Methods for diagnosing and treating cancers

Patent metadata

Field	Value
Publication number	US-12404332-B2
Application number	US-202117200729-A
Country	US
Kind code	B2
Filing date	Mar 12, 2021
Priority date	Mar 13, 2020
Publication date	Sep 2, 2025
Grant date	Sep 2, 2025

Abstract

Provided herein are methods for the diagnosis, assessment, and treatment of cancer. In some aspects, detection of intracellular or cytoplasmic PD-L1, or measuring the ratio of cytoplasmic to surface PD-L1, can be used to identify cancers that may respond to immunotherapies or a DDR inhibitor such as, e.g., a Chk1 inhibitor, a PARP inhibitor, an ATM inhibitor, or an ATR inhibitor.

First claim

What is claimed is:

1. A method of treating a melanoma, bladder, breast or ovarian cancer in a human subject, comprising measuring in cells of the melanoma, bladder, breast or ovarian cancer the expression of
i) cytoplasmic or intracellular PD-L1 and/or
ii) one or more Lamtor proteins; and

administering an anti-cancer therapy to the subject having the melanoma, bladder, breast or ovarian cancer, wherein the cancer expresses cytoplasmic or intracellular PD-L1 and/or one or more LAMTOR proteins at a decreased level as compared to such expression in control cells; wherein:
i) when the cancer is melanoma the control cells are B16 cells;
ii) when the cancer is bladder cancer the control cells are RT4 cells;
iii) when the cancer is breast cancer control cells are 4TI cells; and
iv) when the cancer is ovarian cancer and wherein the control cells are ES2 cells.

2. The method of claim 1 , wherein the anti-cancer therapy is a DDR inhibitor D(DDRi) or an immune blockade therapy.

3. The method of claim 1 , wherein the anti-cancer therapy is a DDR inhibitor (DDRi).

4. The method of claim 2 , wherein the DDR inhibitor is a Chk1 inhibitor (Chk1i), a PARP inhibitor (PARPi), ATM inhibitor (ATMi), or an ATR inhibitor (ATRi).

5. The method of claim 1 , wherein the PARP inhibitor is rucaprib, olaparib, or niraparib.

6. The method of claim 1 , wherein the ATM inhibitor is AZD0156 or KU-55933.

7. The method of claim 1 , wherein the ATR inhibitor is VE-821, AZD6738, or VX970.

8. The method of claim 4 , wherein the Chk1 inhibitor is MK8776 (SCH900776), rabusertib (LY2603618), prexasertib, CCT245737, or GDC-0575.

9. The method of claim 2 , wherein the immune blockade therapy is an antibody that selectively binds PD-L1 or PD-1.

10. The method of claim 9 , wherein the antibody selectively binds PD-1, wherein the antibody is cemiplimab, nivolumab, pembrolizumab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), AMP-224, or AMP-514.

11. The method of claim 9 , wherein the antibody selectively binds PD-L1, wherein the antibody is atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, or BMS-986189.

12. The method of claim 1 , wherein the anti-cancer therapy is 9-(2-phosphonylmethoxyethyl) guanine (PMEG) or chlorambucil.

13. The method of claim 12 , wherein the anti-cancer therapy is 9-(2-phosphonylmethoxyethyl) guanine (PMEG).

14. The method of claim 12 , wherein the anti-cancer therapy is chlorambucil.

15. The method of claim 1 , wherein the anti-cancer therapy is a beta-lactam antibiotic.

16. The method of claim 15 , wherein the beta-lactam antibiotic is a penam, carbapenem, an oxapenam, a penem, a carbapenem, a monobactam, a cephem, a carbacephem, or an oxacephem.

17. The method of claim 16 , wherein the beta-lactam antibiotic is a cephem.

18. The method of claim 17 , wherein the cephem is cefazolin, cephalexin, cephalosporin, cephalothin, cefapirin, cefaclor, cefamandole, cefuroxime, cefotetan, cefoxitin, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefdinir, cefepime, cefpirome, or ceftaroline.

