# US 11,998,593 B2 · Combination vaccine devices and methods of killing cancer cells > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,998,593 B2 - Document ID: US11998593B2 - Status: Granted - Kind: B2 - Application number: 16/877,274 - Filed: 2020-05-18 - Published: 2020-09-03 - Granted: 2024-06-04 - Earliest claimed: 2014-04-30 - Assignees: President and Fellows of Harvard College; Dana-Farber Cancer Institute, Inc. - Applicants: President and Fellows of Harvard College; Dana-Farber Cancer Institute, Inc. - Inventors: Omar Abdel-Rahman Ali; David J. Mooney; Glenn Dranoff - Web page: https://patentgrep.com/patent/US11998593B2 ## CPC - A61K 39/0011: {Cancer antigens} - A61K 39/001102: {Receptors, cell surface antigens or cell surface determinants} - A61K 39/001156: {Tyrosinase and tyrosinase related proteinases [TRP-1 or TRP-2]} - A61K 39/001157: {Telomerase or TERT [telomerase reverse transcriptase]} - A61K 39/00117: {Mucins, e.g. MUC-1} - A61K 39/001171: {Gangliosides, e.g. GM2, GD2 or GD3} - A61K 39/00118: {from embryonic or fetal origin} - A61K 39/001182: {Carcinoembryonic antigen [CEA]} - A61K 39/001186: {MAGE} - A61K 39/001191: {Melan-A/MART} - A61K 39/001192: {Glycoprotein 100 [Gp100]} - A61K 39/02: Bacterial antigens - A61K 39/12: Viral antigens - A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) - A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin - A61P 31/04: Antibacterial agents - A61P 31/12: Antivirals - A61P 35/00: Antineoplastic agents - A61P 37/04: Immunostimulants - C07K 16/2803: {against the immunoglobulin superfamily} - C07K 16/2818: {against CD28 or CD152} - C07K 16/30: from tumour cells - C07K 16/3053: {Skin, nerves, brain} - 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 2039/507: {Comprising a combination of two or more separate antibodies} - A61K 2039/5152: {Tumor cells} - A61K 2039/54: {characterised by the route of administration} - A61K 2039/55516: {Proteins; Peptides} - A61K 2039/55522: {Cytokines; Lymphokines; Interferons} - A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers} - A61K 2039/55561: {CpG containing adjuvants; Oligonucleotide containing adjuvants} - A61K 2039/64: {characterised by the architecture of the carrier-antigen complex, e.g. repetition of carrier-antigen units} - C07K 2317/21: from primates, e.g. man - C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered - 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) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - 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 The present invention comprises compositions, methods, and devices for enhancing an endogenous immune response against a cancer. Devices and methods provide therapeutic immunity to subjects against cancer. ## Claims ### Claim 1 A method of treating a poorly immunogenic cancer in a subject in need thereof, wherein the poorly immunogenic cancer is resistant to cytotoxic T-lymphocyte (CTL)-mediated lysis or natural killer (NK) cell mediated killing, the method comprising administering to the subject: a) an inhibitor of an immune checkpoint protein; and b) a device comprising (i) a macroporous scaffold composition comprising open, interconnected pores, (ii) a cell recruitment composition that recruits an immune cell, wherein the cell recruitment composition is selected from the group consisting of a cytokine, a chemokine, a growth factor, and a combination thereof; and (iii) an antigen derived from the cancer, wherein the inhibitor is administered concurrent and subsequent to the administration of the device, wherein the subsequent administration is in the absence of the device, and wherein the method enhances the CD8 T cell: Treg cell ratio in the cancer, thereby treating the cancer. ### Claim 2 (depends on 1) The method of claim 1, wherein the immune checkpoint protein is selected from the group consisting of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1), programmed cell death protein 1 ligand 1 (PDL1), programmed cell death protein ligand 2 (PDL2), lymphocyte activation gene 3 (LAG3), B7-H3, B7-H4, and T cell membrane protein 3 (TIM3) adenosine A2a receptor (A2aR), and kill inhibitory receptors (KIRs). ### Claim 3 (depends on 1) The method of claim 1, wherein the inhibitor of an immune checkpoint protein is an antibody or an antigen binding fragment thereof. ### Claim 4 (depends on 3) The method of claim 3, wherein the antibody is selected from the group consisting of BMS-936558, MK-3475, pidilizumab, MDX1105, and MGA271. ### Claim 5 (depends on 1) The method of claim 1, wherein the inhibitor of the immune checkpoint protein is selected from the group consisting of a PDL2-immunoglobulin (Ig) fusion protein, and a LAG3-Ig fusion protein. ### Claim 6 (depends on 1) The method of claim 1, wherein the macroporous scaffold composition comprises a polymer or co-polymer selected from the group consisting of polylactic acid, polyglycolic acid, PLGA, alginate, gelatin, collagen, agarose, poly(lysine), polyhydroxybutyrate, poly-epsilon-caprolactone, polyphosphazines, poly(vinyl alcohol), poly(alkylene