Immunotherapeutic constructs and methods of their use

Abstract

Disclosed herein are immunotherapeutic constructs comprising a delivery particle, at least one adjuvant, and one or more therapeutic agents/compounds that cause antigen release and/or modulate immunosuppressive tumor microenvironment. These immunotherapeutic constructs create adaptive immunity or anti-cancer immune response(s) that can be used, for instance, to prevent and treat broad types of cancer. Further disclosed are uses of the immunotherapeutic constructs, including to prevent and treat cancer in humans and animals.

What is claimed is: 
     
         1 . An immunotherapeutic construct comprising:
 a delivery system comprising at least one therapeutic agent, wherein the therapeutic agent causes tumor antigen release and/or modulates an immunosuppressive tumor microenvironment and at least one adjuvant,   wherein the immunotherapeutic construct does not comprise a tumor-specific antigen or ovalbumin.   
     
     
         2 . The immunotherapeutic construct of  claim 1 , wherein the delivery system comprises a liposome, a lipid-based particle, a polymeric particle, an inorganic particle, or a hybrid thereof. 
     
     
         3 . The immunotherapeutic construct of  claim 2 , wherein the delivery vehicle is a liposome, a lipid-based particle, a polymeric particle, an inorganic particle, or an inorganic particle coated with polymer or lipid. 
     
     
         4 . The immunotherapeutic construct of  claim 3 , wherein the delivery vehicle is an inorganic particle and comprises one or more of mesoporous silica, gold, aluminum, silver, iron oxide, calcium phosphate, or an antioxidant particle. 
     
     
         5 . The immunotherapeutic construct of  claim 4 , wherein the inorganic particle comprises an antioxidant particle comprising cerium oxide. 
     
     
         6 . The immunotherapeutic construct of  claim 4 , wherein the delivery vehicle comprises a mesoporous silica particle. 
     
     
         7 . The immunotherapeutic construct of  claim 1 , wherein the delivery vehicle comprises one or more of fullerenes, endohedral metallofullerenes, trimetallic nitride templated endohedral metallofullerenes, single-walled and multi-walled carbon nanotubes, branched and dendritic carbon nanotubes, gold nanorods, silver nanorods, single-walled and multi-walled boron/nitrate nanotubes, carbon nanotube peapods, carbon nanohorns, carbon nanohorn peapods, liposomes, nanoshells, dendrimers, microparticles, quantum dots, superparamagnetic nanoparticles, nanorods, cellulose nanoparticles, silicon, silica and polymer micro- and nano-spheres, silica-shells, biodegradable PLGA micro- and nano-spheres, gold particles, cerium oxide particles, zinc oxide particles, silver particles, aluminum particles, carbon particles, iron particles, iron oxide particles, adjuvant particles, and/or modified micelles. 
     
     
         8 . The immunotherapeutic construct of any one of  claims 1 - 7 , wherein the delivery vehicle is a polymeric particle comprising one or more of PLGA, PLL, dextran, dendrimer, polyarginine, PEG, PEI, or chitosan. 
     
     
         9 . The immunotherapeutic construct of any one of  claims 1 - 8 , having a hydrodynamic size of 5 nm to 999 nm. 
     
     
         10 . The immunotherapeutic construct of any one of  claims 1 - 8 , having a hydrodynamic size of 1 micron to 1000 microns. 
     
     
         11 . The immunotherapeutic construct of  claim 6 , wherein the delivery vehicle comprises a mesoporous silica nanoparticle having a size of about 5-200 nm. 
     
     
         12 . The immunotherapeutic construct of  claim 11 , wherein the mesoporous silica nanoparticle is coated with cross-linked polyethyleneimine and polyethylene glycol. 
     
     
         13 . The immunotherapeutic construct of any one of  claims 1 - 12 , wherein the at least one therapeutic agent comprises a siRNA, a miRNA, an antisense oligonucleotide, a mRNA, a DNA, a sgRNA (CRISPR-cas9 element), an oligonucleotide, a polynucleotide, a peptide, a protein, a chemotherapy drug, a toxin, an antioxidant, a small molecule inhibitor, an antibody, or a radio-therapeutic agent. 
     
     
         14 . The immunotherapeutic construct of  claim 13 , wherein the at least one therapeutic agent comprises a siRNA, a miRNA, an antisense oligonucleotide, a mRNA, or a DNA. 
     
     
         15 . The immunotherapeutic construct of  claim 14 , wherein the at least one therapeutic agent comprises a siRNA. 
     
