US2017066711W WO2018112364A1 WO 2018112364 A1 WO2018112364 A1 WO 2018112364A1 US 2017066711 W US2017066711 W US 2017066711W WO 2018112364 A1 WO2018112364 A1 WO 2018112364A1
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bacterial composition
bcg
days
subject
hours
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PCT/US2017/066711
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English (en)
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Brian Goodman
Peter SANDY
Jacqueline PAPKOFF
Holly PONICHTERA
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Evelo Biosciences, Inc.
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Publication of WO2018112364A1 publication Critical patent/WO2018112364A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • a subject e.g., a human subject
  • a bacterial composition comprising bacillus Calmette-Guerin (BCG) and an inhibitor of the PD-1 pathway (e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor).
  • BCG Bacillus Calmette-Guerin
  • an inhibitor of the PD-1 pathway e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor
  • the administration of the bacterial composition and the PD-1 pathway inhibitor induces an immune response against a tumor in the subject.
  • the administration of the bacterial composition and the PD-1 pathway inhibitor treats the melanoma in the subject.
  • a bacterial composition comprising a BCG (e.g., a inactivated BCG, a live BCG and/or an attenuated BCG).
  • the bacterial composition is administered to the subject by an injection into, or proximal to, a tumor or in the subject.
  • the bacterial composition is administered to the subject by an injection to, or proximal to, a site previously occupied by a tumor in a subject (e.g., a site occupied by a tumor before its surgical removal).
  • the BCG bacterium and is of a strain selected from BCG Birkhaug, BCG Brazilian, BCG China, BCG Connaught, BCG Danish, BCG
  • the bacterial composition comprises BCG bacteria from two or more strains. In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the bacteria in the bacterial composition are BCG and/or one of the aforementioned strains of BCG. In some embodiments, all or substantially all of the bacteria in the bacterial formulation are BCG and/or one of the aforementioned strains of BCG.
  • the bacterial formulation comprises at least 1 x 10 5 , 5 x 10 5 , 1 x 10 6 , 2 x 10 6 , 3 x 10 6 , 4 x 10 6 , 5 x 10 6 , 6 x 10 6 , 7 x 10 6 , 8 x 10 6 , 9 x 10 6 , 1 x 10 7 , 2 x 10 7 , 3 x 10 7 , 4 x 10 7 , 5 x 10 7 , 6 x 10 7 , 7 x 10 7 , 8 x 10 7 , 9 x 10 7 , 1 x 10 8 , 2 x 10 8 , 3 x 10 8 , 4 x 10 8 , 5 x 10 8 , 6 x 10 8 , 7 x 10 8 , 8 x 10 8 , 9 x 10 8 or 1 x 10 9 colony forming units (CFUs) of BCG and/or one of the aforementioned strains of BCG.
  • CFUs colony forming units
  • the bacterial composition is administered in 2 or more (e.g., 3 or more, 4 or more or 5 or more doses).
  • the administration to the subject of the two or more doses of the bacterial composition are separated by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days.
  • the method further comprises administering (e.g., administering by injection, such as an intravenous, intramuscular, intratumoral, peritumoral, subtumoral, intradermal, or subcutaneous injection) to the subject, an inhibitor of the PD-1 pathway.
  • the PD-1 pathway inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to a PD-1 pathway protein (e.g., PD-1 , PD-Ll, PD-L2).
  • the PD-1 pathway inhibitor is an inhibitor nucleic acid (e.g., an siRNA molecule, an shRNA molecule or an antisense RNA molecule) that inhibits expression of a PD-1 pathway protein (e.g., PD-1 , PD-Ll , PD-L2).
  • a PD-1 pathway protein e.g., PD-1 , PD-Ll , PD-L2.
  • the PD-1 pathway inhibitor is atezolizumab, avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, BGB-A317, STI-A11 10, TSR-042, RG-7446, BMS-936559, AUR-012 or STI- A1010.
  • the bacterial composition and the PD-1 pathway inhibitor are identical to each other.
  • a PD-1 inhibitor e.g., a PD-1 inhibitor, a PD-Ll inhibitor, a PD-L2 inhibitor
  • a PD-1 inhibitor e.g., a PD-1 inhibitor, a PD-Ll inhibitor, a PD-L2 inhibitor
  • the bacterial composition and the PD-1 pathway inhibitor are administered conjointly.
  • the bacterial composition and the PD-1 pathway inhibitor are administered to the subject at about the same time.
  • the PD-1 pathway inhibitor and the bacterial composition are administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days of each other.
  • the PD-1 pathway inhibitor is administered before the bacterial composition (e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days before).
  • the PD-1 pathway inhibitor is administered before the bacterial composition (e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 days, 18 days, 19 days, 20 days or 21 days before).
  • the PD-1 pathway inhibitor is administered after the bacterial composition (e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days after).
  • the bacterial composition e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days after).
  • the administration of the bacterial composition reduces the dose of the PD-1 pathway inhibitor that needs to be administered to the subject to achieve therapeutic efficacy.
  • the subject is administered a dose of the PD-1 pathway inhibitor that is lower than the therapeutically effective dose of the PD-1 pathway inhibitor when administered without the bacterial composition.
  • the subject is administered a dose of the PD-1 pathway inhibitor that is no more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5% of the therapeutically effective dose of the PD-1 pathway inhibitor when administered without the bacterial composition.
  • the dose is no more than 10 mg/kg, 9 mg/kg, 8 mg/kg, 7 mg/kg, 6 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/kg, 0.9 mg/kg, 0.8 mg/kg, 0.7 mg/kg 0.6 mg/kgm 0.5 mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg or 0. lmg/kg.
  • the melanoma is treated by the dose of the PD-1 pathway inhibitor that is lower than the therapeutically effective dose of the PD-1 pathway inhibitor when administered without administering the bacterial composition.
  • the subject experiences fewer and/or less severe adverse reactions following administration of the lower dose of the PD- 1 pathway inhibitor compared to subjects who are administered the therapeutically effective dose of the PD-1 pathway inhibitor when administered without the bacterial composition.
  • the bacterial composition and PD-1 pathway inhibitor are administered to a subject who has undergone, will undergo and/or is undergoing one or more other cancer therapies.
  • the one or more other cancer therapies include surgical removal of a tumor.
  • the bacterial composition and/or the PD-1 pathway inhibitor is administered before and/or after a surgery (e.g., a tumor resection).
  • the one or more other cancer therapies includes administering to the subject a chemotherapy agent.
  • the chemotherapy agent is thiotepa
  • cyclosphosphamide busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, trietylenephosphoramide,
  • triethiylenethiophosphoramide trimethylolomelamine, bullatacin, bullatacinone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, cryptophycin 1 , cryptophycin 8, dolastatin, duocarmycin, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil,
  • the bacterial composition and the other cancer therapy can be administered to the subject in any order. In some embodiments, the bacterial composition and the other cancer therapy are administered conjointly. In some embodiments, the bacterial composition and the other cancer therapy are administered to the subject at about the same time.
  • the other cancer therapy and the bacterial composition are administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 1 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days of each other.
  • the other cancer therapy is administered before the bacterial composition (e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days before).
  • the other cancer therapy is administered after the bacterial composition (e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days after).
  • the bacterial composition e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days after).
  • the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal (e.g., a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee).
  • a non-human mammal e.g., a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.
  • a pharmaceutical composition provided herein (e.g., a composition comprising a bacillus Calmette-Guerin (BCG), one or more immune checkpoint inhibitors) and a pharmaceutically acceptable carrier.
  • BCG Bacillus Calmette-Guerin
  • Figure 1 shows inhibition of tumor growth (by volume) by the administration of both a bacterial composition comprising BCG and a PD-1 pathway inhibitor in a melanoma mouse model.
  • Figure 2 shows inhibition of tumor growth (by mass) by the administration of both a bacterial composition comprising BCG and a PD-1 pathway inhibitor in a melanoma mouse model.
  • Figure 3 shows the number of CD45+ cells per gram of tumor in mice administered either a bacterial composition comprising BCG, a PD-1 pathway inhibitor, both a bacterial composition comprising BCG and a PD-1 pathway inhibitor, or a control.
  • the groups of mice pre-immunized with BCG are labeled "IMU".
  • the non-immunized mice are controls.
