Compositions and methods to improve anti-angiogenic therapy and immunotherapy
Agents that inhibit CX3CL1 in endothelial cells to reduce or inhibit immunosuppression mechanisms that are co-opted by cancer cells to evade host immune system, and that reduce immunosuppression in context of therapies that target VEGF-dependent signaling, and methods of use thereof.
1. A composition comprising one or more inhibitory nucleic acids that comprises a siRNA or a locked nucleic acid (LNA) that bind to and reduce expression or activity of C-X3-C chemokine ligand 1 (CX3CL1), encapsulated within or linked to an endothelial cell delivery vehicle that comprises a lipid nanoparticle that comprises 7C1 nanoparticles, SAINT-C 18 lipoplexes, PEGylated SAINT-C18 lipoplexes, polyethyleneimine (PEI) PEGylated with an Arg-Gly-Asp (RGD) peptide (RGD-PEG-PEI) (RPP-nanoplexes), or Polycation Liposome-encapsulated Calcium Phosphate nanoparticles (PLCP).
2. The composition of claim 1 , wherein the siRNA is chemically modified to have increased siRNA half-life.
3. The composition of claim 1 , wherein the one or more inhibitory nucleic acids are linked to a cell-penetrating peptide.
4. A pharmaceutical composition comprising the composition of claim 1 , and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4 , further comprising an anti-angiogenic agent.
6. The pharmaceutical composition of claim 5 , wherein the anti-angiogenic agent is a VEGF inhibitor.
7. A method of treating a solid cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 4 .
8. The method of claim 7 , further comprising administering a therapeutically effective amount of an anti-angiogenic agent to the subject.
9. The method of claim 7 , wherein the subject has been treated with an anti-angiogenic agent prior to administration of the pharmaceutical composition of claim 4 .
10. The method of claim 8 , wherein the cancer is resistant to the anti-angiogenic.
11. The method of claim 8 , wherein the anti-angiogenic agent is a VEGF inhibitor.
12. The method of claim 8 , wherein the anti-angiogenic agent is administered prior to or concurrently with the pharmaceutical composition.
13. The method of claim 7 , wherein the cancer is a carcinoma.
14. The method of claim 13 , wherein the carcinoma is a colorectal, breast, or lung carcinoma.
15. The method of claim 7 , wherein the cancer is colorectal carcinoma.
16. The composition of claim 1 , wherein the endothelial cell delivery vehicle comprises 7C1 nanoparticles.