oxide), poly(ethylene oxide), poly(allylamine), poly(acrylate), poly(4-aminomethylstyrene), pluronic polyol, polyoxamer, poly(uronic acid), poly(anhydride) or poly(vinylpyrrolidone). ### Claim 7 (depends on 1) The method of claim 1, wherein the immune cell comprises an antigen presenting cell. ### Claim 8 (depends on 7) The method of claim 7, wherein the antigen presenting cell is a dendritic cell. ### Claim 9 (depends on 1) The method of claim 1, wherein the cell recruitment composition is selected from the group consisting of GM-CSF, Flt3L, and CCL20. ### Claim 10 (depends on 1) The method of claim 1, wherein the antigen is derived from a cancer selected from the group consisting of a melanoma, a central nervous system (CNS) cancer, a CNS germ cell tumor, a lung cancer, a leukemia, a multiple myeloma, a renal cancer, a malignant glioma, a medulloblatoma, a breast cancer, an ovarian cancer, a prostate cancer, a bladder cancer, a fibrosarcoma, a pancreatic cancer, a gastric cancer, a head and neck cancer, and a colorectal cancer. ### Claim 11 (depends on 1) The method of claim 1, wherein the antigen is selected from the group consisting of a MAGE series of antigens, MART-1/melana, Tyrosinase, ganglioside, gp100, GD-2, O-acetylated GD-3, GM-2, MUC-1, Sos1, Protein kinase C-binding protein, Reverse transcriptase protein, AKAP protein, VRK1, KIAA1735, Cytokeratin-19 (CYFRA21-1), Squamous Cell Carcinoma Antigen 1 (SCCA-1), Protein T4-A, Squamous Cell Carcinoma Antigen 2 (SCCA-2), Ovarian carcinoma antigen CA125, Mucin 1, Carcinoma-Associated Mucin, Polymorphic Epithelial Mucin, PEMT, Episialin, Tumor-Associated Epithelial Membrane Antigen, EMA, H23AG, Peanut-Reactive Urinary Mucin, Breast Carcinoma-Associated Antigen DF3, CTCL tumor antigen se1-1, CTCL tumor antigen se14-3, CTCL tumor antigen se20-4, CTCL tumor antigen se20-9, CTCL tumor antigen se33-1, CTCL tumor antigen se37-2, CTCL tumor antigen se57-1, CTCL tumor antigen se89-1, Prostate-specific membrane antigen, 5T4 oncofetal trophoblast glycoprotein, Orf73 Kaposi's sarcoma-associated herpesvirus, MAGE-C1 (cancer/testis antigen CT7), MAGE-B1 antigen, MAGE-B2 antigen, MAGE-2 antigen, MAGE-4a antigen, MAGE-4b antigen, Colon cancer antigen NY-CO-45, Lung cancer antigen NY-LU-12 variant A, Cancer associated surface antigen, Adenocarcinoma antigen ART1, Paraneoplastic associated brain-testis-cancer antigen (onconeuronal antigen MA2; paraneoplastic neuronal antigen), Neuro-oncological ventral antigen 2 (NOVA2), Hepatocellular carcinoma antigen gene 520, Tumor-Associated Antigen CO-029, Tumor-associated antigen MAGE-X2, Synovial sarcoma, X breakpoint 2, Squamous cell carcinoma antigen recognized by T cell, Serologically defined colon cancer antigen 1, Serologically defined breast cancer antigen NY-BR-15, Serologically defined breast cancer antigen NY-BR-16, Chromogranin A, parathyroid secretory protein 1, DUPAN-2, CA 19-9, CA 72-4, CA 195, Carcinoembryonic antigen (CEA). ### Claim 12 (depends on 1) The method of claim 1, wherein the antigen comprises a tumor lysate or an irradiated tumor cell. ### Claim 13 (depends on 1) The method of claim 1, wherein the device further comprises an adjuvant. ### Claim 14 (depends on 13) The method of claim 13, wherein the adjuvant comprises a TLR agonist. ### Claim 15 (depends on 14) The method of claim 14, wherein the TLR agonist is a TLR3 or TLR9 agonist. ### Claim 16 (depends on 15) The method of claim 15, wherein the TLR agonist is selected from the group consisting of a CpG rich oligonucleotide, a PEI-CpG oligonucleotide, a polyinosine-polycytidylic acid (poly (I:C)) and PEI-poly (I:C). ### Claim 17 (depends on 1) The method of claim 1, wherein the inhibitor is further administered to the subject prior to the administration of the device. ### Claim 18 A method of treating a poorly immunogenic cancer a subject in need thereof, wherein the poorly immunogenic cancer is resistant to cytotoxic T-lymphocyte (CTL)-mediated lysis or natural killer (NK) cell mediated killing, the method comprising administering to the subject: a) an antibody selected from the group consisting of an anti-PD1 antibody, an anti-CTLA4 antibody, and a combination thereof; b) a device comprising (i) a PLG macroporous scaffold comprising open, interconnected pores, (ii) a granulocyte macrophage-colony stimulating factor (GM-CSF); and (iii) a tumor cell lysate, wherein the antibody is administered concurrent and subsequent to the administration of the device, wherein the subsequent administration is in the absence of the device, and wherein the method enhances the CD8 T cell: Treg cell ratio in the cancer, thereby treating the cancer. ### Claim 19 (depends on 1) The method of claim 1, wherein the poorly immunogenic cancer is selected from the group consisting of a melanoma, an ovarian cancer, a renal cancer, and a lung cancer. ### Claim 20 (depends on 1) The method of claim 1, wherein PDL1 is overexpressed in the poorly immunogenic cancer. ### Claim 21 (depends on 19) The method of claim 19, wherein the poorly immunogenic cancer is a melanoma.