  • Figure 4A and Figure 4B show the number of dendritic cells (Fig. 4A) or CD8+
  • T cells per gram of tumor in mice administered either a bacterial composition comprising BCG, a PD-1 pathway inhibitor, both a bacterial composition comprising BCG and a PD-1 pathway inhibitor, or a control.
  • the groups of mice pre-immunized with BCG are labeled "IMU".
  • the non-immunized mice are controls.
  • Figure 5A and Figure 5B show the number of macrophages/monocytes (Fig. 5A) or M2 macrophages (Fig. 5B) per gram of tumor in mice administered either a bacterial composition comprising BCG, a PD-1 pathway inhibitor, both a bacterial composition comprising BCG and a PD-1 pathway inhibitor, or a control.
  • the groups of mice pre-immunized with BCG are labeled "IMU".
  • the non-immunized mice are controls.
  • Figure 6 shows inhibition of tumor growth (by volume) in the treated tumor by the administration of a bacterial composition comprising BCG, anti-PDLl or BCG + anti-PDLl in a melanoma mouse model.
  • Figure 7 shows inhibition of tumor growth (by volume) in the untreated tumor by the administration of a bacterial composition comprising BCG, anti-PDLl or BCG + anti-PDLl in a melanoma mouse model.
  • compositions related to the treatment of melanoma in a subject comprising administering to the subject a bacterial composition comprising bacillus Calmette-Guerin (BCG) and an inhibitor of the PD-1 pathway (e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor) inhibitor.
  • BCG Bacillus Calmette-Guerin
  • an inhibitor of the PD-1 pathway e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor
  • the administration of the bacterial composition and the PD-1 pathway inhibitor induces an immune response against a tumor in the subject.
  • the administration of the bacterial composition and the PD-1 pathway inhibitor treats the melanoma in the subject.
  • adjuvant or “Adjuvant therapy” broadly refers to an agent that affects an immunological or physiological response in a patient or subject.
  • an adjuvant might increase the presence of an antigen over time or to an area of interest like a tumor, help absorb an antigen presenting cell antigen, activate macrophages and lymphocytes and support the production of cytokines.
  • an adjuvant might permit a smaller dose of an immune interacting agent to increase the effectiveness or safety of a particular dose of the immune interacting agent.
  • an adjuvant might prevent T cell exhaustion and thus increase the effectiveness or safety of a particular immune interacting agent.
  • administering broadly refers to a route of administration of a composition to a subject.
  • routes of administration include oral administration, rectal administration, topical administration, inhalation (nasal) or injection.
  • Administration by injection includes intravenous (IV), intramuscular (IM), intratumoral (IT), peritumoral (PT), subtumoral (ST), intradermal (ID), and subcutaneous (SC) administration.
  • compositions described herein can be administered in any form by any effective route, including but not limited to intratumoral, oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), intradermal, ophthalmic, (intra)nasally, local, non-oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans)rectal, vaginal, intraarterial, and intrathecal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), intravesical, intrapulmonary, intraduodenal,
  • compositions described herein are administered orally, rectally, intratumorally, topically, intravesically, by injection into or adjacent to a draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously.
  • the term "antibody” may refer to both an intact antibody and an antigen binding fragment thereof.
  • Intact antibodies are glycoproteins that include at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain includes a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • Each light chain includes a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the term "antibody” includes, for example, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multispecific antibodies (e.g., bispecific antibodies), single-chain antibodies and antigen-binding antibody fragments.
  • antigen binding fragment and "antigen-binding portion" of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to bind to an antigen.
  • binding fragments encompassed within the term "antigen- binding fragment” of an antibody include Fab, Fab', F(ab') 2 , Fv, scFv, disulfide linked Fv, Fd, diabodies, single-chain antibodies, NANOBODIES®, isolated CDRH3, and other antibody fragments that retain at least a portion of the variable region of an intact antibody. These antibody fragments can be obtained using conventional recombinant and/or enzymatic techniques and can be screened for antigen binding in the same manner as intact antibodies.
  • carcinomas which are cancers of the epithelial tissue (e.g., skin, squamous cells); sarcomas which are cancers of the connective tissue (e.g., bone, cartilage, fat, muscle, blood vessels, etc.); leukemias which are cancers of blood forming tissue (e.g., bone marrow tissue); lymphomas and myelomas which are cancers of immune cells; and central nervous system cancers which include cancers from brain and spinal tissue.
  • carcinomas which are cancers of the epithelial tissue (e.g., skin, squamous cells)
  • sarcomas which are cancers of the connective tissue (e.g., bone, cartilage, fat, muscle, blood vessels, etc.)
  • leukemias which are cancers of blood forming tissue (e.g., bone marrow tissue)
  • lymphomas and myelomas which are cancers of immune cells
  • central nervous system cancers which include cancers from brain and spinal tissue.
  • cancer refers to all types of cancer or neoplasm or malignant tumors including leukemias, carcinomas and sarcomas, whether new or recurring. Specific examples of cancers are: carcinomas, sarcomas, myelomas, leukemias, lymphomas and mixed type tumors.
  • Non- limiting examples of cancers are new or recurring cancers of the brain, melanoma, bladder, breast, cervix, colon, head and neck, kidney, lung, non-small cell lung, mesothelioma, ovary, prostate, sarcoma, stomach, uterus and medulloblastoma.
  • epitope means a protein determinant capable of specific binding to an antibody.
  • Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains. Certain epitopes can be defined by a particular sequence of amino acids to which an antibody is capable of binding.
  • genomic is used broadly to refer to any nucleic acid associated with a biological function.
  • gene applies to a specific genomic sequence, as well as to a cDNA or an mRNA encoded by that genomic sequence.
  • nucleic acid sequences of two nucleic acid molecules can be determined as a percentage of identity using known computer algorithms such as the
  • FASTA Pearson et al. (1988) Proc. Natl. Acad. Sci. USA 85:2444
  • Other programs include the GCG program package (Devereux, J., et al, Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA Atschul, S. F., et al, J Molec Biol 215:403 (1990); Guide to Huge Computers, Mrtin J. Bishop, ed., Academic Press, San Diego, 1994, and Canllo et al (1988) SIAM J Applied Math 48: 1073).
  • the BLAST function of the National Center for Biotechnology Information database can be used to determine identity.
  • Other commercially or publicly available programs include, DNAStar "MegAlign” program (Madison, Wis.) and the University of Wisconsin Genetics Computer Group (UWG) "Gap” program (Madison Wis.)).
  • an "inhibitor of the PD-1 pathway” and the term “PD-1 pathway inhibitor” refers to any agent that inhibits the expression or activity of a PD-lpathway protein ⁇ e.g., PD-1, PD-Ll, PD-L2).
  • agents can be, for example, small molecule inhibitors, protein or polypeptide inhibitors ⁇ e.g., antibodies or antigen binding fragments thereof) or inhibitory nucleic acids ⁇ e.g. siRNAs, shRNAs, ribozymes, antisense RNAs).
  • PD-1 pathway inhibitors examples include atezolizumab, avelumab, durvalumab, nivolumab, pembrolizumab, pidihzumab, AMP-224, AMP-514, BGB-A317, STI-Al l lO, TSR-042, RG-7446, BMS-936559, AUR-012 or STI-A1010.
  • Immunotherapy is treatment that uses a subject's immune system to treat cancer and includes, for example, checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR- T cells, and dendritic cell therapy.
  • the term "increase” means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 4-fold, 10- fold, 100-fold, 10 ⁇ 3 fold, 10 ⁇ 4 fold, 10 ⁇ 5 fold, 10 ⁇ 6 fold, and/or 10 ⁇ 7 fold greater after treatment when compared to a pre-treatment state.
  • Properties that may be increased include immune cells, bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites, and cytokines.
  • polynucleotide and “nucleic acid” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function.
  • polynucleotides coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
  • loci locus
  • polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. A polynucleotide may be further modified, such as by conjugation with a labeling component. In all nucleic acid sequences provided herein, U nucleotides are interchangeable with T nucleotides.
  • Oxidal taxonomic units and “OTU(s)” refer to a terminal leaf in a phylogenetic tree and is defined by a nucleic acid sequence, e.g., the entire genome, or a specific genetic sequence, and all sequences that share sequence identity to this nucleic acid sequence at the level of species.
