Checkpoint blockade and microsatellite instability

Patent metadata

Field	Value
Publication number	US-10934356-B2
Application number	US-201816144549-A
Country	US
Kind code	B2
Filing date	Sep 27, 2018
Priority date	Nov 13, 2014
Publication date	Mar 2, 2021
Grant date	Mar 2, 2021

Abstract

Blockade of immune checkpoints such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) shows promise in patients with cancer. Inhibitory antibodies directed at these receptors have been shown to break immune tolerance and promote anti-tumor immunity. These agents work particularly well in patients with a certain category of tumor. Such tumors may be particularly susceptible to treatment because of the multitude of neoantigens which they produce.

First claim

We claim:

1. A method for treating cancer in a patient in need thereof, comprising:
determining that the patient has a tumor that exhibits a high microsatellite instability (MSI-high) or a mismatch repair (MMR) deficiency status;
administering an effective amount of pembrolizumab to the patient;
determining that the patient exhibits an outcome that is improved as compared to a corresponding outcome that would be observed in a reference patient that has been administered pembrolizumab, wherein the reference patient has a tumor that does not exhibit a MSI-high or a MMR deficiency status; and
wherein the patient has received a prior cancer therapy drug.

2. The method of claim 1 , wherein the step of determining that the patient has a tumor that exhibits a high microsatellite instability (MSI-high) status includes detecting in a tumor sample obtained from the patient a microsatellite marker in a DNA sequence.

3. The method of claim 2 , wherein the microsatellite marker is BAT-25, BAT-26, MONO-27, NR-21 or NR-24.

4. The method of claim 1 , wherein the step of determining that the patient has a tumor that exhibits a MMR deficiency status includes detecting in a tumor sample obtained from the patient a mismatch repair marker in a DNA sequence.

5. The method of claim 1 , wherein the MMR deficiency status of the tumor is detected by immunohistochemistry.

6. The method of claim 1 , wherein the cancer in the patient has progressed after the patient received the prior cancer therapy drug.

7. The method of claim 1 , wherein the outcome that is improved is an improved objective response rate (ORR), an improved progression-free survival (PFS), or an improved overall survival.

8. The method of claim 7 , wherein the outcome is assessed in the patient within approximately 20 weeks after administering pembrolizumab.

9. The method of claim 1 , wherein the cancer is a metastatic cancer.

10. The method of claim 1 , wherein the cancer is a metastatic colorectal cancer.

11. A method for treating cancer in a patient in need thereof, the method comprising:
detecting a high microsatellite instability (MSI-high) or a mismatch repair (MMR) deficiency status in a tumor sample from the patient;
wherein the tumor sample exhibits an instability of one or more microsatellite markers or a deficiency of one or more mismatch repair markers;
administering an effective amount of pembrolizumab to the patient;
determining that the patient exhibits an outcome that is improved as compared to a corresponding outcome that would be observed in a reference patient that has been administered pembrolizumab, wherein reference patient has a tumor that does not exhibit an instability of the one or more microsatellite markers or a deficiency of the one or more mismatch repair markers; and
wherein the patient has received a prior cancer therapy drug.

12. The method of claim 11 , wherein the microsatellite marker is BAT-25, BAT-26, MONO-27, NR-21, or NR-24.

13. The method of claim 11 , wherein the cancer is a metastatic cancer.

14. The method of claim 11 , wherein the cancer is a metastatic colorectal cancer.

15. The method of claim 14 , wherein the metastatic colorectal cancer in the patient has progressed after the patient received the prior cancer therapy drug.

16. The method of claim 11 , wherein the outcome that is improved is an improved objective response rate (ORR), an improved progression-free survival (PFS), or an improved overall survival.

17. The method of claim 16 , wherein the outcome is assessed in the patient at 20 weeks after administering pembrolizumab.

18. The method of claim 11 , wherein pembrolizumab is administered by intravenous infusion.

19. A method for treating cancer in a patient in need thereof comprising:
selecting a patient who has an unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient solid tumor, the tumor having progressed following a cancer therapy;
administering an effective amount of pembrolizumab to the patient; and
determining that the patient exhibits an outcome that is improved as compared to a corresponding outcome that would be observed in a reference patient that has been administered pembrolizumab, wherein the reference patient has a tumor that does not exhibit a MSI-high or a MMR deficiency status.

20. The method of claim 19 , wherein the solid tumor exhibits instability in a microsatellite marker.

21. The method of claim 20 , wherein the microsatellite marker is BAT-25, BAT-26, MONO-27, NR-21 or NR-24.

22. The method of claim 19 , wherein the outcome that is improved is an improved objective response rate (ORR), an improved progression-free survival (PFS), or an improved overall survival.

23. A method for treating cancer in a population of cancer patients in need thereof, comprising:
administering an effective amount of pembrolizumab to patients in the population of cancer patients, which patients have a tumor that exhibits a high microsatellite instability (MSI-high) or a mismatch repair (MMR) deficiency status, said tumor having progressed following a prior treatment; and
observing an objective response rate of about 12% to 96% in the population of cancer patients after administration of pembrolizumab.

24. The method of claim 23 , wherein the tumor exhibits instability of a microsatellite marker.

25. The method of claim 24 , wherein the microsatellite marker is BAT-25, BAT-26, MONO-27, NR-21 or NR-24.

26. The method of claim 23 , wherein the cancer is a metastatic cancer.

27. The method of claim 23 , wherein the objective response rate is assessed in the population of cancer patients at 20 weeks after administering pembrolizumab.

28. The method of claim 23 , wherein the cancer is not colorectal cancer.

Assignees

• Univ Johns Hopkins

Inventors

• Diaz Luis
• Vogelstein Bert
• Kinzler Kenneth W
• Papadopoulos Nickolas
• Le Dung
• Pardoll Drew M
• Topalian Suzanne L

Classifications

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title

• C12Q1/6886

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title