# US 9,750,807 B2 · Combination of local and systemic immunomodulative therapies for melanoma and liver cancer

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- Number: US 9,750,807 B2
- Document ID: US9750807B2
- Status: Granted
- Kind: B2
- Application number: 14/748,634
- Filed: 2015-06-24
- Published: 2015-10-15
- Granted: 2017-09-05
- Earliest claimed: 2011-03-10
- Assignees: Provectus Pharmatech, Inc.; Pfizer Inc.
- Applicants: Provectus Pharmaceuticals, Inc.; Pfizer, Inc.
- Inventors: Craig J. Eagle; H. Craig Dees; Eric A. Wachter; Jamie Singer
- Web page: https://patentgrep.com/patent/US9750807B2

## CPC

- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 31/352: condensed with carbocyclic rings, e.g. methantheline {(cannabinoids A61K31/658)}
- A61K 31/365: Lactones
- A61K 38/193: {Colony stimulating factors [CSF]}
- A61K 38/20: Interleukins [IL]
- A61K 38/204: {IL-6}
- A61K 38/2006: {IL-1}
- A61K 38/2013: {IL-2}
- A61K 38/21: Interferons {[IFN]}
- A61K 38/212: {IFN-alpha}
- A61K 38/217: {IFN-gamma}
- A61K 39/0005: {Vertebrate antigens (from snakes A61K39/38)}
- A61K 39/0011: {Cancer antigens}
- A61K 39/245: Herpetoviridae, e.g. herpes simplex virus
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/02: Inorganic compounds
- A61K 47/48215
- C07K 16/30: from tumour cells
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- A61K 2039/505: {comprising antibodies}
- C12N 2710/16021: Viruses as such, e.g. new isolates, mutants or their genomic sequences
- C12N 2710/16034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

A method for the treatment of cancer comprising administration of a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition, or variant of said composition, in combination with a therapeutically effective amount of a systemic immunomodulatory anticancer agent. A further method for the treatment of cancer comprising administration of a therapeutically effective amount of an intralesional chemoablative pharmaceutical composition, or variant of said composition, in combination with a therapeutically effective amount of a systemic targeted anticancer agent. The present invention is further directed to pharmaceutical compositions for treatment of cancer. The intralesional chemoablative pharmaceutical composition can comprise an IL chemoablative agent comprising primarily a halogenated xanthene.

## Claims

### Claim 1

A method of treatment of a melanoma, or a primary or metastatic liver cancer tumor in a human comprising separately administering a therapeutically effective amount of: (1) an intralesional chemoablative pharmaceutical composition to elicit ablation of at least one melanoma, or primary or metastatic liver cancerous tumor; and (2) a therapeutically effective amount of a systemic immunomodulatory anticancer agent that comprises interferon-gamma, anti-CTLA-4 antibodies, anti-PD-L1 antibodies or anti-PD-1 antibodies,
wherein said intralesional chemoablative pharmaceutical composition comprises an intralesional (IL) chemoablative agent comprising rose bengal (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein) in an appropriate pharmaceutical composition, including a 0.1% (w/v) or higher concentration aqueous solution of rose bengal, or a physiologically acceptable salt of rose bengal, said intralesional chemoablative pharmaceutical composition being administered intralesionally into said at least one melanoma, or primary or metastatic liver cancerous tumor at about 0.1 mL/cc lesion volume to about 2 mL/cc lesion volume.

### Claim 2 (depends on 1)

The method of claim 1, wherein said systemic immunomodulatory anticancer agent that is a systemic inhibitor of immune system down-regulation comprises anti-CTLA-4 antibodies.

### Claim 3 (depends on 1)

The method of claim 1, wherein the rose bengal salt is rose bengal disodium.

### Claim 4 (depends on 1)

The method of claim 1, wherein said rose bengal is present at a concentration of about 0.1% (w/v) up to about 20% (w/v), and the pharmaceutical composition includes an electrolyte comprising at least one cation selected from the group consisting of sodium, potassium, calcium and magnesium and at least one anion selected from the group consisting of chloride, phosphate and nitrate, wherein the electrolyte is at a concentration of between about 0.1% (w/v) and about 2% (w/v).

### Claim 5 (depends on 4)

The method of claim 4, wherein the concentration of said electrolyte in the IL chemoablative pharmaceutical composition is between 0.5 to 1.5% (w/v).

### Claim 6 (depends on 1)

The method of claim 1, wherein said chemoablative pharmaceutical composition has an osmolality of the composition of greater than about 100 mOsm/kg.

### Claim 7 (depends on 4)

The method of claim 4, wherein said electrolyte is sodium chloride.

### Claim 8 (depends on 1)

The method of claim 1, wherein said pharmaceutical composition comprises a hydrophilic vehicle.

### Claim 9 (depends on 1)

The method of claim 1, wherein said pharmaceutical composition has a pH in the range of between about 4 to about 10.

### Claim 10 (depends on 9)

The method of claim 9, wherein said pharmaceutical composition has a pH in the range of between about 5 to about 7.

