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WO 2019/094983 Al 16 May 2019 (16.05.2019) W 1P O PCT

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WO 2019/094983 Al 16 May 2019 (16.05.2019) W 1P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2019/094983 Al 16 May 2019 (16.05.2019) W 1P O PCT (51) International Patent Classification: (72) Inventors; and A61K 38/16 (2006.01) A61P 35/00 (2006.01) (71) Applicants: TIROSH, Itay [US/US]; c/o 415 Main Street, A61K 39/395 (2006.01) A61P 37/02 (2006.01) Cambridge, Massachusetts 02142 (US). MATHEWSON, A61P 29/00 (2006.01) C07K 14/05 (2006.01) Nathan [US/US]; c/o 450 Brookline Avenue, Boston, Massachusetts 02215 (US). (21) International Application Number: PCT/US20 18/060857 (72) Inventors: SUVA, Mario; c/o 55 Fruit Street, Boston, Massachusetts 021 14 (US). WUCHERPFENNIG, Kai; (22) International Filing Date: c/o 450 BROOKLINE AVENUE, Boston, Massachusetts 13 November 2018 (13. 11.2018) 02215 (US). REGEV, Aviv; c/o 415 Main Street, Cam¬ (25) Filing Language: English bridge, Massachusetts 02142 (US). (26) Publication Language: English (74) Agent: REY, Gertrud U. et al.; Johnson, Marcou & Isaacs, LLC, P.O. Box 691, Hoschton, Georgia 30548 (US). (30) Priority Data: 62/585,422 13 November 2017 (13. 11.2017) US (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (71) Applicants: THE BROAD INSTITUTE, INC. [US/US]; AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 415 Main Street, Cambridge, Massachusetts 02142 (US). CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, MASSACHUSETTS INSTITUTE OF TECHNOLO¬ DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, GY [US/US]; 77 Massachusetts Avenue, Cambridge, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, Massachusetts 02139 (US). THE GENERAL HOSPI¬ KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, TAL CORPORATION [US/US]; 55 Fruit Street, Boston, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, Massachusetts 021 14 (US). DANA-FARBER CANCER OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, INSTITUTE, INC. [US/US]; 450 Brookline Avenue, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, Boston, Massachusetts 02215 (US). TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (54) Title: METHODS AND COMPOSITIONS FOR TREATING CANCER BY TARGETING THE CLEC2D-KLRB 1 PATHWAY FIG. 1A < 2 (57) Abstract: Provided are methods and compositions for treating cancer in a subject in need thereof. One of the top gene products in glioblastoma multiforme (GBM) is KLRB 1 (also known as CD 161), a C-type lectin protein that binds to CLEC2D. Binding of CLEC2D to the KLRB 1 receptor inhibits the cytotoxic function of NK cells as well as cytokine secretion. KLRB 1 is only expressed by small as © subpopulations of human blood T cells, and consequently little is known about the function of this receptor in T cells. However, prelim¬ inary data demonstrate that KLRB 1 expression is induced in T cells within the GBM microenvironment. In an exemplary embodiment, a method is provided comprising administering an agent capable of blocking the interaction of KLRB 1 with its ligand. The agent may comprise an antibody or fragment thereof, which may bind KLRB 1 or CLEC2D. o [Continued on nextpage] W O 2019/094983 A l Illlll II lllll lllll lllll llll III III lllll lllll lllll lllll lllll llll llll llll llll (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARJPO (BW, GH, GM, KE, LR, LS, MW, ML, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) METHODS AND COMPOSITIONS FOR TREATING CANCER BY TARGETING THE CLEC2D-KLRB1 PATHWAY CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/585,422, filed November 13, 2017. The entire contents of the above-identified application are hereby fully incorporated herein by reference. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (BROD-2355WP.ST25.txt"; Size is 8 Kilobytes and it was created on November 13, 2018) is herein incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0003] This invention was made with government support under Grant No. CA173750 and Grant No. CA202820 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD [0004] The subject matter disclosed herein is generally directed to compositions and methods for treating cancer. BACKGROUND [0005] Glioblastoma multiforme (GBM) is one of the most challenging human cancers. It is the most aggressive type of brain cancer, and there is no clear way to prevent the disease. [0006] Over the past few years novel immunosuppressive mechanisms have been