Compositions and methods for the prevention and treatment of cancer
Conventional cancer immunotherapy falls short at efficiently expanding T cells that specifically target cancerous cells in numbers sufficient to significantly reduce the tumor size or cancerous cell number in vivo. To overcome this limitation, provided herein are nanoparticles coated with MHC class I and/or class II molecules presenting tumor-specific antigens and co-stimulatory molecules and their use to expand antigen-specific anti-tumorigenic T cells to levels not achieved in current immunotherapeutic techniques. These antigen-specific anti-tumorigenic T cells include cytotoxic T cells, effector T cells, memory T cells, and helper T cells that are necessary to initiate and maintain a substantial immune response against metastatic or non-metastatic cancerous, pre-cancerous, or neoplastic cells in vivo. The present invention describes a systemic approach to targeting cancerous or pre-cancerous cells that are circulating cells, as in lymphomas, migratory metastatic cells, and solid tumors.
1. A complex comprising:
(a) a nanoparticle core having a diameter from about 1 nm to about 100 nm;
(b) from 10-500 cancer or tumor-relevant antigen/MHC protein complexes coupled to the nanoparticle core, wherein the antigen/MHC protein complexes comprise MHC proteins selected from classical MHC class I proteins and MHC class II proteins; and
(c) a plurality of co-stimulatory molecule complexes coupled to the nanoparticle core;
wherein the ratio of co-stimulatory molecule complexes to the cancer or tumor-relevant antigen/MHC protein complexes is from about 0.1:1 to about 50:1.
2. The complex of claim 1 , wherein the nanoparticle core has a biodegradable layer on the outer surface of the nanoparticle core, wherein the 10-500 cancer or tumor-relevant antigen/MHC protein complexes and/or the plurality of co-stimulatory molecule complexes are coupled to the nanoparticle core or to the biodegradable layer on the nanoparticle core.
3. The complex of claim 1 or 2 , wherein the ratio of co-stimulatory molecule complexes to the 10-500 cancer or tumor-relevant antigen-MHC protein complexes is from about 1:1 to about 50:1.
4. The complex of claim 1 , wherein the nanoparticle core has a diameter from about 1 nm to about 50 nm.
5. The complex of claim 4 , wherein the nanoparticle core has a diameter from about 1 nm to about 30 nm.
6. The complex of claim 1 , wherein the MHC class I proteins are independently selected from all or part of any of: a HLA-A, a HLA-B, and a HLA-C protein.
7. The complex of claim 6 , wherein the HLA-A protein comprises all or part of a HLA-A*0201 protein.
8. The complex of claim 1 , wherein the MHC class II proteins are independently selected from all or part of any of a: HLA-DR, HLA-DQ, and HLA-DP protein.
9. The complex of claim 1 , wherein the cancer or tumor-relevant antigen is a melanoma-relevant antigen or a lung cancer-relevant antigen.
10. The complex of claim 1 , wherein a plurality of identical cancer or tumor-relevant antigen epitopes are contained in the 10-500 cancer or tumor relevant antigen/MHC complexes.
11. The complex of claim 10 , wherein the plurality of antigen epitopes are derived from a single antigen or a plurality of antigens.
12. The complex of claim 1 , wherein the co-stimulatory molecule complexes of the plurality comprise a co-stimulatory molecule that targets a receptor selected from the group of the CD28 receptor (CD80(B7.1), CD86(B7.2)), 4-IBBL, CD40, IL-15/IL15Rα, and ICOS.
13. The complex of claim 1 , wherein the nanoparticle core comprises one or more of a metal, a metal oxide, a metal sulfide, a metal selenide, a magnetic material, a polymer, gold, iron, or iron oxide.
14. The complex of claim 13 , wherein the nanoparticle core comprises one or more of gold, iron, or iron oxide.
15. The complex of claim 1 , wherein the plurality of co-stimulatory molecule complexes and/or the 10-500 cancer or tumor-relevant antigen/MHC protein complexes are covalently coupled to the nanoparticle core via a linker.
16. The complex of claim 15 , wherein the linker comprises ethylene glycol.
17. The complex of claim 2 , wherein the biodegradable layer on the nanoparticle core comprises dextran, mannitol, and/or poly(ethylene glycol).
18. The complex of claim 2 , wherein the 10-500 cancer or tumor-relevant antigen-MHC protein complexes are coupled to the nanoparticle core or the biodegradable layer.
19. The complex of claim 2 , wherein the plurality of co-stimulatory molecule complexes and/or the cancer or tumor-relevant antigen/MHC protein complexes are coupled to the nanoparticle core or the biodegradable layer on the nanoparticle core, each via one or more of a dimer, a trimer, and/or a dimer of a trimer.
20. A pharmaceutical composition comprising a plurality of complexes of claim 1 and a pharmaceutically acceptable carrier.