  • the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence.
  • the entire genomes of two entities are sequenced and compared.
  • select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared.
  • MMT multilocus sequence tags
  • OTUs that share > 97% average nucleotide identity across the entire 16S or some variable region of the 16S are considered the same OTU. See e.g. Claesson MJ, Wang Q, O' Sullivan O, Greene- Diniz R, Cole JR, Ross RP, and O' Toole PW. 2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res 38: e200. Konstantinidis KT, Ramette A, and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361 : 1929-1940.
  • OTUs For complete genomes, MLSTs, specific genes, other than 16S, or sets of genes OTUs that share > 95% average nucleotide identity are considered the same OTU. See e.g., Achtman M, and Wagner M. 2008. Microbial diversity and the genetic nature of microbial species. Nat. Rev. Microbiol. 6: 431-440. Konstantinidis KT, Ramette A, and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361 : 1929-1940. OTUs are frequently defined by comparing sequences between organisms. Generally, sequences with less than 95% sequence identity are not considered to form part of the same OTU.
  • OTUs may also be characterized by any combination of nucleotide markers or genes, in particular highly conserved genes (e.g., "house-keeping" genes), or a combination thereof.
  • Operational Taxonomic Units (OTUs) with taxonomic assignments made to, e.g., genus, species, and phylogenetic clade are provided herein.
  • specific binding refers to the ability of an antibody to bind to a predetermined antigen or the ability of a polypeptide to bind to its predetermined binding partner.
  • an antibody or polypeptide specifically binds to its predetermined antigen or binding partner with an affinity corresponding to a KD of about 10 "7 M or less, and binds to the predetermined antigen/binding partner with an affinity (as expressed by KD) that is at least 10 fold less, at least 100 fold less or at least 1000 fold less than its affinity for binding to a nonspecific and unrelated antigen/binding partner (e.g., BSA, casein).
  • specific binding applies more broadly to a two component system where one component is a protein, lipid, or carbohydrate or combination thereof and engages with the second component which is a protein, lipid, carbohydrate or combination thereof in a specific way.
  • subject refers to any animal.
  • a subject or a patient described as "in need thereof refers to one in need of a treatment for a disease.
  • Mammals i.e., mammalian animals
  • mammals include humans, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs), and household pets (e.g., dogs, cats, rodents).
  • the subject may be a non- human mammal including but not limited to of a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.
  • the subject or patient may be healthy, or may be suffering from a neoplasm at any developmental stage, wherein any of the stages are either caused by or opportunistically supported of a cancer associated or causative pathogen, or may be at risk of developing a neoplasm, or transmitting to others a cancer associated or cancer causative pathogen.
  • patients have lung cancer, prostate cancer, ovarian cancer, and/or melanoma.
  • the patients may have tumors that show enhanced macropinocytosis with the underlying genomics of this process including Ras activation.
  • patients suffer from other cancers.
  • the subject has undergone a cancer therapy.
  • strain refers to a member of a bacterial species with a genetic signature such that it may be differentiated from closely-related members of the same bacterial species.
  • the genetic signature may be the absence of all or part of at least one gene, the absence of all or part of at least on regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the absence (“curing") of at least one native plasmid, the presence of at least one recombinant gene, the presence of at least one mutated gene, the presence of at least one foreign gene (a gene derived from another species), the presence at least one mutated regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the presence of at least one non-native plasmid, the presence of at least one antibiotic resistance cassette, or a combination thereof.
  • regulatory region e.g., a promoter, a terminator,
  • strains may be identified by PCR amplification optionally followed by DNA sequencing of the genomic region(s) of interest or of the whole genome.
  • strains may be differentiated by selection or counter-selection using an antibiotic or nutrient/metabolite, respectively.
  • treating refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of one or more agents, such that at least one symptom of the disease is decreased or prevented from worsening.
  • a pharmaceutical treatment e.g., the administration of one or more agents, such that at least one symptom of the disease is decreased or prevented from worsening.
  • “treating” refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof.
  • the methods and compositions provided herein relate to bacterial compositions comprising bacillus Calmette-Guerin (BCG).
  • BCG Bacillus Calmette-Guerin
  • the methods and compositions provided herein relate to bacterial compositions comprising bacillus Calmette-Guerin (BCG).
  • BCG is an attenuated strain of Mycobacterium bovis.
  • a combinatorial therapy that includes administration of both a bacterial composition comprising BCG and one or more PD-1 pathway inhibitors provides a synergistic therapeutic effect that allows for the successful treatment of melanoma not amenable to treatment with BCG alone.
  • Exemplary BCG strains useful in certain embodiments of the methods and compositions provided herein include, but are not limited to, BCG Australia (e.g., ATCC 35739), BCG
  • BCG Pasteur e.g., ATCC 35734
  • BCG Phipps e.g., ATCC 35744
  • BCG Pragure BCG Russia (e.g., ATCC 35740), BCG Sweden
  • BCG Tice e.g., ATCC 35743
  • Strains of the BCG may be selected for improved properties, including one or more of improved immunogenicity, improved attachment to tumors, improved selectivity for tumor cells over healthy cells, decreased lymphadenitis, decreased virulence, decreased osteitis, increased resistance to reactive oxygen species (ROS), increased metabolism or import of nutrients common to a tumor microenvironment, increased tolerance of low local pH or low local oxygen concentration (hypoxia), or other desired characteristics.
  • improved immunogenicity including one or more of improved immunogenicity, improved attachment to tumors, improved selectivity for tumor cells over healthy cells, decreased lymphadenitis, decreased virulence, decreased osteitis, increased resistance to reactive oxygen species (ROS), increased metabolism or import of nutrients common to a tumor microenvironment, increased tolerance of low local pH or low local oxygen concentration (hypoxia), or other desired characteristics.
  • ROS reactive oxygen species
  • the bacterial composition comprises engineered BCG.
  • engineered BCG include microbes harboring i) one or more genetic changes, such change being an insertion, deletion, translocation, or substitution, or any combination thereof, of one or more nucleotides contained on the bacterial chromosome or on an endogenous plasmid, wherein the genetic change may result in the alteration, disruption, removal, or addition of one or more protein coding genes, non-protein-coding genes, gene regulatory regions, or any combination thereof, and wherein such change may be a fusion of two or more separate genomic regions or may be synthetically derived; ii) one or more foreign plasmids containing a mutant copy of an endogenous gene, such mutation being an insertion, deletion, or substitution, or any combination thereof, of one or more nucleotides; iii) one or more foreign plasmids containing a mutant or non-mutant exogenous gene or a fusion of two or more endogenous, exogen
  • the engineered BCG may be produced using techniques including but not limited to site-directed mutagenesis, transposon mutagenesis, knock-outs, knock-ins, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light mutagenesis, transformation (chemically or by electroporation), phage transduction, or any combination thereof.
  • Suitable microbes for engineering are known in the art.
  • the bacterial composition comprises at least 1 x 10 3 colony forming units (CFUs), 1 x 10 4 colony forming units (CFUs), 1 x 10 5 colony forming units (CFUs), 5 x 10 5 colony forming units (CFUs), 1 x 10 6 colony forming units (CFUs), 2 x 10 6 colony forming units (CFUs), 3 x 10 6 colony forming units (CFUs), 4 x 10 6 colony forming units (CFUs), 5 x 10 6 colony forming units (CFUs), 6 x 10 6 colony forming units (CFUs), 7 x 10 6 colony forming units (CFUs), 8 x 10 6 colony forming units (CFUs), 9 x 10 6 colony forming units (CFUs), 1 x 10 7 colony forming units (CFUs), 2
  • the BCG is received from Aeras (Rockville, MD, USA), using their proprietary growth methods followed by storage in buffer containing 10% glycerol, 0.85% NaCl, and 0.05% tyloxapol in water (Middlebrook 7H10 agar may be used to determine CFUs).
  • the BCG is grown in Sauton medium (purchased from
  • the medium is supplemented with 0.47% Middlebrook 7H9 powder, 0.5% glycerol, 0.05% tyloxapol, 0.2% casamino acids, and 10% OADC Middlebrook enrichment, and filter sterilized (0.2 ⁇ ).