     
         16 . The immunotherapeutic construct of  claim 15 , wherein the at least one therapeutic agent comprises a siRNA that inhibits expression or an activity of STAT3, CD39, CD73, TGFβ, PD-L1, PD1, CTLA4, MIF, PLK1, HIF, NOX1-4, HER2, EGFR, BCL2, AKT1, HIF1-alpha, NOX1-4, AR, MYC, BRAF, BRAF V600E, or MTDH. 
     
     
         17 . The immunotherapeutic construct of  claim 15  or  16 , wherein the at least one therapeutic agent comprises a siRNA that inhibits expression or an activity of STAT3. 
     
     
         18 . The immunotherapeutic construct of any one of  claims 15 - 17 , wherein the at least one therapeutic agent comprises a siRNA that inhibits expression of an activity of HER2. 
     
     
         19 . The immunotherapeutic construct of any one of  claims 1 - 12 , wherein the at least one therapeutic agent inhibits expression or an activity of STAT3, CD39, CD73, TGFβ, PD-L1, PD1, CTLA4, MIF, PLK1, HIF, NOX1-4, HER2, EGFR, BCL2, AKT1, HIF1-alpha, NOX1-4, AR, MYC, BRAF, BRAF V600E, or MTDH. 
     
     
         20 . The immunotherapeutic construct of any one of  claims 1 - 19 , wherein the at least one therapeutic agent comprises one or more anti-cancer agents selected from an antibiotic, a plant alkaloid, a PLK1 inhibitor, a mitotic kinase inhibitor, an immune checkpoint inhibitor, a platinum- based chemotherapeutic agent, a HER2 small molecule inhibitor, an anti-EGFR antibody, and an anti-HER2 antibody. 
     
     
         21 . The immunotherapeutic construct of  claim 20 , wherein the at least one therapeutic agent comprises an immune checkpoint inhibitor, and the immune checkpoint inhibitor is an antibody against PD-L1, PD1, or CTLA4. 
     
     
         22 . The immunotherapeutic construct of  claim 21 , wherein the immune checkpoint inhibitor is an antibody against PD-L1. 
     
     
         23 . The immunotherapeutic construct of any one of  claims 1 - 22 , wherein the at least one therapeutic agent comprises a PLK1 inhibitor. 
     
     
         24 . The immunotherapeutic construct of  claim 23 , wherein the PLK1 inhibitor is volasertib. 
     
     
         25 . The immunotherapeutic construct of any one of  claims 1 - 24 , wherein the at least one therapeutic agent comprises one or more of docetaxel, mitoxantrone, or cabazitaxel. 
     
     
         26 . The immunotherapeutic construct of any one of  claims 1 - 25 , wherein the at least one therapeutic agent comprises an anti-EGFR antibody, 
     
     
         27 . The immunotherapeutic construct of  claim 26 , wherein the anti-EGFR antibody is cetuximab. 
     
     
         28 . The immunotherapeutic antibody of any one of  claims 1 - 25 , wherein the at least one therapeutic agent comprises an anti-HER2 antibody. 
     
     
         29 . The immunotherapeutic antibody of  claim 28 , wherein the anti-HER2 antibody is trastuzumab. 
     
     
         30 . The immunotherapeutic construct of any one of  claims 1 - 29 , wherein the adjuvant has immunostimulatory activity and comprises one or more of a CpG oligonucleotide, a DNA TLR agonist containing a CpG sequence, a non-CpG DNA TLR agonist, an RNA TLR agonist, an aluminum salt, an anti-CD40 antibody, a fusion protein, a cytokine, a small molecule TLR agonist, an oil- or surfactant-based adjuvant, a lipopolysaccharide, a plant extract, or a derivative thereof. 
     
     
         31 . The immunotherapeutic construct of any one of  claims 1 - 30 , wherein the adjuvant comprises a CpG oligonucleotide, imiquimod, resiquimod, gardiquimod, poly I:C, poly ICLC, dSLIM, or EnanDIM. 
     
     
         32 . The immunotherapeutic construct of any one of  claims 1 - 31 , wherein the adjuvant comprises a CpG oligonucleotide. 
     
     
         33 . A composition comprising:
 the immunotherapeutic construct of any one of  claims 1 - 32 ; and   at least one pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.   
     
     
         34 . A method of treating cancer comprising administering to a subject with cancer an effective amount of the immunotherapeutic construct of any one of  claims 1 - 32 , or the composition of  claim 33 . 
     
