Combination therapies using caspase-1 dependent anticancer agents and PGE2 antagonists

1. A method for enhancing an immune response against a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of an C-1 Antitumor Agent, a PGE2 antagonist, and an anti-PD-1 antibody or an anti-PD-L1 antibody, wherein the C-1 antitumor agent is a TLR ligand, a RIG-I-like receptor agonist, a STING pathway agonist, or an immune-DASH inhibitor; the PGE2 antagonist is a cyclooxygenase inhibitor or a phospholipase 2 inhibitor; and the combination of C-1 Antitumor Agent, PGE2 antagonist, and anti-PD-1 antibody or an anti-PD-L1 antibody induces and/or enhances cell-mediated immune response against the tumor.

2. A pharmaceutical formulation for enhancing an immune response against a tumor, comprising (i) a therapeutically effective amount of a C-1 Antitumor Agent; (ii) an amount of a PGE2 antagonist effective to permit safe dosing of patients with the therapeutically effective amount of the C-1 Antitumor Agent; and (iii) an anti-PD-1 antibody or an anti-PD-L1 antibody, wherein the C-1 Antitumor Agent is a TLR ligand, a RIG-I-like receptor agonist, a STING pathway agonist, or an immune-DASH inhibitor; the PGE2 antagonist is a cyclooxygenase inhibitor or a phospholipase 2 inhibitor; and the combination of C-1 Antitumor Agent, PGE2 antagonist, and anti-PD-1 antibody or an anti-PD-L1 antibody induces and/or enhances cell-mediated immune response against the tumor.

3. A single oral dosage formulation, comprising (i) an C-1 Antitumor Agent; (ii) a PGE2 antagonist; (iii) an anti-PD-1 antibody or an anti-PD-L1 antibody; and (iv) one or more pharmaceutically acceptable excipients, wherein the C-1 antitumor agent is a TLR ligand, a RIG-I-like receptor agonist, a STING pathway agonist, or an immune-DASH inhibitor; the PGE2 antagonist is a cyclooxygenase inhibitor or a phospholipase 2 inhibitor; and the C-1 Antitumor Agent is provided in an amount sufficient to produce macrophage pyroptosis and/or induces caspase-1 dependent generation of extracellular of interleukin-1β (IL-1β) and/or IL-18, and the PGE2 antagonist is present in an amount to reduce eicosanoid induction by the C-1 Antitumor Agent and increase the maximum tolerated dose of the C-1 Antitumor Agent by at least 5-fold.

4. An intratumoral dosage formulation, comprising (i) an C-1 Antitumor Agent; (ii) a PGE2 antagonist; (iii) an anti-PD-1 antibody or an anti-PD-L1 antibody; and (iv) one or more pharmaceutically acceptable excipients, wherein the C-1 antitumor agent is a TLR ligand, a RIG-I-like receptor agonist, a STING pathway agonist, or an immune-DASH inhibitor; the PGE2 antagonist is a cyclooxygenase inhibitor or a phospholipase 2 inhibitor; and the C-1 Antitumor Agent is provided in an amount sufficient to produce macrophage pyroptosis and/or induces caspase-1 dependent generation of extracellular of interleukin-1β (IL-1β) and/or IL-18, and the PGE2 antagonist is present in an amount to reduce eicosanoid induction by the C-1 Antitumor Agent and increase the maximum tolerated dose of the C-1 Antitumor Agent by at least 5-fold.

5. The formulation of claim 2 , wherein the PGE2 antagonist is a cyclooxygenase inhibitor.

6. The formulation of claim 5 , wherein the cyclooxygenase inhibitor is a selective inhibitor of cyclooxygenase 2 (COX-2) inhibitor.

7. The formulation of claim 2 , wherein the PGE2 antagonist is a phopholipase A2 inhibitor.

8. The formulation of claim 2 , wherein the PGE2 antagonist is a cytosolic phopholipase A2 inhibitor.

9. The formulation of claim 2 , wherein at the therapeutically effective amount, the C-1 Antitumor Agent decreases the number of cancer associated macrophages.

10. The formulation of claim 2 , wherein at the therapeutically effective amount, the C-1 Antitumor Agent reduces monocytic myeloid-derived suppressor cells in the cancer.

11. The formulation of claim 2 , wherein at the therapeutically effective amount, the C-1 Antitumor Agent reduces T-cell suppressive activity of granulocytic myeloid-derived suppressor cells in the cancer.

12. The formulation of claim 2 , wherein the C-1 Antitumor Agent is provided in an amount that produces, within 6 hours of administration, at least a 100% increase in mean plasma levels of one or more of G-CSF, IL-6, IL-8 and/or IL-18.

13. The formulation of claim 2 , wherein the C-1 Antitumor Agent is provided in an amount that produces a serum drug concentration from 1-10 times the EC50 for induction of a statistically significant increase in mean plasma levels of IL-1β.

14. The formulation of claim 2 , wherein the C-1 Antitumor Agent is provided in an amount that produces a serum drug concentration from 1-10 times the EC50 for induction of tumor-associated macrophage pyroptosis.

15. The formulation of claim 2 , wherein at the therapeutically effective amount, the combination of the C-1 Antitumor Agent and the PGE2 antagonist produces full cancer regression, and the therapeutically effective amount is at least two-fold less than the maximum tolerated dose of the combination.

16. The formulation of claim 2 , wherein the C-1 Antitumor Agent and PGE2 antagonist are administered in combination with one or more additional checkpoint inhibitors.

17. The formulation of claim 2 , wherein the C-1 Antitumor Agent and PGE2 antagonist are administered in combination with one or more costimulatory molecules.

18. The formulation of claim 2 , wherein the C-1 Antitumor Agent and the PGE2 antagonist are used as part of a treatment protocol including one or more other chemotherapeutic agents, immuno-oncology agents or radiation.

19. The formulation of claim 2 , wherein the C-1 Antitumor Agent and the PGE2 antagonist are used as part of a treatment protocol including a tumor vaccine, adoptive cell therapy, gene therapy or oncolytic viral therapy.

20. The formulation of claim 6 , wherein the selective COX-2 inhibitor is celecoxib or rofecoxib.

21. The formulation of claim 16 , wherein the additional checkpoint inhibitor is an inhibitor of one or more of PD-1, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGFR beta.

22. The formulation of claim 2 , wherein the C-1 Antitumor Agent is an immune-DASH inhibitor; and the immune-DASH inhibitor is Val-boroPro or a pharmaceutically acceptable salt thereof.

23. The formulation of claim 22 , wherein the immune-DASH inhibitor is Val-boroPro mesylate.

24. A pharmaceutical formulation for enhancing an immune response against a tumor, comprising Val-boroPro, celecoxib, and an anti-PD-1 antibody or an anti-PD-L1 antibody, wherein the pharmaceutical formulation induces and/or enhances cell-mediated immune response against the tumor.