  • the BCG is grown in Sauton or Middlebrook 7H9 medium as described by Venkataswamy et al. (2012). See Venkataswamy et al. 2012. In vitro culture medium influences the vaccine efficacy of Mycobacterium bovis BCG. Vaccine: 30(6): 1038-1049.
  • the methods provided herein comprise administering a PD-1 pathway inhibitor.
  • PD-1 pathway inhibition broadly refers to inhibiting the PD-1 pathway checkpoints that cancer cells can produce to prevent or downregulate an immune response.
  • Examples of PD-1 pathway pproteins include, but are not limited to, PD-1, PD-L1, and PD-L2.
  • PD-1 pathway inhibitors can be antibodies or antigen binding fragments thereof that bind to and inhibit aPD-1 pathway protein.
  • Such antibodies can be polyclonal or monoclonal and can be, for example, murine, chimeric, humanized or fully human.
  • Polyclonal antibodies can be prepared by immunizing a suitable subject ⁇ e.g. a mouse) with a protein immunogen ⁇ e.g., an PD-1 pathway protein or fragment thereof).
  • a protein immunogen e.g., an PD-1 pathway protein or fragment thereof.
  • the antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized polypeptide.
  • ELISA enzyme linked immunosorbent assay
  • the antibody directed against the antigen can be isolated from the mammal ⁇ e.g., from the blood) and further purified by well-known techniques, such as protein A chromatography to obtain the IgG fraction.
  • antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies using standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975) Nature 256:495-497) (see also Brown et al. (1981) J. Immunol. 127:539-46; Brown et al. (1980) J. Biol. Chem. 255:4980-83; Yeh et al. (1976) Proc. Natl. Acad. Sci. 76:2927-31 ; and Yeh et al. (1982) Int. J.
  • an immortal cell line typically a myeloma
  • lymphocytes typically splenocytes
  • the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds to the polypeptide antigen, preferably specifically.
  • a monoclonal specific for a receptor or ligand provided herein can be identified and isolated by screening a recombinant combinatorial immunoglobulin library ⁇ e.g., an antibody phage display library or an antibody yeast display library) with the appropriate protein ⁇ e.g. PD-1 pathway proteins or a fragment thereof) to thereby isolate immunoglobulin library members that bind the polypeptide.
  • a recombinant combinatorial immunoglobulin library ⁇ e.g., an antibody phage display library or an antibody yeast display library
  • the appropriate protein e.g. PD-1 pathway proteins or a fragment thereof
  • recombinant antibodies specific for a receptor or ligand provided herein can be made using standard recombinant DNA techniques.
  • Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in US Pat No. 4,816,567; US Pat. No. 5,565,332; Better et al. (1988) Science
  • Human monoclonal antibodies specific for a receptor or ligand provided herein can be generated using transgenic or transchromosomal mice carrying parts of the human immune system rather than the mouse system.
  • “HuMAb mice” which contain a human immunoglobulin gene miniloci that encodes unrearranged human heavy ( ⁇ and ⁇ ) and ⁇ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous ⁇ and ⁇ chain loci (Lonberg, N. et al. (1994) Nature 368(6474): 856-859).
  • mice exhibit reduced expression of mouse IgM or ⁇ , and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgGK monoclonal antibodies (Lonberg, N. et al. (1994), supra; reviewed in Lonberg, N. (1994) Handbook of Experimental Pharmacology 113:49 101 ; Lonberg, N. and Huszar, D. (1995) Intern. Rev. Immunol. Vol. 13: 65 93, and Harding, F. and Lonberg, N. (1995) Ann. N. Y Acad. Sci 764:536 546).
  • the preparation of HuMAb mice is described in Taylor, L. et al.
  • the antibodies provided herein are able to bind to a receptor or ligand described herein with a dissociation constant of no greater than 10 "6 , 10 "7 , 10 "8 or 10 "9 M.
  • Standard assays to evaluate the binding ability of the antibodies are known in the art, including for example, ELISAs, Western blots and RIAs.
  • the binding kinetics ⁇ e.g., binding affinity) of the antibodies also can be assessed by standard assays known in the art, such as by Biacore analysis.
  • the binding of the antibody to a receptor described herein substantially inhibits the ability of the corresponding ligand to bind to the receptor.
  • the binding of the antibody to a ligand described herein substantially inhibits the ability of the ligand to bind to the corresponding receptor.
  • an antibody substantially inhibits binding of a receptor and a ligand when an excess of polypeptide reduces the quantity of receptor bound to ligand by at least about 20%, 40%, 60% or 80%, 85% or 90% (as measured in an in vitro competitive binding assay).
  • PD-1 pathway inhibitors include, but are not limited to,
  • Atezolizumab (trade name TecentriqTM) is a fully humanized, engineered monoclonal antibody of IgGl isotype against the protein programmed cell death-ligand 1 (PD- Ll). Atezolizumab is currently in clinical trials as an immunotherapy for several types of solid tumors and has been approved to treat bladder cancer. Additional information on Atezolizumab can be found in PCT patent application publication WO 2010/077634 and US Patent No.
  • Nivolumab (trade name OpdivoTM) is a human IgG4 anti-PD-1 monoclonal antibody. Nivolumab is approved to treat melanoma, squamous cell cancer, renal cell carcinoma, and classical Hodgkin lymphoma. Additional information on Nivolumab can be found in PCT patent application WO 2006/121168 and US Patent Nos. 7,595,048, 8,008,449, 8,728,474, 8,779,105, 9,073,994, 9,067,999, 9,084,776, 9,358,289, and 9,387,247, each of which are hereby incorporated by reference in their entirety.
  • Pembrolizumab (trade name KeytrudaTM) is a humanized antibody that targets the programmed cell death 1 (PD-1) receptor. Pembrolizumab is used in treating metastatic melanoma and metastatic non-small cell lung cancer. Additional information on Pembrolizumab can be found in PCT patent application publication WO 2012/135408 and US Patent Nos.
  • PD-1 pathway inhibitors can be an inhibitory nucleic acid molecule (e.g., an siRNA molecule, an shRNA molecule or an antisense RNA molecule) that inhibits expression of a PD-1 pathway protein.
  • an inhibitory nucleic acid molecule e.g., an siRNA molecule, an shRNA molecule or an antisense RNA molecule
  • the PD-1 pathway inhibitor is a siRNA molecule.
  • siRNA molecules should include a region of sufficient homology to the target region, and be of sufficient length in terms of nucleotides, such that the siRNA molecule down-regulate target RNA (e.g., RNA of an PD-1 pathway protein).
  • target RNA e.g., RNA of an PD-1 pathway protein.
  • ribonucleotide or nucleotide can, in the case of a modified RNA or nucleotide surrogate, also refer to a modified nucleotide, or surrogate replacement moiety at one or more positions.
  • the sense strand need only be sufficiently complementary with the antisense strand to maintain the overall double-strand character of the molecule.
  • an siRNA molecule may be modified or include nucleoside surrogates.
  • Single stranded regions of an siRNA molecule may be modified or include nucleoside surrogates, e.g., the unpaired region or regions of a hairpin structure, e.g., a region which links two complementary regions, can have modifications or nucleoside surrogates.
  • Modification to stabilize one or more 3'- or 5'-terminus of an siRNA molecule, e.g., against exonucleases, or to favor the antisense siRNA agent to enter into RISC are also useful.
  • Modifications can include C3 (or C6, C7, CI 2) amino linkers, thiol linkers, carboxyl linkers, non-nucleotidic spacers (C3, C6, C9, CI 2, abasic, tri ethylene glycol, hexaethylene glycol), special biotin or fluorescein reagents that come as phosphoramidites and that have another DMT- protected hydroxyl group, allowing multiple couplings during RNA synthesis.
  • Each strand of an siRNA molecule can be equal to or less than 35, 30, 25, 24, 23,
  • siRNA agents have a duplex region of 17, 18, 19, 29, 21, 22, 23, 24, or 25 nucleotide pairs, and one or more overhangs, such as one or two 3' overhangs, of 2-3 nucleotides.
  • the PD-1 pathway inhibitor is a shRNA molecule.
  • shRNA small hairpin RNA
  • shRNA short hairpin RNA
  • shRNA includes a short RNA sequence that makes a tight hairpin turn that can be used to silence gene expression via RNA interference.
  • the shRNAs provided herein may be chemically synthesized or transcribed from a transcriptional cassette in a DNA plasmid.
