Immunotherapeutic tumor treatment method
Disclosed herein are methods in the field of cancer immunotherapy that involve the treatment of a subject having cancer by administering to the subject a toll-like receptor 7/8 (TLR7/8) agonist in combination with a long-acting IL-2Rβ-biased agonist and a programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis inhibitor, and related compositions, dosage forms, and kits.
1. A kit comprising:
(a) a PD-1/PD-L1 axis inhibitor;
(b) a toll-like receptor (TLR) agonist covalently attached to a multi-arm, water-soluble, non-peptidic polymer, wherein the TLR agonist is selected from a multi-armed polymer conjugate of R848, a multi-armed polymer conjugate of imiquimod, or a multi-armed polymer conjugate of 44(6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)-benzamide; and
(c) an IL-2Rβ-activating amount of a long acting interleukin-2 receptor beta (IL-2Rβ)-preferential agonist; and
instructions for their administration to a subject having a cancer.
2. The kit of claim 1 , wherein the PD-1/PD-L1 axis inhibitor and the long acting IL-2Rβ-preferential agonist are formulated for parenteral administration.
3. The kit of claim 1 , wherein at least one of the PD-1/PD-L1 axis inhibitor or the long acting IL-2Rβ-preferential agonist is formulated for intravenous administration.
4. The kit of claim 1 , wherein the kit comprises at least the PD-1/PD-L1 axis inhibitor and the long acting IL-2Rβ-preferential agonist formulated in a single formulation.
5. The kit of claim 1 , wherein the kit comprises (i) the PD-1/PD-L1 axis inhibitor and the long acting IL-2Rβ-preferential agonist formulated in a single formulation, and (ii) the toll-like receptor agonist formulated in a separate formulation.
6. The kit of claim 1 , wherein each of the PD-1/PD-L1 axis inhibitor, the long-acting IL-2Rβ-preferential agonist, and the TLR agonist is in a solid form suitable for reconstitution in an aqueous diluent.
7. The kit of claim 1 , wherein the toll-like receptor agonist is formulated for intratumoral injection or peritumoral injection.
8. The kit of claim 1 , wherein the PD-1/PD-L1 axis inhibitor is selected from atezolizumab, avelumab, durvalumab, nivolumab, pembrolizumab, or BGB-A317.
9. The kit of claim 1 , wherein the long acting IL-2Rβ-preferential agonist is selected from multi(2,7-(bis-methoxyPEG-carboxyamide)(9H-fluorene-9-yl)methyl N-carbamate)interleukin-2, (2,7-(bis-methoxyPEG 10 kD -carboxyamide)(9H-fluorene-9-yl)methyl N-carbamate) 4-6 interleukin-2, or (2,7-(bis-methoxyPEG-carboxyamide)(9H-fluorene-9-yl)methyl N-carbamate) 6 avg interleukin-2.
10. The kit of claim 1 , wherein the TLR agonist is selected from 4-arm-PEG20kD-CM-imiquimod, 4-arm-PEG20kD-CM-glycine-N-imiquimod, 4-arm-PEG20kD-CM-N-R848, 4-arm-PEG20kD-CM-glycine-N-R848,
or a pharmaceutically acceptable salt thereof, wherein each n for each of Compounds 1-10 and 12-16 is independently an integer from 40 to 350.
11. A method of treating a subject having a cancer, the method comprising: (a) administering to the subject having a cancer an effective amount of a PD-1/PD-L1 axis inhibitor; (b) administering to the subject an effective, IL-2Rβ-activating amount of a long acting interleukin-2 receptor beta (IL-2Rβ)-preferential agonist, wherein the long acting IL-2Rβ-preferential agonist is selected from multi(2,7-(bis-methoxyPEG-carboxyamide)(9H-fluorene-9-yl)methyl N-carbamate)interleukin-2,(2,7-(bis-methoxyPEG 10 kD -carboxyamide)(9H-fluorene-9-yl)methyl N-carbamate) 4-6 interleukin-2, or (2,7-(bis-methoxyPEG-carboxyamide)(9H-fluorene-9-yl)methyl N-carbamate)6 avg interleukin-2; and (c) administering to the subject an effective amount of a toll-like receptor (TLR) agonist covalently attached to a multi-arm, water-soluble, non-peptidic polymer, wherein the TLR agonist is selected from a multi-armed polymer conjugate of R848, a multi-armed polymer conjugate of imiquimod, or a multi-armed polymer conjugate of 4-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)-benzamide.