     
         35 . The method of  claim 34 , wherein the subject is a mammal. 
     
     
         36 . The method of  claim 35 , wherein the mammal is a human. 
     
     
         37 . A method of treating a cell exhibiting symptoms of cancer comprising contacting the cell with a therapeutically effective amount of the immunotherapeutic construct of any one of  claims 1 - 32 , or the composition of  claim 33 . 
     
     
         38 . A method of treating a cell obtained from a subject exhibiting symptoms of cancer or another hyperproliferative disorder, comprising contacting the cell with a therapeutically effective amount of the immunotherapeutic construct of any one of  claims 1 - 32 , or the composition of  claim 33 . 
     
     
         39 . A method of treating a cell obtained from a subject exhibiting symptoms of cancer or another hyperproliferative disorder, comprising contacting a cell ex vivo with a therapeutically effective amount of the immunotherapeutic construct of any one of  claims 1 - 32 , or the composition of  claim 33 . 
     
     
         40 . The method of  claim 38  or  claim 39 , wherein the cell is a cancer cell. 
     
     
         41 . The method of  claim 38  or  claim 39 , wherein the cell is not a cancer cell. 
     
     
         42 . The method of  claim 41 , wherein the cell is an immune cell. 
     
     
         43 . The method of  claim 38  or  claim 39 , wherein the cell is immortalized. 
     
     
         44 . The method of any one of  claims 37 - 43 , further comprising administering at least one treated cell back to a subject. 
     
     
         45 . A method of treating a subject diagnosed as having a hyperproliferative disease or condition or having a high-risk of developing such disease or condition, comprising administering to the subject an effective amount of the composition of  claim 33 . 
     
     
         46 . The method of  claim 45 , wherein the subject is a mammal. 
     
     
         47 . The method of  claim 46 , wherein the mammal is a human. 
     
     
         48 . The method of any one of  claims 45 - 47 , wherein the hyperproliferative disease or condition comprises one or more of cancer, pre-cancer, or cancer metastasis. 
     
     
         49 . The method of any one of claims  claim 45 - 48 , wherein the hyperproliferative disease comprises one or more of melanoma, lung cancer, breast cancer, pancreatic cancer, brain cancer, prostate cancer, head and neck cancer, kidney cancer, colorectal cancer, lymphoma, gastric cancer, colon cancer, liver cancer, or rare cancer. 
     
     
         50 . The method of any one of  claims 45 - 49 , wherein the administering comprises:
 injection to or at a tumor in the subject;   infusion locally to or at a tumor in the subject;   systemic injection in the subject;   systemic infusion in the subject; or   topical application to the subject.   
     
     
         51 . The method of any one of  claims 45 - 50 , wherein the administering comprises microneedle application to the subject. 
     
     
         52 . A method of enhancing effect of an anti-cancer therapy in a subject in need thereof, comprising administering to a subject in need thereof:
 an effective amount of the immunotherapeutic construct of any one of  claims 1 - 32 , or the composition of  claim 33 ; and   at least one anti-cancer agent.   
     
     
         53 . The method of  claim 52 , wherein the anti-cancer agent is a chemotherapeutic agent or a targeted therapeutic agent. 
     
     
         54 . A method of enhancing a checkpoint blockade immunotherapy effect in a subject diagnosed as having a neoplasia, comprising administering to a subject in need thereof:
 an effective amount of the immunotherapeutic construct of any one of  claims 1 - 32 , or the composition of  claim 33 ; and   at least one immune checkpoint inhibitor.   
     
     
         55 . A method of enhancing a radiation therapy effect in a subject diagnosed as having a neoplasia, comprising administering to a subject in need thereof:
 an effective amount of the immunotherapeutic construct of any one of  claims 1 - 32 , or the composition of  claim 33 ; and   at least one radiation therapy.   
     
     
         56 . The method of any one of  claims 52 - 55 , wherein the immunotherapeutic construct or composition and the anti-cancer therapy are administered sequentially or concurrently. 
     
     
         57 . The method of any one of  claims 52 - 56 , wherein the subject is a mammal. 
     
     
         58 . The method of  claim 57 , wherein the mammal is a human. 
     
     
         59 . A kit comprising:
 the immunotherapeutic construct of any one of  claims 1 - 32 ; and   at least one anti-cancer agent.   
     
     
         60 . The kit of  claim 59 , wherein the anti-cancer agent is a chemotherapeutic agent, a targeted therapeutic agent, or an immune checkpoint inhibitor.