  • the shRNA hairpin structure is cleaved by the cellular machinery into siRNA, which is then bound to the RNA-induced silencing complex (RISC).
  • RISC RNA-induced silencing complex
  • shRNAs are about 15-60, 15-50, or 15-40 (duplex) nucleotides in length, about 15-30, 15-25, or 19-25 (duplex) nucleotides in length, or are about 20-24, 21-22, or 21 -23 (duplex) nucleotides in length (e.g., each complementary sequence of the double-stranded shRNA is 15-60, 15-50, 15-40, 15-30, 15-25, or 19-25 nucleotides in length, or about 20-24, 21-22, or 21 -23 nucleotides in length, and the double-stranded shRNA is about 15- 60, 15-50, 15-40, 15-30, 15-25, or 19-25 base pairs in length, or about 18-22, 19-20, or 19-21 base pairs in length).
  • shRNA duplexes may comprise 3 ' overhangs of about 1 to about 4 nucleotides or about 2 to about 3 nucleotides on the antisense strand and/or 5 '-phosphate termini on the sense strand.
  • the shRNA comprises a sense strand and/or antisense strand sequence of from about 15 to about 60 nucleotides in length (e.g., about 15-60, 15-55, 15- 50, 15-45, 15-40, 15-35, 15-30, or 15-25 nucleotides in length),or from about 19 to about 40 nucleotides in length (e.g., about 19-40, 19-35, 19-30, or 19-25 nucleotides in length), or from about 19 to about 23 nucleotides in length (e.g., 19, 20, 21, 22, or 23 nucleotides in length).
  • Non-limiting examples of shRNA include a double-stranded polynucleotide molecule assembled from a single-stranded molecule, where the sense and antisense regions are linked by a nucleic acid-based or non-nucleic acid-based linker; and a double-stranded polynucleotide molecule with a hairpin secondary structure having self-complementary sense and antisense regions.
  • the sense and antisense strands of the shRNA are linked by a loop structure comprising from about 1 to about 25 nucleotides, from about 2 to about 20 nucleotides, from about 4 to about 15 nucleotides, from about 5 to about 12 nucleotides, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more nucleotides.
  • a loop structure comprising from about 1 to about 25 nucleotides, from about 2 to about 20 nucleotides, from about 4 to about 15 nucleotides, from about 5 to about 12 nucleotides, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more nucleotides.
  • the PD-1 pathway inhibitor is an antisense oligonucleotide compounds that inhibits expression of an PD-1 pathway protein.
  • the degree of complementarity between the target sequence and antisense targeting sequence is sufficient to form a stable duplex. The region of complementarity of the antisense
  • oligonucleotides with the target RNA sequence may be as short as 8-11 bases, but can be 12-15 bases or more, e.g., 10-40 bases, 12-30 bases, 12-25 bases, 15-25 bases, 12-20 bases, or 15-20 bases, including all integers in between these ranges.
  • An antisense oligonucleotide of about 14- 15 bases is generally long enough to have a unique complementary sequence.
  • antisense oligonucleotides may be 100% complementary to the target sequence, or may include mismatches, e.g., to improve selective targeting of allele containing the disease-associated mutation, as long as a heteroduplex formed between the oligonucleotide and target sequence is sufficiently stable to withstand the action of cellular nucleases and other modes of degradation which may occur in vivo.
  • oligonucleotides may have about or at least about 70% sequence complementarity, e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence complementarity, between the oligonucleotide and the target sequence.
  • Oligonucleotide backbones that are less susceptible to cleavage by nucleases are discussed herein.
  • Mismatches are typically less destabilizing toward the end regions of the hybrid duplex than in the middle.
  • the number of mismatches allowed will depend on the length of the oligonucleotide, the percentage of G:C base pairs in the duplex, and the position of the mismatch(es) in the duplex, according to well understood principles of duplex stability.
  • the inhibitory nucleic acid molecule can be prepared, for example, by chemical synthesis, in vitro transcription, or digestion of long dsRNA by Rnase III or Dicer. These can be introduced into cells by transfection, electroporation, or other methods known in the art. See Hannon, GJ, 2002, RNA Interference, Nature 418: 244-251; Bernstein E et al, 2002, The rest is silence. RNA 7: 1509-1521 ; Hutvagner G et al., RNAi: Nature abhors a double-strand. Curr. Opin.
  • Short hairpin RNAs induce sequence-specific silencing in mammalian cells. Genes & Dev. 16:948-958; Paul CP, Good PD, Winer I, and Engelke DR. (2002). Effective expression of small interfering RNA in human cells. Nature Biotechnol. 20:505-508; Sui G, Soohoo C, Affar E-B, Gay F, Shi Y, Forrester WC, and Shi Y. (2002). A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl.
  • RNA interference by expression of short- interfering RNAs and hairpin RNAs in mammalian cells Proc. Natl. Acad. Sci. USA 99(9): 6047-6052.
  • the inhibitory nucleic acid molecule can be administered to the subject, for example, as naked nucleic acid, in combination with a delivery reagent, and/or as a nucleic acid comprising sequences that express an interfering nucleic acid molecule.
  • the nucleic acid comprising sequences that express the interfering nucleic acid molecules are delivered within vectors, e.g. plasmid, viral and bacterial vectors. Any nucleic acid delivery method known in the art can be used in the methods described herein. Suitable delivery reagents include, but are not limited to, e.g., the Mirus Transit TKO lipophilic reagent;
  • atelocollagen as a delivery vehicle for nucleic acid molecules is described in Minakuchi et al. Nucleic Acids Res., 32(13):el09 (2004); Hanai et al. Ann NY Acad Sci., 1082:9-17 (2006); and Kawata et al. Mol Cancer Ther., 7(9):2904-12 (2008); each of which is incorporated herein in their entirety.
  • Exemplary interfering nucleic acid delivery systems are provided in U.S. Patent Nos. 8,283,461, 8,313,772, 8,501,930. 8,426,554, 8,268,798 and
  • the methods provided herein further comprise another cancer therapy.
  • the other cancer therapy include e.g., surgical resection, radiotherapy, or a cancer therapeutic.
  • the bacterial composition and the other cancer therapy can be administered to the subject in any order.
  • the bacterial composition and the other cancer therapy are administered conjointly.
  • the bacterial composition and the other cancer therapy are administered to the subject at about the same time.
  • the other cancer therapy and the bacterial composition are administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 1 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days of each other.
  • the other cancer therapy is administered before the bacterial composition (e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days before).
  • the other cancer therapy is administered after the bacterial composition (e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days after).
  • the bacterial composition e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days after).
  • the subject may undergo surgery.
  • Types of surgery include but are not limited to preventative, diagnostic or staging, curative and palliative surgery.
  • Curative surgery is a cancer treatment that may be used in conjunction with other therapies, such as the treatment of the present invention, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy and/or alternative therapies.
  • Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed.
  • Tumor resection refers to physical removal of at least part of a tumor.
  • treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Mohs' surgery). Upon excision of part of all of cancerous cells, tissue, or tumor, a cavity may be formed in the body.
  • the subject may undergo radiation therapy.
  • Radiation therapy includes the administration or application of a radiotherapeutic agents and factors including but not limited to ⁇ -irradiation, X-rays, UV-irradiation, microwaves, electronic emissions, and radioisotopes.
  • the localized tumor site may be irradiated, including by one or more the above described forms of radiations. All of these factors may effect a broad range of damage DNA, on the precursors of DNA, the replication and repair of DNA, and the assembly and maintenance of chromosomes.
  • Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 weeks), to single doses of 2000 to 6000 roentgens.
  • Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
  • the methods provided herein further comprise administering another cancer therapeutic to the subject.
  • the cancer therapeutic is a chemotherapeutic agent.
  • chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin;
  • alkylating agents such as thiotepa and cyclosphosphamide
  • alkyl sulfonates such as busulfan, improsulfan and piposulfan
  • aziridines such as
  • callystatin including its adozelesin, carzelesin and bizelesin synthetic analogues
  • cryptophycins particularly cryptophycin 1 and cryptophycin 8
  • dolastatin duocarmycin (including the synthetic analogues, KW-2189 and CBl-TMl); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,
  • cholophosphamide estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall ; dynemicin, including dynemicin A;
  • bisphosphonates such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, no
  • demecolcine diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin;
  • losoxantrone podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol;
  • pipobroman gacytosine; arabinoside ("Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine;
  • methotrexate platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine
  • the BCG is coadministered with an antibiotic.
