CANCER TREATMENT AND MONITORING METHODS USING OX40 AGONISTS

• US 20150098942A1
• Filed: 02/06/2012
• Published: 04/09/2015
• Est. Priority Date: 02/06/2012
• Status: Active Grant

• Current Assignee: Providence Health & Services - Oregon (Providence St. Joseph Health)
• Original Assignee: Providence Health & Services - Oregon (Providence St. Joseph Health)
• Inventors: Curti, Brendan, Kovacsovics-Bankowski, Magdalena, Walker, Ed, Walker, Josh, Weinberg, Andy
• Granted Patent: US 9,828,432 B2
• Time in Patent Office: Days
• US Class Current: 424/134.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/6031 Proteins
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/7151 for tumor necrosis factor [TNF], for lymphotoxin [LT]
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/20 characterized by taxonomic origin
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C07K 2319/74 containing a fusion for binding to a cell surface receptor
• CPC Class Codes: G01N 2333/705 Assays involving receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 2800/7028 Cancer
• CPC Class Codes: G01N 33/56966 Animal cells

Abstract

OX40 is a potent immune stimulating target. Provided herein are methods for the treatment of cancer patients using (3X40 agonists methods to predict clinical outcome of the treatment by correlation of the treatment and an increase in OX40-induced T cell proliferation.

Claims

1. A method of treating cancer, comprising administering to a patient in need of treatment an effective amount of an OX40 agonist, wherein the administration increases the level of Ki-67 expression in T-lymphocytes of the patient, or a subpopulation thereof over a corresponding baseline level, and can stimulate T-lymphocyte activity against cancer cells in the patient.

9. The method of claim 1, wherein the corresponding baseline level of Ki-67 expression is established by averaging the Ki-67 expression level in T-lymphocytes or the same subpopulation thereof, obtained from a population of donors.

12. The method of claim 1, wherein the corresponding baseline level of Ki-67 expression is the Ki-67 expression level in T-lymphocytes, or the same subpopulation thereof, obtained from the patient prior to administration of the OX40 agonist.

13. The method of claim 1, wherein the subpopulation of T-lymphocytes is effector T-lymphocytes.

14. The method of claim 1, wherein the subpopulation of T-lymphocytes is CD4⁺ Foxp3⁻

T-lymphocytes or CD8⁺ T-lymphocytes.

18. The method of claim 14, wherein the subpopulation of T-lymphocytes is CD8⁺ lymphocytes and wherein the administration of an OX40 agonist additionally increases the proportion of T-lymphocytes expressing CD38, HLA-DR expression, or both CD38 and HLA-DR.

19. The method of claim 1, wherein an increase in Ki-67 expression is not detected in CD4⁺ FoxP3⁺ T-lymphocytes.

20. The method of claim 1, wherein the increase in Ki-67 expression in the patient'"'"'s T-lymphocytes, or subpopulation thereof, is at least about 0.5-fold relative to the corresponding baseline level.

22. The method of claim 1, wherein an increase in the level of Ki-67 expression is detected in a subpopulation of T-lymphocytes which respond to a tumor-specific antigen.

23. The method of claim 1, wherein an increase in the level of Ki-67 expression is detected in memory T-lymphocytes.

25. The method of claim 1, wherein the OX40 agonist is an antibody which specifically binds to OX40, or an antigen-binding fragment thereof.

35. The method of claim 25, wherein the antibody or antigen-binding fragment thereof binds to the same OX40 epitope as mAb 9B12.

36. The method of claim 1, wherein the OX40 agonist comprises an OX40 ligand or OX40-binding fragment thereof.

39. The method of claim 1, wherein the OX40 agonist comprises a fusion polypeptide comprising in an N-terminal to C-terminal direction:

an immunoglobulin domain, wherein the immunoglobulin domain comprises an Fe domain;

a trimerization domain, wherein the trimerization domain comprises a coiled coil trimerization domain; and

a receptor binding domain, wherein the receptor binding domain is an OX40 receptor binding domain,

and wherein the fusion polypeptide self-assembles into a trimeric fusion protein.

2. A method of treating cancer, comprising:

(a) administering to a patient in need of treatment an effective amount of an OX40 agonist; and

(b) (i) detecting the level of Ki-67 expression in the patient'"'"'s T-lymphocytes, or a subpopulation thereof, obtained at one or more time points following the administration,

(ii) obtaining T-lymphocytes from the patient at one or more time points following the administration and submitting the T-lymphocytes for detection of the level of Ki-67 expression in the T-lymphocytes or a subpopulation thereof and comparison to a corresponding baseline level of Ki-67 expression, or

(iii) obtaining T-lymphocytes from the patient at one or more time points following the administration, detecting the level of Ki-67 expression in the T-lymphocytes or a subpopulation thereof and comparison to a corresponding baseline level of Ki-67 expression, and comparing the Ki-67 expression level to a corresponding baseline level;

wherein the administration can stimulate T-lymphocyte activity against the cancer cells in the patient; and

wherein an increase in the Ki-67 expression level in the patient'"'"'s T-lymphocytes or subpopulation thereof compared to a corresponding baseline level is prognostic of effective treatment.

53. The method of claim 2, wherein the level of Ki-67 expression in T-lymphocytes is detected by flow cytometry of peripheral blood mononuclear cells (PBMCs) for expression of the CD3, CD95, and CD4 markers or for expression of CD3, CD95, and CD8 markers.

54. The method of claim 53, wherein the PBMCs are analyzed by flow cytometry for expression of (i) CD3, CD95, CD4, and FoxP3 markers, or (ii) CD3, CD95, CD8, and CD28 markers.

3-4. -4. (canceled)

5. A method of monitoring whether a cancer patient will respond to treatment with the OX40 agonist, comprising:

(a) detecting the level of Ki-67 expression in the patient'"'"'s T-lymphocytes, or a subpopulation thereof, obtained from the patient at one or more time points following administration of the OX40 agonist; and

(b) comparing the level of Ki-67 expression obtained in (a) to a corresponding baseline level of Ki-67 expression,

wherein an increase over baseline in the level of Ki-67 expression in the T-lymphocytes or subpopulation thereof obtained following administration of the OX40 agonist identifies a patient who will respond to treatment with an OX40 agonist.

6-8. -8. (canceled)

10-11. -11. (canceled)

15-17. -17. (canceled)

21. (canceled)

24. (canceled)

26-34. -34. (canceled)

37-38. -38. (canceled)

40-52. -52. (canceled)

55-61. -61. (canceled)