identified in GBM patients, with a primary focus on scRNA-seq analysis of T cells directly isolated from surgically resected lesions. One of the top gene products identified is KLRBl (also known as CD161), a C-type lectin protein that binds to CLEC2D. Binding of CLEC2D to the KLRBl receptor inhibits the cytotoxic function of NK cells as well as cytokine secretion. KLRBl is only expressed by small subpopulations of human blood T cells, and consequently little is known about the function of this receptor in T cells. However, preliminary data demonstrate that KLRBl expression is induced in T cells within the GBM microenvironment. An immunohistochemistry study demonstrated that CLEC2D (also called LLT1) is expressed by human gliomas, with expression increasing with WHO grade of malignancy. In contrast, there was little labeling with a CLEC2D specific antibody in sections from normal human brain tissue. These conclusions are supported by an analysis of TCGA RNA-seq data performed in collaboration with Dr. Shirley Liu (DFCI) which demonstrated significantly increased expression of CLEC2D in GBM compared to normal brain tissue (p = 5.1 x 10 11) . This analysis also highlighted increased expression of CLEC2D relative to the corresponding normal tissue in many other cancer types, including all types of renal cancer (p <2 x 10 16 for KIRC), lung adenocarcinoma (p = 5.5 x 10 11), colon adenocarcinoma (p = 10 12) and other cancers. Accordingly, it seems that KLRB1 functions as an inhibitory receptor for human T cells by binding to the CLEC2D ligand on tumor cells. This hypothesis is supported by preliminary data from a humanized mouse model of GBM which demonstrate that inactivation of the KLRB1 gene in primary human T cells greatly enhances their cytotoxic function within tumors. SUMMARY [0007] In one aspect, the invention provides a method of treating a disease characterized by increased expression of killer cell lecting like receptor (KLRB1) in immune cells, comprising administering to a subject in need thereof one or more agents in an amount sufficient to either: (i) block binding of CD161 to one or more CD161 ligands; (ii) reduce expression of KLRB1 (the gene encoding CD 161); (iii) reduce expression of one or more CD161 ligands (iv) block binding of CLEC2D to a receptor of CLEC2D other than CD161, or any combination thereof. [0008] In some embodiments, the one or more agents may comprise an antibody, or fragment thereof, that binds CD161 . The one or more agents may comprise an antibody, or fragment thereof, that binds to the one or more CD161 ligands. Alternatively, the method comprises administering a soluble CD161 protein, or fragment thereof, that binds to one or more of the CD161 ligands. In some embodiments, the antibody may be a humanized or chimeric antibody. [0009] In some embodiments, reducing expression of KLRB1, or expression of one or more CD161 ligands, comprises administering a programmable nucleic acid modifying agent configured to reduce expression of KLRB1, or reduce expression of one or more CD161 ligands. [0010] In some embodiments, the programmable nucleic acid modifying agent may be a CRISPR-Cas, a zinc finger, a TALE, or a meganuclease. The CRISPR-Cas may be a CRISP-Cas9, a CRISPR-Casl2, a CRISPR-Casl3, or a CRISPR-Casl4. [0011] In some embodiments, the disease is cancer. The cancer may be characterized by increased expression of a CD161 ligand by cancer cells or other cells in the tumor microenvironment. Alternatively, one or more immune cell types in the tumor microenvironment may be characterized by increased expression of KLRB1. In some embodiments, the one or more CD161 ligands comprises CLEC2D. [0012] In some embodiments, the one or more immune cells are tumor infiltrating lymphocytes (TILs). [0013] In some embodiments, the cancer is a glioblastoma, melanoma, liver cancer, renal cancel, lung adenocarcinoma, or colon adenocarcinoma. [0014] In some embodiments, the one or more agents may be administered in a combination treatment regimen comprising checkpoint blockade therapy, vaccines, targeted therapies, radiation therapy, chemotherapy, and/or adoptive cell therapy (ACT). [0015] The checkpoint blockade therapy may comprise anti-PD-1, anti-CTLA4, anti-TIM-3 and/or anti-LAG3. [0016] The vaccine may be a neoantigen vaccine or other cancer vaccine. [0017] In some embodiments, the disease is an infectious disease. In some embodiments, the infectious disease is a chronic infectious disease.
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