12. The method of claim 11 , wherein each of the PD-1/PD-L1 axis inhibitor, the toll-like receptor agonist and the long acting IL-2Rβ-preferential agonist are administered at substantially the same time.
13. The method of claim 11 , wherein the PD-1/PD-L1 axis inhibitor is administered separately from at least one of the toll-like receptor agonist or the long acting IL-2Rβ-preferential agonist.
14. The method of claim 11 , wherein each of the PD-1/PD-L1 axis inhibitor and the long acting IL-2Rβ-preferential agonist are administered at substantially the same time.
15. The method of claim 11 , wherein each of the PD-1/PD-L1 axis inhibitor and the toll-like receptor agonist are administered at substantially the same time.
16. The method of claim 11 , wherein the toll-like receptor agonist is administered separately from at least one of the PD-1/PD-L1 axis inhibitor or the long acting IL-2Rβ-preferential agonist.
17. The method of claim 11 , wherein administering steps (a) and (b) both comprise parenteral administering.
18. The method of claim 11 , wherein the toll-like receptor agonist is administered by a method selected from intratumoral injection and peritumoral injection.
19. The method of claim 11 , wherein the PD-1/PD-L1 axis inhibitor is an anti-PD-1 antibody.
20. The method of claim 19 , wherein the anti-PD-1 antibody is selected from atezolizumab, avelumab, durvalumab, nivolumab, pembrolizumab, or BGB-A317.
21. The method of claim 11 , wherein the TLR agonist is selected from 4-arm-PEG20kD-CM-imiquimod, 4-arm-PEG20kD-CM-glycine-N-imiquimod, 4-arm-PEG20kD-CM-N-R848, 4-arm-PEG20kD-CM-glycine-N-R848,
or a pharmaceutically acceptable salt thereof, wherein each n for each of Compounds 1-10 and 12-16 is independently an integer from 40 to 350.
22. The method of claim 11 , wherein the cancer is a solid cancer.
23. The method of claim 22 , wherein the cancer is selected from breast cancer, ovarian cancer, colon cancer, prostate cancer, bone cancer, colorectal cancer, gastric cancer, lymphoma, malignant melanoma, liver cancer, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, thyroid cancers, kidney cancer, cancer of the bile duct, brain cancer, cervical cancer, maxillary sinus cancer, bladder cancer, esophageal cancer, Hodgkin's lymphoma or adrenocortical cancer.
24. The method of claim 11 , wherein administration of the PD-1/PD-L1 axis inhibitor, the IL-2Rβ-activating amount of the long acting IL-2Rβ-preferential agonist, and the toll-like receptor agonist is effective to promote activation of the immune system.
25. The method of claim 11 , wherein administration of the PD-1/PD-L1 axis inhibitor, the IL-2Rβ-activating amount of the long acting IL-2Rβ-preferential agonist, and the toll-like receptor agonist is effective to (i) promote activation of at least one of CD8 T cells, CD11c+ and CD8+dendritic cells, and neutrophils, and (ii) stimulate T cells.
26. The method of claim 11 , wherein administration of the PD-1/PD-L1 axis inhibitor, the IL-2Rβ-activating amount of the long acting IL-2Rβ-preferential agonist, and the toll-like receptor agonist is effective to suppress T regulatory cells, macrophages, and monocytes.
27. The method of claim 11 , wherein administration of the PD-1/PD-L1 axis inhibitor, the IL-2Rβ-activating amount of the long acting IL-2Rβ-preferential agonist, and the toll-like receptor agonist is effective to produce an abscopal effect on the cancer.
28. The method of claim 11 , wherein step (a) is carried out before, after, or simultaneously with step (b).