  • the subject is administered an antibiotic with, before , or after adminstereing the bacterial composition.
  • the bacterial composition and the antibiotics can be administered to the subject in any order.
  • the bacterial composition and the antibiotics are administered conjointly.
  • the bacterial composition and the antibiotics are administered to the subject at about the same time.
  • the antibiotics and the bacterial composition are administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 1 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days of each other.
  • the antibiotics are administered before the bacterial composition (e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days before).
  • the antibiotics are administered after the bacterial composition (e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days after).
  • the bacterial composition e.g., at least or about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 15 days
  • Antibiotics include, but are not limited to aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, and anti-mycobacterial compounds, and combinations thereof.
  • Aminoglycosides include, but are not limited to Amikacin, Gentamicin,
  • Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, and Spectinomycin are examples of the compounds listed in the following paragraphs.
  • Aminoglycosides are effective, e.g., against Gram-negative bacteria, such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa, and Francisella tularensis, and against certain aerobic bacteria but less effective against obligate/facultative anaerobes. Aminoglycosides are believed to bind to the bacterial 30S or 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.
  • Ansamycins include, but are not limited to, Geldanamycin, Herbimycin,
  • Carbacephems include, but are not limited to, Loracarbef. Carbacephems are believed to inhibit bacterial cell wall synthesis.
  • Carbapenems include, but are not limited to, Ertapenem, Doripenem,
  • Carbapenems are bactericidal for both Gram-positive and Gram-negative bacteria as broad-spectrum antibiotics. Carbapenems are believed to inhibit bacterial cell wall synthesis.
  • Cephalosporins include, but are not limited to, Cefadroxil, Cefazolin, Cefalotin,
  • Cefalothin Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil,and Ceftobiprole. Selected
  • Cephalosporins are effective, e.g., against Gram-negative bacteria and against Gram-positive bacteria, including Pseudomonas, certain Cephalosporins are effective against methicillin- resistant Staphylococcus aureus (MRSA). Cephalosporins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
  • Glycopeptides include, but are not limited to, Teicoplanin, Vancomycin, and
  • Glycopeptides are effective, e.g., against aerobic and anaerobic Gram-positive bacteria including MRSA and Clostridium difficile. Glycopeptides are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
  • Lincosamides include, but are not limited to, Clindamycin and Lincomycin.
  • Lincosamides are effective, e.g., against anaerobic bacteria, as well as Staphylococcus, and Streptococcus. Lincosamides are believed to bind to the bacterial 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.
  • Lipopeptides include, but are not limited to, Daptomycin. Lipopeptides are effective, e.g., against Gram-positive bacteria. Lipopeptides are believed to bind to the bacterial membrane and cause rapid depolarization.
  • Macrolides include, but are not limited to, Azithromycin, Clarithromycin,
  • Macrolides are effective, e.g., against Streptococcus and Mycoplasma. Macrolides are believed to bind to the bacterial or 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.
  • Monobactams include, but are not limited to, Aztreonam. Monobactams are effective, e.g., against Gram-negative bacteria. Monobactams are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
  • Nitrofurans include, but are not limited to, Furazolidone and Nitrofurantoin.
  • Oxazolidonones include, but are not limited to, Linezolid, Posizolid, Radezolid, and Torezolid. Oxazolidonones are believed to be protein synthesis inhibitors.
  • Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin,
  • Penicillins are effective, e.g., against Gram-positive bacteria, facultative anaerobes, e.g., Streptococcus, Borrelia, and Treponema. Penicillins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
  • Penicillin combinations include, but are not limited to, Amoxicillin/clavulanate,
  • Ampicillin/sulbactam Piperacillin/tazobactam, and Ticarcillin/clavulanate.
  • Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and
  • Polymyxin B and E. Polypeptide Antibiotics are effective, e.g., against Gram-negative bacteria. Certain polypeptide antibiotics are believed to inhibit isoprenyl pyrophosphate involved in synthesis of the peptidoglycan layer of bacterial cell walls, while others destabilize the bacterial outer membrane by displacing bacterial counter-ions.
  • Quinolones and Fluoroquinolone include, but are not limited to, Ciprofloxacin,
  • Quinolones/Fluoroquinolone are believed to inhibit the bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription.
  • Sulfonamides include, but are not limited to, Mafenide, Sulfacetamide,
  • Sulfadiazine Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), and Sulfonamidochrysoidine.
  • Sulfonamides are believed to inhibit folate synthesis by competitive inhibition of dihydropteroate synthetase, thereby inhibiting nucleic acid synthesis.
  • Tetracyclines include, but are not limited to, Demeclocycline, Doxycycline,
  • Tetracyclines are effective, e.g., against Gram- negative bacteria. Tetracyclines are believed to bind to the bacterial 30S ribosomal subunit thereby inhibiting bacterial protein synthesis.
  • Anti-mycobacterial compounds include, but are not limited to, Clofazimine,
  • Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin PI, clarithromycin, erythromycins, furazolidone, fusidic acid, Na fusidate, gramicidin, imipenem, indolicidin, josamycin, magainan II, metronidazole, nitroimidazoles, mikamycin, mutacin B-Ny266, mutacin B-JH1 140, mutacin J-T8, nisin, nisin A, novobiocin, ole
  • the BCG is coadministered with other injectable agents including oncolytic viruses, TLR agonists, cyclic dynucleotides and other STING agonists, cytokines, tumor associated antigens, enzymes (e.g., metalloproteases).
  • injectable agents including oncolytic viruses, TLR agonists, cyclic dynucleotides and other STING agonists, cytokines, tumor associated antigens, enzymes (e.g., metalloproteases).
  • the delivery of a cancer therapeutic in combination with the bacteria described herein reduces the adverse effects and/or improves the efficacy of the cancer therapeutic.
  • the toxicity of a cancer therapeutic is the level of adverse effects experienced by the subject during and following treatment.
  • Adverse events associated with cancer therapy toxicity include, but are not limited to, abdominal pain, acid indigestion, acid reflux, allergic reactions, alopecia, anaphylaxis, anemia, anxiety, lack of appetite, arthralgias, asthenia, ataxia, azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, elevated blood pressure, difficulty breathing, bronchitis, bruising, low white blood cell count, low red blood cell count, low platelet count, cardiotoxicity, cystitis, hemorrhagic cystitis, arrhythmias, heart valve disease, cardiomyopathy, coronary artery disease, cataracts, central neurotoxicity, cognitive impairment, confusion, conjunctivitis, constipation, coughing, cramping, cystitis, deep vein thrombosis, dehydration, depression, diarrhea, dizziness, dry mouth, dry skin, dyspepsia
  • the methods provided herein include the step of administering a bacterial composition comprising a BCG and an PD-1 pathway inhibitor to a subject.
  • the bacterial composition and an PD-1 pathway inhibitor are administered to the subject in a pharmaceutical composition.
  • the pharmaceutical composition is a bacterial composition described herein and PD-1 pathway inhibitor and a pharmaceutically acceptable carrier.
  • compositions for administration to subjects are combined with additional active and/or inactive materials in order to produce a final product, which may be in single dosage unit or in a multi- dose format.
  • the composition comprises at least one carbohydrate.
  • Carbohydrate refers to a sugar or polymer of sugars.
  • saccharide polysaccharide
  • carbohydrate oligosaccharide
  • Most carbohydrates are aldehydes or ketones with many hydroxyl groups, usually one on each carbon atom of the molecule.
  • Carbohydrates generally have the molecular formula CnthnOn.
  • a carbohydrate may be a monosaccharide, a disaccharide, trisaccharide, oligosaccharide, or polysaccharide.
  • the most basic carbohydrate is a monosaccharide, such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose, and fructose.
  • Disaccharides are two joined monosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose.
  • an oligosaccharide includes between three and six monosaccharide units (e.g., raffinose, stachyose), and
  • polysaccharides include six or more monosaccharide units.
  • Exemplary polysaccharides include starch, glycogen, and cellulose.