### Claim 11

A method of treatment of a melanoma, or primary or metastatic liver cancer tumor in a human comprising separately administering a therapeutically effective amount of: (1) an intralesional chemoablative pharmaceutical composition to elicit ablation of at least one melanoma, or primary or metastatic liver cancerous tumor; and (2) a therapeutically effective amount of a systemic immunomodulatory anticancer agent that comprises interferon-gamma, anti-CTLA-4 antibodies, anti-PD-L1 antibodies or anti-PD-1 antibodies, wherein said intralesional chemoablative pharmaceutical composition comprises an intralesional (IL) chemoablative agent comprising a halogenated xanthene in an appropriate pharmaceutical composition, including a 0.1% (w/v) or higher concentration aqueous solution of the halogenated xanthene or mixtures thereof, or a physiologically acceptable salt of the halogenated xanthene.

### Claim 12 (depends on 11)

The method of claim 11, wherein the halogenated xanthene is selected from the group consisting of erythrosin B, phloxine B, 4,5,6,7-tetrabromo-2′,4′,5′,7′-tetraiodofluorescein, 2′,4,5,6,7-pentachloro-4′,5′,7′-triiodofluorescein, 4,4′,5,6,7-pentachloro-2′,5′,7′-triiodofluorescein, 2′,4,5,6,7,7′-hexachloro-4′,5′-diiodofluorescein, 4,4′,5,5′,6,7-hexachloro-2′,7′-diiodofluorescein, 2′,4,5,5′,6,7-hexachloro-4′,7′-diiodofluorescein, 4,5,6,7-tetrachloro-2′,4′,5′-triiodofluorescein, 4,5,6,7-tetrachloro-2′,4′,7′-triiodofluorescein, 4,5,6,7-tetrabromo-2′,4′,5′-triiodofluorescein, and 4,5,6,7-tetrabromo-2′,4′,7′-triiodofluorescein.

### Claim 13 (depends on 11)

The method of claim 11, wherein the halogenated xanthene is rose bengal (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein) or a physiologically acceptable salt of rose bengal.

### Claim 14 (depends on 13)

The method of claim 13 wherein the halogenated xanthene is rose bengal disodium.

### Claim 15 (depends on 11)

The method of claim 11, wherein said rose bengal is present at a concentration of about 0.1% (w/v) up to about 20% (w/v), and the pharmaceutical composition includes an electrolyte comprising at least one cation selected from the group consisting of sodium, potassium, calcium and magnesium and at least one anion selected from the group consisting of chloride, phosphate and nitrate, wherein the electrolyte is at a concentration of between about 0.1% (w/v) and about 2% (w/v).

### Claim 16 (depends on 15)

The method of claim 15, wherein the concentration of said electrolyte in the IL chemoablative pharmaceutical composition is between 0.5 to 1.5% (w/v).

### Claim 17 (depends on 16)

The method of claim 16, wherein said chemoablative pharmaceutical composition has an osmolality of the composition of greater than about 100 mOsm/kg.

### Claim 18 (depends on 15)

The method of claim 15, wherein said electrolyte is sodium chloride.

### Claim 19 (depends on 11)

The method of claim 11, wherein said pharmaceutical composition comprises a hydrophilic vehicle.

### Claim 20 (depends on 11)

The method of claim 11, wherein said pharmaceutical composition has a pH value in the range of about 4 to about 10.

### Claim 21 (depends on 20)

The method of claim 20, wherein said pharmaceutical composition has a pH value in the range of about 5 to about 7.

### Claim 22 (depends on 11)

The method of claim 11, wherein said systemic immunomodulatory anticancer agent comprises one or more of anti-CTLA-4 antibodies, anti-PD-L1 antibodies or anti-PD-1 antibodies.

### Claim 23 (depends on 22)

The method of claim 22, wherein said administration of said systemic immunomodulatory anticancer agent is commenced prior to administration of said intralesional chemoablative pharmaceutical composition.

### Claim 24 (depends on 23)

The method of claim 23, wherein the rose bengal salt is rose bengal disodium.

### Claim 25

A method of treatment of a melanoma, or a primary or metastatic liver cancer tumor in a human comprising separately administering a therapeutically effective amount of: (1) an intralesional chemoablative pharmaceutical composition to elicit ablation of at least one melanoma, or primary or metastatic liver cancerous tumor; and (2) a therapeutically effective amount of a systemic immunomodulatory anticancer agent that is a systemic inhibitor of immune system down-regulation or that is a systemic enhancer of immune system up-regulation in a combination therapeutic regimen,
wherein said intralesional chemoablative pharmaceutical composition comprises an intralesional (IL) chemoablative agent comprising rose bengal (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein) in an appropriate pharmaceutical composition, including a 0.1% (w/v) or higher concentration aqueous solution of rose bengal, or a physiologically acceptable salt of rose bengal, said intralesional chemoablative pharmaceutical composition being administered intralesionally into said at least one melanoma, or primary or metastatic liver cancerous tumor at about 0.1 mL/cc lesion volume to about 2 mL/cc lesion volume, and
wherein said systemic immunomodulatory anticancer agent that is a systemic inhibitor of immune system down-regulation comprises anti-CTLA-4 antibodies, anti-PD-L1 antibodies or anti-PD-1 antibodies.