Immunotherapeutic constructs and methods of their use
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.
1. An immunotherapeutic construct comprising:
a nanoparticle platform (NP) comprising:
a mesoporous silica nanoparticle (MSNP);
polyethylenimine (PEI) coating an exterior surface of the MSNP;
polyethylene glycol (PEG) bound to the PEI or to the MSNP;
an siRNA that inhibits expression or an activity of STAT3 (siSTAT3) non-covalently attached to the PEI; and
an adjuvant comprising a CpG oligonucleotide non-covalently attached to the PEI, wherein the immunotherapeutic construct does not comprise a tumor-specific antigen or ovalbumin.
2. The immunotherapeutic construct of claim 1 , wherein the PEI is cross-linked.
3. The immunotherapeutic construct of claim 1 , wherein the CpG oligonucleotide is CpG ODN 7909 (SEQ ID NO: 8).
4. The immunotherapeutic construct of claim 1 , wherein the MSNP has a size of about 30-80 nm.
5. The immunotherapeutic construct of claim 1 , having a hydrodynamic size of about 80 nm to 200 nm.
6. The immunotherapeutic construct of claim 1 , wherein the siRNA is 0.5 to 10% by weight of the immunotherapeutic construct.
7. The immunotherapeutic construct of claim 1 , wherein the adjuvant is 0.5 to 20% by weight of the immunotherapeutic construct.
8. A composition comprising:
the immunotherapeutic construct of claim 1 ; and
at least one pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.
9. 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 8 .
10. The method of claim 9 , wherein the subject is a mammal.
11. The method of claim 9 , wherein the mammal is a human.
12. The method of claim 9 , wherein the hyperproliferative disease or condition comprises one or more of cancer, pre-cancer, or cancer metastasis.
13. The method of claim 12 , 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, ovarian cancer, or bladder cancer.
14. The method of claim 9 , 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.
15. The method of claim 9 , wherein the administering comprises microneedle application to the subject.
16. The method of claim 9 , further comprising administering
an anti-cancer therapy, wherein the anti-cancer therapy comprises an anti-cancer agent or a radiation therapy.
17. The method of claim 16 , wherein the immunotherapeutic construct is administered with the anti-cancer agent.
18. The method of claim 17 , wherein the anti-cancer agent is a chemotherapeutic agent, a targeted therapeutic agent, or an immune checkpoint inhibitor.
19. The method of claim 18 , wherein the anti-cancer agent is an immune checkpoint inhibitor selected from a PD-L1 antibody, a PD-1 antibody, a CTLA4 antibody, or a combination thereof.
20. The method of claim 16 , wherein the immunotherapeutic construct is administered with the radiation therapy.
21. The method of claim 16 , wherein the immunotherapeutic construct and the anti-cancer therapy are administered sequentially or concurrently.