  • Carbohydrates may contain modified saccharide units such as 2'- deoxyribose wherein a hydroxyl group is removed, 2'-fluororibose wherein a hydroxyl group is replaced with a fluorine, or N-acetylglucosamine, a nitrogen-containing form of glucose (e.g., - fluororibose, deoxyribose, and hexose).
  • Carbohydrates may exist in many different forms, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.
  • the composition comprises at least one lipid.
  • a lipid includes fats, oils, triglycerides, cholesterol, phospholipids, fatty acids in any form including free fatty acids. Fats, oils and fatty acids can be saturated, unsaturated (cis or trans) or partially unsaturated (cis or trans).
  • the lipid comprises at least one fatty acid selected from lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16: 1), margaric acid (17:0), heptadecenoic acid (17: 1), stearic acid (18:0), oleic acid (18: 1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid (20: 1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EPA), docosanoic acid (22:0), docosenoic acid (22: 1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), and t
  • the composition comprises at least one supplemental mineral or mineral source.
  • supplemental mineral or mineral source examples include, without limitation: chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium.
  • Suitable forms of any of the foregoing minerals include soluble mineral salts, slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals such as carbonyl minerals, and reduced minerals, and combinations thereof.
  • the composition comprises at least one supplemental vitamin.
  • the at least one vitamin can be fat-soluble or water soluble vitamins.
  • Suitable vitamins include but are not limited to vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin.
  • Suitable forms of any of the foregoing are salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity of the vitamin, and metabolites of the vitamin.
  • the composition comprises an excipient.
  • suitable excipients include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, and a coloring agent.
  • the excipient is a buffering agent.
  • suitable buffering agents include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate.
  • the excipient comprises a preservative.
  • suitable preservatives include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol.
  • the composition comprises a binder as an excipient.
  • suitable binders include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C 12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof.
  • the composition comprises a lubricant as an excipient.
  • Non-limiting examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc,
  • polyethyleneglycol sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.
  • the composition comprises a dispersion enhancer as an excipient.
  • suitable dispersants include starch, alginic acid,
  • polyvinylpyrrolidones polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.
  • the composition comprises a disintegrant as an excipient.
  • the disintegrant is a non-effervescent disintegrant.
  • suitable non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro- crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth.
  • the disintegrant is an effervescent disintegrant.
  • suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.
  • provided herein is a method of delivering a bacterial composition described herein to a subject.
  • the bacterial compositions are administered in conjunction or conjointly with the administration of a PD-1 pathway inhibitor.
  • the bacterial composition is co-formulated in a pharmaceutical composition with the PD-1 pathway inhibitor.
  • the bacterial compositions is co-administered with the PD-1 pathway inhibitor.
  • the same mode of delivery are used to deliver both the bacterial composition and the PD-1 pathway inhibitor.
  • different modes of delivery are used to administer the bacterial composition and the PD-1 pathway inhibitor.
  • the bacterial composition administered by injection into or proximal to a tumor while the PD-1 pathway inhibitor is administered via intravenous or intramuscular injection.
  • the bacterial composition is administered to the subject via an injection into a tumor or an injection proximal to the tumor.
  • the PD-1 pathway inhibitor is administered to the subject before the bacterial formulation is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
  • the PD-1 pathway inhibitor is administered to the subject after the bacterial formulation is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23 or 24 hours after or at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29 or 30 days after).
  • the PD- 1 pathway inhibitor and the cancer therapeutic are administered to the subject simultaneously (e.g., at about the same time) or nearly simultaneously (e.g., administrations occur within an hour of each other).
  • the PD-1 pathway inhibitor and the cancer therapeutic are administered to the subject on the same day.
  • the subject is administered multiple PD-1 pathway inhibitors (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 different PD-1 pathway inhibitors).
  • the subject is administered two or more inhibitors of the PD-1 pathway described herein (e.g., an antibody that blocks the interaction between PD-1 and PD-L1 and/or PD-L2, such as an anti-PD-1 antibody, an anti-PD-Ll antibody and/or an anti-PD-L2 antibody).
  • the two or more PD-1 pathway inhibitors and/or the bacterial formulation are administered to the subject simultaneously (e.g., at about the same time) or nearly
  • the PD-1 pathway inhibitors and/or the bacterial formulation are administered to the subject on the same day.
  • the PD-1 pathway inhibitors are administered to the subject after the bacterial formulation is administered (e.g., at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
  • the PD-1 pathway inhibitors are administered to the subject before the bacterial formulation is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23 or 24 hours after or at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16,
  • the methods disclosed herein further comprise immunizing the subject with a BCG bacterium prior to administration of the bacterial composition to the subject.
  • the subject is immunized at least one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks prior to
  • the subject is immunized between 1 and 10 weeks, between 1 and 9 weeks, between 1 and 8 weeks, between 1 and 7 weeks, between 1 and 6 weeks, between 1 and 5 weeks, between 1 and 4 weeks, between 1 and 3 weeks, 2 and 10 weeks, between 2 and 9 weeks, between 2 and 8 weeks, between 2 and 7 weeks, between 2 and 6 weeks, between 2 and 5 weeks, between 2 and 4 weeks, or between 2 and 3 weeks prior to administration of the bacterial composition to the subject.
  • the subject is immunized about one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks prior to administration of the bacterial composition to the subject.
  • the pharmaceutical compositions, dosage forms, and kits described herein can be administered in conjunction with any other conventional anti-cancer treatment, such as, for example, radiation therapy and surgical resection of the tumor. These treatments may be applied as necessary and/or as indicated and may occur before, concurrent with or after administration of the pharmaceutical compositions, dosage forms, and kits described herein.
  • the bacterial composition is administered before a surgery (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23 or 24 hours before or at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before).
  • the bacterial composition is administered after a surgery (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17,
  • the surgery is a tumor resection.
  • the dosage regimen can be any of a variety of methods and amounts, and can be determined by one skilled in the art according to known clinical factors. As is known in the medical arts, dosages for any one patient can depend on many factors, including the subject's species, size, body surface area, age, sex, immunocompetence, and general health, the particular microorganism to be administered, duration and route of administration, the kind and stage of the disease, for example, tumor size, and other compounds such as drugs being administered concurrently. In addition to the above factors, such levels can be affected by the infectivity of the microorganism, and the nature of the microorganism, as can be determined by one skilled in the art.
  • appropriate minimum dosage levels of microorganisms can be levels sufficient for the microorganism to survive, grow and replicate in a tumor or metastasis.
  • the methods of treatment described herein may be suitable for the treatment of a primary tumor, a secondary tumor or metastasis, as well as for recurring tumors or cancers.
  • the dose of the pharmaceutical compositions described herein may be appropriately set or adjusted in accordance with the dosage form, the route of administration, the degree or stage of a target disease, and the like.
  • the general effective dose of the agents may range between
  • the effective dose may be 0.01, 0.05, 0.1, 0.5,
  • the dose administered to a subject is sufficient to prevent cancer, delay its onset, or slow or stop its progression.
  • dosage will depend upon a variety of factors including the strength of the particular compound employed, as well as the age, species, condition, and body weight of the subject.
  • the size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect.
  • Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • An effective dosage and treatment protocol can be determined by routine and conventional means, starting e.g., with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Animal studies are commonly used to determine the maximal tolerable dose ("MTD”) of bioactive agent per kilogram weight. Those skilled in the art regularly extrapolate doses for efficacy, while avoiding toxicity, in other species, including humans.
  • MTD maximal tolerable dose
  • the dosages of the active agents used in accordance with the invention vary depending on the active agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and most preferably causing complete regression of the cancer.
  • Separate administrations can include any number of one or more administrations
  • administrations can be determined according to methods known in the art for monitoring therapeutic methods and other monitoring methods provided herein.
  • the doses may be separated by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days or 1, 2, 3, or 4 weeks.
  • the methods provided herein include methods of providing to the subject one or more administrations of a bacterial composition, where the number of administrations can be determined by monitoring the subject, and, based on the results of the monitoring, determining whether or not to provide one or more additional administrations.
  • Deciding on whether or not to provide one or more additional administrations can be based on a variety of monitoring results, including, but not limited to, indication of tumor growth or inhibition of tumor growth, appearance of new metastases or inhibition of metastasis, the subject's anti-BCG antibody titer, the subject's anti-tumor antibody titer, the overall health of the subject and/or the weight of the subject.
