RNA containing composition for treatment of tumor diseases
The present invention relates to RNA containing compositions for use in the treatment or prophylaxis of tumor and/or cancer diseases, to a pharmaceutical composition, to a kit and to uses of the RNA containing compositions for the treatment or prophylaxis of tumor and/or cancer diseases.
1. A method of treating cancer in a patient having a solid tumor, the method comprising administering to the patient, by intratumoral application, a pharmaceutically effective amount of a composition comprising an mRNA encoding IL-12, wherein the mRNA encodes the sequence of wild type human IL-12 or a sequence at least 90% identical to mature IL-12 and having IL-12 activity and wherein the mRNA is complexed with one or more lipids, thereby forming liposomes, lipid nanoparticles and/or lipoplexes.
2. The method of claim 1 , wherein intratumoral application of the composition comprises injection of the composition into the cancerous tissue.
3. The method of claim 1 , further comprising the administration of a further anticancer therapy.
4. The method of claim 3 , wherein the further anticancer therapy is a chemotherapy, a hormone therapy, an immunotherapy, a checkpoint modulator therapy, a further cytokine therapy, a radiation therapy, and/or a surgery.
5. The method of claim 1 , wherein the checkpoint modulator therapy is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, an OX-40 stimulator, a 4-1BB stimulator, a CD40L stimulator, a CD28 stimulator, and a GITR stimulator.
6. The method of claim 1 , wherein the checkpoint modulator therapy is selected from the group consisting of an agonistic antibody, an antagonistic antibody, a dominant negative receptor, a decoy receptor, and a ligand.
7. The method of claim 6 , wherein the antagonistic antibody is directed against PD-1, PD-L1, or CTLA-4.
8. The method of claim 6 , wherein the decoy receptor is a soluble PD-1 receptor.
9. The method of claim 6 , wherein the checkpoint modulator comprises a mRNA encoding an agonistic antibody, an antagonistic antibody, a dominant negative receptor, a decoy receptor, or a ligand.
10. The method of claim 1 , wherein the G/C content of the coding region of the mRNA is increased compared with the G/C content of the coding region of the wild type mRNA, and wherein the coded amino acid sequence of said G/C-enriched mRNA is not modified compared with the encoded amino acid sequence of the wild type mRNA.
11. The method of claim 1 , wherein the mRNA comprises a 5′-UTR element and/or a 3′-UTR element.
12. The method of claim 11 , wherein the mRNA comprises at least one histone stem-loop.
13. The method of claim 11 , wherein the mRNA comprises a 5′-CAP structure, a poly(A) sequence, and/or a poly(C) sequence.
14. The method of claim 1 , wherein the mRNA is complexed with one or more cationic or polycationic compound selected from the group consisting of cationic or polycationic polymers, cationic or polycationic peptides, or cationic or polycationic proteins, cationic or polycationic polysaccharides, and cationic or polycationic lipids.
15. The method of claim 14 , wherein the cationic or polycationic protein is protamine.
16. The method of claim 1 , wherein the one or more lipids comprise cationic lipids.
17. The method of claim 1 , wherein the cancer comprises prostate cancer, lung cancer, breast cancer, brain cancer, head and neck cancer, thyroid cancer, colon cancer, stomach cancer, liver cancer, pancreas cancer, ovary cancer, skin cancer, urinary, bladder, uterus cancer, lymphoma or cervical cancer.
18. The method of claim 1 , further comprising administering at least a second mRNA encoding a cytokine.
19. The method of claim 18 , comprising administering at least a second mRNA encoding IL-18.
20. The method of claim 1 , wherein the mRNA encoding IL-12 comprises a 5′-CAP structure and a poly(A) sequence, and wherein the composition is administered by injection into the cancerous tissue.
21. The method of claim 20 , further comprising administering at least a second mRNA encoding IL-18.
22. The method of claim 17 , wherein the cancer is a colon cancer.
23. The method of claim 17 , wherein the mRNA encoding IL-12 is administered in conjunction with a checkpoint modulator therapy.