Compounds for inducing anti-tumor immunity and methods thereof

• US 10,450,566 B2
• Filed: 03/14/2018
• Issued: 10/22/2019
• Est. Priority Date: 09/25/2013
• Status: Active Grant

• Current Assignee: Cornell University
• Original Assignee: Cornell University
• Inventors: Cubillos-Ruiz, Juan R., Glimcher, Laurie H.
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US15/921,322
• Publication Number:
  US 20180201933A1
• Time in Patent Office: 587 Days
• Field of Search: 514 44
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2320/31 Combination therapy
• CPC Class Codes: C12Y 207/11 Protein-serine/threonine kinases (2.7.11)

Abstract

Described herein is a previously unknown function of XBP1 in controlling anti-tumor immunity. It is shown that inhibiting XBP1 in tumor-associated dendritic cells inhibits tumor growth and induces protective anti-tumor immune responses.

Claims

1. A method for treatment of cancer in a subject in need thereof, the method comprising:

contacting antigen presenting cells (APCs) with a direct inhibitor of IRE-1α

, wherein the direct inhibitor of IRE1α

is present in an amount sufficient to increase antigen presentation in the APCs; and

administering the APCs contacted with the direct inhibitor of IRE-1α

, to a subject, wherein the subject has a solid cancer, and wherein the solid cancer comprises an epithelial cancer, a germ cell cancer, or a stromal tumor.

2. The method of claim 1, wherein the solid cancer is further characterized as an ovarian cancer.

3. The method of claim 1, wherein the epithelial cancer is a carcinoma or an adenocarcinoma.

4. The method of claim 1, wherein the APCs are dendritic cells.

5. The method of claim 4, wherein the dendritic cells are tumor-associated dendritic cells.

6. The method of claim 1, wherein the APCs provided are obtained from the subject.

7. The method of claim 1, wherein the direct inhibitor of IRE-1α

is an IRE-1α

-specific antibody or a small molecule inhibitor of IRE-1α

.

8. The method of claim 1, wherein the direct inhibitor of IRE-1α

reduces or eliminates IRE-1α

mRNA expression in the APCs.

9. The method of claim 1, wherein the direct inhibitor of IRE-1α

reduces or eliminates IRE-1α

protein expression in the APCs.

10. The method of claim 1, wherein the direct inhibitor of IRE-1α

is a nucleic acid molecule that is antisense to an IRE-1α

-encoding nucleic acid molecule, an IRE-1α

shRNA, an IRE-1α

siRNA, or a microRNA that targets IRE-1α

.

11. The method of claim 1, further comprising administering an additional therapeutic agent to the subject.

12. The method of claim 11, wherein the additional therapeutic agent is a chemotherapeutic agent or an antibody.

13. A method for treatment of ovarian cancer in a subject in need thereof, the method comprising:

contacting antigen presenting cells (APCs) with a small molecule inhibitor of IRE-1α

, wherein the small molecule inhibitor of IRE1α

is present in an amount sufficient to increase antigen presentation in the APCs; and

administering the APCs contacted with the small molecule inhibitor of IRE-1α

to a subject, wherein the subject has ovarian cancer.

14. The method of claim 13, wherein the APCs are dendritic cells.

15. The method of claim 13, wherein the APCs provided are obtained from the subject.

16. A method for treatment of ovarian cancer in a subject in need thereof, the method comprising:

contacting antigen presenting cells (APCs) with an inhibitor of IRE-1α

, wherein the inhibitor of IRE1α

is present in an amount sufficient to increase antigen presentation in the APCs, and wherein the inhibitor of IRE-1α

reduces or eliminates IRE-1α

mRNA expression in the APCs; and

administering the APCs contacted with the inhibitor of IRE-1α

to a subject, wherein the subject has ovarian cancer.

17. The method of claim 16, wherein the APCs are dendritic cells.

18. The method of claim 16, wherein the APCs provided are obtained from the subject.

19. The method of claim 16, wherein the inhibitor of IRE-1α

is a nucleic acid molecule that is antisense to an IRE-1α

-encoding nucleic acid molecule, an IRE-1α

shRNA, or an IRE-1α

siRNA.