  • the time period between administrations can be any of a variety of time periods.
  • the time period between administrations can be a function of any of a variety of factors, including monitoring steps, as described in relation to the number of administrations, the time period for a subject to mount an immune response and/or the time period for a subject to clear the BCG from normal tissue.
  • the time period can be a function of the time period for a subject to mount an immune response; for example, the time period can be more than the time period for a subject to mount an immune response, such as more than about one week, more than about ten days, more than about two weeks, or more than about a month; in another example, the time period can be less than the time period for a subject to mount an immune response, such as less than about one week, less than about ten days, less than about two weeks, or less than about a month.
  • the time period can be a function of the time period for a subject to clear the BCG from normal tissue; for example, the time period can be more than the time period for a subject to clear the BCG from normal tissue, such as more than about a day, more than about two days, more than about three days, more than about five days, or more than about a week.
  • the PD-1 pathway inhibitor treats the melanoma.
  • the bacterial composition and the PD-1 pathway inhibitor induces an anti -tumor immune response in the subject.
  • the delivery of a PD-1 pathway inhibitor in combination with the bacteria described herein reduces the adverse effects and/or improves the efficacy of the cancer therapeutic.
  • the effective dose of an PD-1 pathway inhibitor described herein is the amount of the therapeutic agent that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, with the least toxicity to the patient.
  • the effective dosage level can be identified using the methods described herein and will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions administered, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • an effective dose of a PD-1 pathway inhibitor will be the amount of the therapeutic agent which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the toxicity of a PD-1 pathway inhibitor is the level of adverse effects experienced by the subject during and following treatment.
  • Adverse events associated with PD-1 pathway inhibitor therapy toxicity include, but are not limited to, abdominal pain, acid indigestion, acid reflux, allergic reactions, alopecia, anaphylaxis, anemia, anxiety, lack of appetite, arthralgias, asthenia, ataxia, azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, elevated blood pressure, difficulty breathing, bronchitis, bruising, low white blood cell count, low red blood cell count, low platelet count, cardiotoxicity, cystitis, hemorrhagic cystitis, arrhythmias, heart valve disease, cardiomyopathy, coronary artery disease, cataracts, central neurotoxicity, cognitive impairment, confusion, conjunctivitis, constipation, coughing, cramping, cystitis, deep vein thrombosis, dehydration, depression, diarrhea, dizziness, dry mouth, dry skin
  • hyperkalemia hyperlipasemia
  • hypermagnesemia hypermagnesemia
  • the methods described herein relate to the treatment of skin cancer (e.g., melanoma).
  • skin cancer e.g., melanoma
  • melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
  • Non-limiting examples of melanomas are Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma subungal melanoma, and superficial spreading melanoma.
  • Example 1 BCG and anti-PD-1 inhibited tumor growth in a mouse melanoma model
  • mice were pre-immunized with lxl 0 6 Mycobacterium bovis BCG Connaught intradermally (in 50ul volume) 28 days prior to tumor cell inoculation. Pre- immunization was performed in the flank opposite to the site of tumor cell inoculation.
  • Mycobacterium bovis BCG Connaught was purchased from ATCC (ATCC 35745), and grown and prepared by Aeras (Rockville, MD, USA). On the day of tumor inoculation (day 0), 100,000 freshly thawed, low-passage B16-F 10 melanoma cells (ATCC CRL-6475) were resuspended in sterile PBS containing 50% Matrigel. Each mouse was inoculated subcutaneously in the right hind flank.
  • mice/group 1) Pre-immunized mice that received intratumoral vehicle + isotype control IgG2a (i.p.); 2) Pre-immunized mice that received intratumoral vehicle + anti-PD-1 (i.p.) (BioxCell); 3) Pre-immunized mice that received intratumoral BCG Connaught; 4) Pre-immunized mice that received intratumoral BCG
  • the intratumoral BCG + anti-PD-1 group showed significant tumor growth inhibition compared to either the BCG alone or anti-PD-1 alone group as determined by tumor volume (Fig. 1) and tumor weight (Fig. 2). The study terminated on day 16, at which time the mice were sacrificed and tumors removed for ex vivo flow cytometric analysis.
  • Tumors were dissociated using a Miltenyi tumor dissociation enzyme cocktail according to the manufacturer's instructions. Tumor weights were recorded and tumors were chopped then placed in 15ml tubes containing the enzyme cocktail and placed on ice. Samples were then placed on a gentle shaker at 37°C for 45 minutes and quenched with up to 15ml complete RPMI (Roswell Park Memorial Institute) medium.
  • Each cell suspension was strained through a 70um filter into a 50ml falcon tube and centrifuged at 1000 rpm for 10 minutes. Cells were resuspended in FACS buffer and washed to remove remaining debris. If necessary, samples were strained again through a second 70um filter into a new tube. Cells were stained for analysis by flow cytometry using techniques known in the art. Staining antibodies included anti-CD45 (leukocytes), anti-CD8 (CD8+ T cells), anti-CDl lc (dendritic cells), anti-MHCII (MHC class II, anti-CDl lb (monocytes and granulocytes), anti-Gr-1 (granulocyte receptor), and anti-CD206 (M2 macrophages).
  • Staining antibodies included anti-CD45 (leukocytes), anti-CD8 (CD8+ T cells), anti-CDl lc (dendritic cells), anti-MHCII (MHC class II, anti-CDl lb (monocyte
  • mice that received both intratumoral BCG and anti-PD-1 had the highest number of infiltrating CD45+ cells (immune cells) per gram of tumor, signifying the induction of a robust anti-tumor immune response.
  • CD45+ infiltrating cells Compared to control mice, there was only a modest increase in CD45+ infiltrating cells in the tumors from the BCG group, and no observable increase in the anti-PD-1 group.
  • Tumors from the BCG + anti-PD-1 group also had the highest number of infiltrating dendritic cells (DCs) (Fig. 4A), CD8+ T cells (Fig. 4B), and macrophages (Fig. 5A) per gram of tumor.
  • DCs dendritic cells
  • Fig. 4B CD8+ T cells
  • macrophages Fig. 5A
  • M2 macrophages are commonly found infiltrating tumors and are thought to actually enhance tumor growth and promote tumor angiogenesis. (See Hao et al. 2012.
  • the BCG + anti-PD-1 group had the lowest number of anti-inflammatory M2 macrophages of any of the treatment groups (Fig. 5B). This shows that the combination of BCG + anti-PD-1 promotes an intratumoral environment more amenable to proinflammatory anti-tumor responses.
  • Example 2 BCG in a mouse melanoma model
  • B16-F10 ATCC CRL-6475 tumor cells were resuspended in sterile PBS containing 50% Matrigel and inoculated in a lOOul final volume into each hind flank (left and right) of each mouse.
  • animals were randomized based on tumor volume of right side tumors and distributed into the following groups: 1) Vehicle + PBS, 2) anti-PDLl antibody, 3) BCG and 4) BCG + anti- PDLl antibody.
  • the left side tumors were treated based on group assigned while right side tumors were not treated. The tumor volume was measured in both the treated and untreated hind flanks .
  • BCG and BCG + ani-PDLl showed better tumor growth inhibition compared to that seen in anti-PDLl alone ( Figures 6 and 7).

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Abstract

La présente invention concerne des méthodes et des compositions associées à l'utilisation du bacille de Calmette-Guérin (BCG) dans le traitement d'un mélanome.
PCT/US2017/066711 2016-12-16 2017-12-15 Polythérapies pour le traitement d'un mélanome WO2018112364A1 (fr)

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WO2021261891A1 (fr) * 2020-06-22 2021-12-30 (주)로제타엑소좀 Procédé et composition pour améliorer l'efficacité de traitement du cancer de vésicules extracellulaires bactériennes
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US11810650B2 (en) 2017-04-03 2023-11-07 Gusto Global, Llc Rational design of microbial-based biotherapeutics
WO2021261891A1 (fr) * 2020-06-22 2021-12-30 (주)로제타엑소좀 Procédé et composition pour améliorer l'efficacité de traitement du cancer de vésicules extracellulaires bactériennes
CN112516319A (zh) * 2020-12-08 2021-03-19 华中农业大学 用于治疗乳腺癌的组合药剂

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