Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof

Patent metadata

Field	Value
Publication number	US-10774388-B2
Application number	US-201515517597-A
Country	US
Kind code	B2
Filing date	Oct 7, 2015
Priority date	Oct 8, 2014
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

Cancer biomarkers and methods of using them are disclosed.

First claim

What is claimed is:

1. A method for treating a subject having a cancer with a CD19 chimeric antigen receptor (CAR19)-expressing cell therapy, the method comprising:
acquiring a value for the level of CD27+ CD45RO− in CD8+ T cells in a sample comprising an immune effector cell population from the subject, wherein an increased level of CD27+ CD45RO− in CD8+ T cells in the sample indicates that the subject is responsive to the CAR19-expressing cell therapy, thereby determining that the subject is responsive to the CAR19-expressing cell therapy; and
administering to the subject determined to be responsive, a therapeutically effective dose of said CAR19-expressing cell therapy,
thereby treating the subject.

2. A method for optimizing manufacturing of a CD19 chimeric antigen receptor (CAR19)-expressing cell product comprising:
acquiring a value for the level of CD27+ CD45RO− in CD8+ T cells in a sample comprising an immune effector cell population from a subject, wherein an increased level of CD27+ CD45RO− in CD8+ T cells in the sample indicates that the immune effector cell population results in a CAR19-expressing cell product having increased potency, thereby determining that the immune effector cell population has increased potency; and
introducing a nucleic acid encoding CAR19 into the immune effector cell population determined to have increased potency,
thereby optimizing the manufacture of the CAR19-expressing cell product.

3. The method of claim 1 , further comprising identifying the subject as: a responder, a partial responder, a complete responder, a non-responder, a relapser or a non-relapser, based on the level of CD27+ CD45RO− immune effector cells in the sample.

4. The method of claim 1 , wherein the level of CD27+ CD45RO− in CD8+ T cells is evaluated using a profile of one or more of gene expression, flow cytometry or protein expression.

5. The method of claim 1 , wherein the level of CD27+ CD45RO− in CD8+ T cells is evaluated using a profile or signature indicative of the percentage of CD27+ CD45RO− in CD8+ T cells in the sample.

6. The method of claim 3 , wherein the subject identified as being responsive to the therapy is a responder or a complete responder.

7. The method of claim 1 , wherein the subject identified as being responsive to the therapy has a greater percentage of CD27+ CD45RO− in CD8+ T cells compared to a reference value.

8. The method of claim 7 , wherein the reference value is a value of a non-responder number of CD27+ CD45RO− in CD8+ T cells.

9. The method of claim 1 , wherein the CAR19-expressing cell therapy comprises a plurality of CAR19-expressing immune effector cells.

10. The method of claim 1 , wherein the CAR19-expressing cell therapy comprises CTL019.

11. The method of claim 1 , wherein the value for the level of CD27+ CD45RO− in CD8+ T cells is determined from an apheresis sample acquired from the subject.

12. The method of claim 1 , wherein the value for the level of CD27+ CD45RO− in CD8+ T cells is determined from a manufactured CAR19-expressing cell product sample.

13. The method of claim 1 , wherein the subject is evaluated prior to, during, or after receiving the CAR19-expressing cell therapy.

14. The method of claim 1 , wherein the cancer is associated with CD19 expression.

15. The method of claim 1 , wherein the cancer is a hematological cancer.

16. The method of claim 15 , wherein the hematological cancer is selected from the group consisting of B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), B cell promyelocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, and Waldenstrom macroglobulinemia.

17. The method of claim 1 , wherein the subject is a human patient.

18. The method of claim 1 , wherein the subject receives a treatment prior to the initiation of a CAR19-expressing cell therapy or a treatment post-CAR19-expressing cell therapy.

19. The method of claim 1 , wherein the sample comprises a CD4+ or a CD8+ T cell population.

20. The method of claim 11 , wherein the apheresis sample is evaluated prior to infusion or re-infusion.

21. The method of claim 2 , further comprising a step of enriching for cells having an increased level of CD27 + CD45RO−.

22. The method of claim 2 , which further comprises a step of depleting T REG cells.

23. The method of claim 2 , wherein the level of CD27 + CD45RO− in CD8+ T cells in the CAR-expressing cell product is evaluated following activation in vitro.

24. The method of claim 2 , wherein the CAR19-expressing cell product comprises CTL019.

25. The method of claim 2 , wherein the manufactured CAR19-expressing cell product is evaluated prior to infusion or re-infusion into the subject.

26. The method of claim 15 , wherein the hematological cancer is CLL.

27. The method of claim 1 , wherein the sample is from a subject having CLL.

28. The method of claim 7 , wherein the subject has 7% or a greater percentage of CD27+ CD45RO− in CD8+ T cells compared to a reference value.

29. The method of claim 2 , wherein the immune effector cell population which is determined to result in a CAR19-expressing cell product having increased potency has a greater percentage of CD27+ CD45RO− in CD8+ T cells compared to a reference value.

30. The method of claim 29 , wherein the immune effector cell population has 7% or a greater percentage of CD27+ CD45RO− in CD8+ T cells compared to a reference value.

31. The method of claim 29 , wherein the reference value is a value of a non-responder number of CD27+ CD45RO− in CD8+ T cells.

Assignees

• Novartis Ag
• Univ Pennsylvania

Inventors

• Bedoya Felipe
• Bitter Hans
• Brogdon Jennifer
• Dorfmeier Corin
• Garg Abhishek
• Glass David Jonathan
• Mannick Joan
• Melenhorst Jan J
• Milone Michael
• Murphy Leon
• Orlando Elena
• Wilcox Nicholas

Classifications

• G01N33/57505 Primary

  of the blood, e.g. leukaemia · CPC title

• G01N33/575

  for cancer · CPC title

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/36

  Immune checkpoint inhibitors · CPC title

• A61K40/35

  Cytokines · CPC title