19. The method of claim 18 , wherein the beta-lactam antibiotic is cefepime or ceftazidime.

20. The method of claim 1 , wherein the method comprises administering to the mammalian subject both: (a) an antibody that selectively binds PD-L1 or PD-1, and (b) a PARP inhibitor, a Chk1 inhibitor, or chlorambucil.

21. The method of claim 20 , wherein the antibody that selectively binds PD-L1 or PD-1 is cemiplimab, nivolumab, pembrolizumab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, or BMS-986189.

22. The method of claim 20 , wherein the PARP inhibitor is rucaprib, olaparib, or niraparib.

23. The method of claim 22 , wherein the PARP inhibitor is olaparib.

24. The method of claim 20 , wherein the Chk1 inhibitor is MK8776 (SCH900776), rabusertib (LY2603618), prexasertib, CCT245737, or GDC-0575.

25. The method of claim 20 , wherein chlorambucil is administered to the mammalian subject.

26. The method of claim 1 , wherein the cancer is a breast cancer.

27. The method of claim 26 , wherein the breast cancer comprises a mutation in BRCA1.

28. The method of claim 26 , wherein the breast cancer does not comprise a mutation in BRCA2.

29. The method of claim 26 , wherein the breast cancer does not comprise a mutation in BRCA1 or BRCA2.

30. The method of claim 1 , wherein the cytoplasmic PD-L1 is located within the nucleus.

31. The method of claim 1 , wherein the measuring comprises immunohistochemistry, mass spectroscopy, immunoprecipitation, flow cytometry, or digital imaging.

32. The method of claim 1 , wherein the method further comprises detecting a mTORC1 signal in the cancer.

33. The method of claim 32 , wherein the one or more LAMTOR protein is LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4, or LAMTOR5.

34. The method of claim 1 , wherein the anti-cancer therapy is an immune checkpoint blockade therapy.

35. The method of claim 34 , wherein the immune checkpoint blockade therapy is an antibody that selectively binds PD-1 or PD-L1.

36. The method of claim 1 , wherein the anti-cancer therapy is a chemotherapeutic, an immunotherapy, a gene therapy, a radiotherapy, a small molecule, a DNA therapy, an RNA therapy, a cryotherapy, a cellular therapy, a toll-like receptor agonist, a dual-targeting agent, a triple-targeting agent, or a surgery.

37. The method of claim 36 , wherein the anti-cancer therapy is cyclophosphamide or bevacizumab.

38. The method of claim 1 , wherein the cancer is a bladder cancer, a breast cancer, or a melanoma; and wherein the DDR inhibitor is a Chk1 inhibitor (Chk1i) or a PARP inhibitor (PARPi).

39. The method of claim 1 , wherein the cancer is a melanoma or an ovarian cancer; and wherein the anti-cancer therapy is pembrolizumab, bevacizumab, or cyclophosphamide.

40. The method of claim 1 , wherein the method does not comprise measuring surface PD-L1 expression in the cancer.

41. The method of claim 1 , wherein the method further comprises measuring surface PD-L1 expression in the cancer.

42. The method of claim 1 , wherein greater than 50% of the total expressed PD-L1 in the cancer is cytoplasmic or intracellular PD-L1.

43. The method of claim 41 , wherein the ratio of cytoplasmic or intracellular PD-L1:surface PD-L1 is at least 1.5, or wherein the cancer expresses at least 1.5 times more cytoplasmic or intracellular PD-L1 than surface PD-L1.

44. The method of claim 41 , wherein the ratio of cytoplasmic or intracellular PD-L1:surface PD-L1 is at least 3, or wherein the cancer expresses at least 3 times more cytoplasmic or intracellular PD-L1 than surface PD-L1.

45. The method of claim 1 , wherein the cancer is melanoma and wherein the control cells are B16 cells.

46. The method of claim 1 , wherein the cancer is blader cancer and wherein the control cells are RT4 cells.

Assignees

• Res Found Dev

Inventors

• Curiel Tyler J
• Kornepati Anand

Classifications

• G01N2800/7028

  Cancer · CPC title

• G01N2333/4703

  Regulators; Modulating activity · CPC title

• G01N33/68

  involving proteins, peptides or amino acids {(involving lipoproteins G01N33/92)} · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K2039/505

  comprising antibodies · CPC title