RU2021114145A - COMBINATIONS FOR IMMUNOMODULATION IN THE TREATMENT OF CANCER - Google Patents

Claims (46)

1. A method of treating cancer or resistant cancer and/or suppressing cancer metastases, recurrence or progression in a patient, or increasing the likelihood of survival in an appropriate period in a patient diagnosed with cancer, comprising administering to the patient a combination of an anticancer agent, a CK2 inhibitor, and optionally an immune checkpoint inhibitor. 2. The method of claim 1, wherein the administration increases the number of tumor-specific T-lymphocytes in the tumor microenvironment of the patients. 3. The method of claim 1, wherein the combination of the anticancer agent and the CK2 inhibitor is administered simultaneously, sequentially, intermittently, or intermittently. 4. The method of claim. 1, which includes at least one cycle of introduction, while the specified cycle is a period of up to eight weeks. 5. The method of claim 1 wherein the combination results in immunological memory of said cancer. 6. The method of claim 1, wherein the anticancer agent, the CK2 inhibitor, and additionally the immune checkpoint inhibitor are used in synergistically effective amounts. 7. The method of claim 4, wherein said cycle is a period of four weeks. 8. The method of claim 4, wherein the administration cycle comprises administering to the patient at least one first therapeutic agent (e.g., an induction therapy such as a combination of a chemotherapeutic agent and a CK2 inhibitor) in an amount and regimen sufficient to achieve a response (partial or complete response), followed by administration of an amount of immune checkpoint inhibitor to the patient. 9. The method of claim 4, wherein the administration cycle comprises administering the CK2 inhibitor daily and the chemotherapeutic agent once a week. 10. The method of claim 9, wherein the administration cycle also comprises administering an immune checkpoint inhibitor twice a week. 11. The method of claim 4, wherein the CK2 inhibitor is administered daily at a dose in the range of about 25 mg/kg of the patient's body weight (about 25 mg/kg) to about 2000 mg/kg. 12. The method of claim 4, wherein the daily dose is in the range of about 50 mg/kg to about 200 mg/kg, wherein the CK2 inhibitor is administered twice a day. 13. The method of claim 4, wherein the antitumor agent is administered at a dose in the range of about 1 mg/kg of the patient's body weight (about 1 mg/kg) to about 20 mg/kg. 14. The method of claim 4, wherein the dose of the anticancer agent is administered in the range of about 5 mg/kg to about 10 mg/kg. 15. The method of claim 4, wherein the immune checkpoint inhibitor is administered at a dose in the range of about 1 mg/kg of the patient's body weight (about 1 mg/kg) to about 20 mg/kg. 16. The method of claim 4, wherein the dose of the immune checkpoint inhibitor is administered in the range of about 8 mg/kg to about 15 mg/kg. 17. The method of claim 1, wherein the cancer is skin cancer (such as melanoma and basal cell carcinoma), liver cancer (such as hepatocellular carcinoma), colon and rectal carcinoma, glioblastoma, gastric cancer, colon and rectal cancer, esophageal cancer, lung cancer (eg, non-small cell lung cancer (NSCLC) and small cell lung cancer), pancreatic cancer, renal cell carcinoma, benign prostatic hyperplasia, prostate cancer, ovarian cancer, melanoma, breast cancer, chronic lymphocytic leukemia (CLL), Merkel cell carcinoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), gallbladder cancer, cholangiocarcinoma, bladder cancer, or uterine cancer. 18. The method of claim 1 wherein the anticancer agent is cisplatin, gemcitabine, carboplatin, methotrexate, vincristine, adriamycin, bleomycin, hydroxyurea, salinosporamide A, bortezomib, PS-519, omuralide, cyclophosphamide, ifosfamide, docetaxel, doxorubicin, 5 -fluorouracil, vinblastine or paclitaxel. 19. The method of claim 1, wherein the CK2 inhibitor is a compound with the structure of formula I, or a pharmaceutically acceptable salt or ester thereof, wherein:

each Z ¹ , Z ² , Z ³ and Z ⁴ is N or CR ³ ; each Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ is N or CR ⁶ ; none, one or two of Z ¹ -Z ⁴ are N and none, one or two of Z ⁵ -Z ⁸ are N and at least one of Z ¹ -Z ⁴ and Z ⁵ -Z ⁸ is is a nitrogen atom; each R ³ and each R ⁶ are independently H or optionally substituted C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, a C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl group, or each R ⁶ is independently halogen, OR, NR ₂ , NROR, NRNR ₂ , SR, SOR, SO ₂ R, SO ₂ NR ₂ , NRSO ₂ R, NRCONR ₂ , NRCOOR, NRCOR, CN, OC(O)R, COR, NO ₂ or a polar substituent selected from a carboxylic acid, carboxylate, ester, carboxamide, tetrazole, or a carboxybioisosteru selected from the group consisting of

and each R ³ is independently halogen, OR, NR ₂ , NROR, NRNR ₂ , SR, SOR, SO ₂ R, SO ₂ NR ₂ , NRSO ₂ R, NRCONR ₂ , NRCOOR, NRCOR, CN, OC(O)R , COR, the polar substituent as defined above, or NO ₂ , and at least one R ³ is a polar substituent; wherein each R is independently H or C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl , C2-C8-heteroacyl, C6-C10-aryl, C5-C10-heteroaryl, C7-C12-arylalkyl or C6-C12-heteroarylalkyl, and wherein two R's on the same atom or on adjacent atoms can join to form a 3- to 8-membered ring, optionally containing one or more N, O, or S atoms; and each R group and each ring formed by joining two R groups is optionally substituted with one or more substituents selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′ ₂ , SR′, SO ₂ R′, SO ₂ NR′ ₂ , NR′SO ₂ R′, NR′CONR′ ₂ , NR′COOR′, NR′COR′, CN, COOR′, CONR′ ₂ , OC(O )R′, COR' and NO ₂ , wherein each R′ is independently H, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 acyl, C2-C6 heteroacyl, C6-C10 aryl, C5-C10 heteroaryl, C7-12- arylalkyl or C6-12 heteroarylalkyl, each optionally substituted with one or more groups selected from halo, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C6 acyl, C1-C6 heteroacyl, hydroxy, amino, and ═O; and in which two R' can be connected to form a 3-7-membered ring, optionally containing up to three heteroatoms selected from N, O and S atoms; R ⁴ is H or an optionally substituted group selected from the group consisting of C1-C6 alkyl, C2-C6 heteroalkyl and C1-C6 acyl; each R ⁵ is an optionally substituted group selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 heteroalkyl, C3-8 carbocyclyl, and C3-8 heterocyclyl optionally fused with an optional substituted carbocyclyl or heterocyclyl; or R ⁵ is C1-10 alkyl, C2-10 alkenyl, or C2-10 heteroalkyl substituted with optionally substituted C3-8 carbocyclyl or C3-8 heterocyclyl; and in each —NR ⁴ R ⁵ , R ⁴ and R ⁵ together with N may form an optionally substituted 3-8 membered ring which may additionally contain an additional heteroatom selected from N, O and S as a ring member; provided that -NR ⁴ R ⁵ in formula (I) is -NH Φ, where Φ is an optionally substituted phenyl: if all Z ⁵ -Z ⁸ are CH or one of Z ⁵ -Z ⁸ is N, at least one of Z ¹ -Z ⁴ is CR ³ and at least one R ³ must not be a hydrogen atom; or if each R ³ is H, then Φ must be substituted; wherein each R ⁷ is independently H or an optionally substituted group selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 heteroalkyl, C3-8 carbocyclyl and C3-8 heterocyclyl, optionally fused with additional optionally substituted carbocyclyl or heterocyclyl; or R ⁷ is C1-10 alkyl, C2-10 alkenyl, or C2-10 heteroalkyl substituted with optionally substituted C3-8 carbocyclyl or C3-8 heterocyclyl. 20. The method of claim 1 wherein the CK2 inhibitor is CX-4945. 21. The method of claim 1 wherein the immune checkpoint inhibitor is a PD-1 inhibitor or a CTLA-4 inhibitor. 22. The method of claim 21, wherein the immune checkpoint inhibitor is lambrolizumab, pidilizumab, nivolumab, ticilimumab, or ipilimumab.