Prediction of Responsiveness to Treatment with Immunomodulatory Therapeutics and Method of Monitoring Abscopal Effects During Such Treatment

• US 20150037346A1
• Filed: 02/22/2013
• Published: 02/05/2015
• Est. Priority Date: 02/23/2012
• Status: Active Application

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Wolchok, Jedd D., Lesokhin, Alexander M.
• Application Number:
  US14/380,837
• Publication Number:
  US 20150037346A1
• Time in Patent Office: Days
• US Class Current: 424/142.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: G01N 2333/70503 Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
• 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 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/57492 involving compounds localized on the membrane of tumor or cancer cells

Abstract

Efficacy of a therapeutic to enhance antitumor immunity in a patient is predicted, where the therapeutic is one that targets an immunomodulatory leukocyte membrane protein (ILMP) to enhance immune activity. Peripheral blood sample from the patient is tested for levels of monocytes having specific cell surface markers (CD14⁺, HLA-DR^low) prior to treatment. Low levels of monocytes of this type (PBM14⁺HLA-DR^low) indicate a greater likelihood of therapeutic efficacy. In specific exemplary embodiments of the invention, the therapeutic is an antibody to CTLA4, such as ipilimumab or tremelimumab.

Claims

1. A method for predicting efficacy of a therapeutic to enhance antitumor immunity in a patient, wherein the therapeutic is one that targets an immunomodulatory leukocyte membrane protein (ILMP) to enhance immune activity, comprising the step of determining pre-treatment levels of peripheral blood monocytes that are CD14⁺ and HLA-DR^low (PBM14⁺HLA-DR^low) in a blood sample from the patient , and comparing the determined pretreatment level to a discrimination threshold, wherein a level of PBM14+HLA-DRlow that is below the discrimination threshold indicate a likelihood of therapeutic efficacy.

2. The method of claim 1, further comprising determining pre-treatment absolute lymphocyte count (ALC) in the blood sample, and comparing the determined ALC to an ALC-discrimination threshold, wherein an ALC value greater than the ALC-discrimination threshold indicates a greater likelihood of therapeutic efficacy.

3. The method of claim 1, further comprising determining pre-treatment LDH level in the blood sample, and comparing the determined LDH level to an LDH-discrimination threshold, wherein an LDH level less than the LDH-discrimination threshold indicates a greater likelihood of therapeutic efficacy.

4. The method of claim 1 wherein the therapeutic is an antibody.

5. The method of claim 1, wherein the ILMP is a member of the immunoglobulin superfamily.

6. The method of claim 5, wherein the ILMP is CTLA4.

7. The method of claim 6, wherein the therapeutic is ipilimumab.

8. The method of claim 5, wherein the ILMP is selected from the group consisting of PD-1, LAG-3 and TIM3.

11. The method of claim 1, wherein the ILMP is a member of the TNF superfamily.

12. The method of claim 11, wherein the ILMP is selected from the group consisting of 4-1BB, GITR, OX40 and CD40.

16. The method of claim 1, wherein the patient is human.

29. The method of claim 2, further comprising determining pre-treatment LDH level in the blood sample, and comparing the determined LDH level to an LDH-discrimination threshold, wherein an LDH level less than the LDH-discrimination threshold indicates a greater likelihood of therapeutic efficacy.

9-10. -10. (canceled)

13-15. -15. (canceled)

17. A method for treating a patient having a tumor that is responsive to a therapeutic, comprising the steps of performing a test to predict efficacy of a therapeutic to enhance antitumor immunity, in a patient, and administering the therapeutic to the patient if the test indicates a likelihood of therapeutic efficacy wherein said test to predict efficacy comprises the steps of

determining pre-treatment levels of peripheral blood monocytes that are CD14⁺ and HLA-DR^low (PBM14⁺HLA-DR^low) in a blood sample from the patient, and

comparing the determined pretreatment level to a discrimination threshold, wherein a level of PBM14HLA-DR^low that is below the discrimination threshold indicate a likelihood of therapeutic efficacy.

30. The method of claim 17, wherein the test to predict efficacy further comprises determining pre-treatment absolute lymphocyte count (ALC) in the blood sample, and comparing the determined ALC to an ALC-discrimination threshold, wherein an ALC value greater than the ALC-discrimination threshold indicates a greater likelihood of therapeutic efficacy.

31. The method of claim 30, test to predict efficacy further comprises determining pre-treatment LDH level in the blood sample, and comparing the determined LDH level to an LDH-discrimination threshold, wherein an LDH level less than the LDH-discrimination threshold indicates a greater likelihood of therapeutic efficacy.

32. The method of claim 17, test to predict efficacy further comprises determining pre-treatment LDH level in the blood sample, and comparing the determined LDH level to an LDH-discrimination threshold, wherein an LDH level less than the LDH-discrimination threshold indicates a greater likelihood of therapeutic efficacy.

18. A method for monitoring therapeutic progress of treatment with a therapeutic that targets an ILMP in combination with radiation therapy, comprising the steps of monitoring levels of PBM14⁺HLA-DR^low in the patient after treatment with the therapeutic and radiation, wherein decreases in PBM14⁺HLA-DR^low indicate therapeutic progress has or is about to commence.

19. The method of claim 18, wherein the therapeutic is an antibody

20. The method claim 18, wherein the ILMP is a member of the immunoglobulin superfamily.

21. The method of claim 20, wherein the ILMP is CTLA4.

22. The method of claim 21 wherein the therapeutic is ipilimumab.

23. The method of claim 20, wherein the ILMP is selected from the group consisting of PD-1, LAG-3 and TIM3.

26. The method of claim 18, wherein the ILMP is a member of the TNF superfamily.

27. The method of claim 26, wherein the ILMP is 4-1BB, GITR, OX40 or CD40.

28. The method of claim 18, wherein the patient is human

24-25. -25. (canceled)