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WO 2018/201056 Al 01 November 2018 (01.11.2018) W!P O PCT

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WO 2018/201056 Al 01 November 2018 (01.11.2018) W!P 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 2018/201056 Al 01 November 2018 (01.11.2018) W!P O PCT (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, A61K38/1 7 (2006.01) C07K 16/28 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 35/17 (2015.01) CI2N 5/0783 (2010.01) C07K 14/725 (2006.01) Published: — with international search report (Art. 21(3)) (21) International Application Number: — with sequence listing part of description (Rule 5.2(a)) PCT/US20 18/029963 (22) International Filing Date: 27 April 2018 (27.04.2018) (25) Filing Language: English (26) Publication Langi English (30) Priority Data: 62/491,598 28 April 2017 (28.04.2017) US 62/593,655 0 1 December 20 17 (01 .12.20 17) US (71) Applicants: NOVARTIS AG [CH/CH]; Lichtstrasse 35, 4056 Basel (CH). THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA [US/US]; 3160 Chestnut Street, Suite 200, Philadelphia, PA 19104 (US). (72) Inventors: DALEY, Michael; 250 Massachusetts Avenue, Cambridge, MA 02139 (US). GRAND A, Brian; Novar- tis Institutes For Biomedical Research, Inc., 250 Massa chusetts Avenue, Cambridge, MA 02139 (US). MILONE, Michale, C ; 314 Surrey Road, Cherry Hill, NJ 08002 (US). NUNEZ CRUZ, Selene, Guadalupe; 2705 Cam bridge Street, Philadelphia, PA 19130 (US). (74) Agent: COLLAZO, Diana, M. et al; Lando & Anastasi, LLP, Riverfront Office, Suite 1100, Cambridge, MA 02142 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, 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, o MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (54) Title: CELLS EXPRESSING A BCMA-TARGETING CHIMERIC ANTIGEN RECEPTOR, AND COMBINATION THERAPY 0 0 WITH A GAMMA SECRETASE INHIBITOR © (57) Abstract: The invention relates to the treatment of diseases associated with expression of BCMA, in particular myelomas. The invention relates to combination therapies of a BCMA CAR-expressing cell and a gamma secretase inhibitor. BCMA-TARGETING CHIMERIC ANTIGEN RECEPTOR, AND COMBINATION THERAPY WITH A GAMMA SECRETASE INHIBITOR RELATED APPLICATIONS This application claims priority to U.S. Serial No. 62/491,598 filed April 28, 2017, and U.S. Serial No. 62/593,655 filed Dec 1, 2017, the contents of each of which are incorporated herein by reference in their entirety. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on April 23, 2018, is named N2067-7132WO_SL.txt and is 791,851 bytes in size. FIELD OF THE INVENTION The present invention relates generally to the use of cells engineered to express a chimeric antigen receptor targeting B-cell maturation antigen protein (BCMA), optionally in combination with a gamma secretase inhibitor, to treat a disease associated with the expression of BCMA. BACKGROUND OF THE INVENTION Gamma secretase is a multi-subunit protease complex that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. The gamma secretase complex comprises four subunits: presenilin, nicastrin, gamma-secretase subunit aph-1, and gamma-secretase subunit PEN-2. Another protein, CD147, has been reported as a non-essential regulator of the gamma secretase complex. Exemplary gamma secretase substrates include amyloid precursor protein, Notch, ErbB4, E- cadherin, N-cadherin, and CD44 (Haapasalo et al., J Alzheimers Dis. 2011;25(l):3-28). Recently, B- cell maturation antigen (BCMA) was identified as another substrate of gamma secretase (Laurent et al., Nat Commun. 2015 Jun 11;6:7333). BCMA is a tumor necrosis family receptor (TNFR) member expressed on cells of the B-cell lineage. BCMA expression is the highest on terminally differentiated B cells that assume the long lived plasma cell fate, including plasma cells, plasmablasts and a subpopulation of activated B cells and memory B cells. BCMA is involved in mediating the survival of plasma cells for maintaining long-term humoral immunity. The expression of BCMA has been recently linked to a number of cancers, autoimmune disorders, and infectious diseases. Cancers with increased expression of BCMA include some hematological cancers, such as multiple myeloma, Hodgkin's and non-Hodgkin's lymphoma, various leukemias, and glioblastoma. Given the ongoing need for improved strategies for targeting diseases such as cancer, new compositions and methods for improving therapeutic agents that target BCMA, e.g., anti-BCMA chimeric antigen receptor (CAR) therapies, are highly desirable. SUMMARY OF THE INVENTION The disclosure features, at least in part, a method of treating a disease or disorder associated with expression of B-cell maturation antigen (BCMA, also known as TNFRSF17, BCM, or CD269). In certain embodiments, the disorder is a cancer, e.g., a hematological cancer. In some embodiments, the method comprises administering to a subject a BCMA-targeting CAR therapy in combination with a gamma secretase inhibitor (GSI). In some embodiments, the BCMA-targeting CAR therapy is a cell (e.g., a population of cells) that expresses a CAR molecule that binds BCMA. In some embodiments, the combination maintains or has better clinical effectiveness as compared to either therapy alone. The disclosure additionally features a BCMA-targeting CAR therapy, e.g., as a monotherapy or in a combination therapy. In one aspect, disclosed herein is a method of treating a subject having a disease associated with expression of B-cell maturation antigen (BCMA) comprising administering to the subject an effective amount of a cell (e.g., a population of cells) that expresses a chimeric antigen receptor (CAR) molecule that binds BCMA (a "BCMA CAR-expressing cell"), in combination with a gamma secretase inhibitor (GSI). In certain embodiments, the GSI is an agent that reduces the expression and/or function of BCMA. In one aspect, disclosed herein is a method of treating a subject having a disease associated with expression of B-cell maturation antigen (BCMA) comprising administering to the subject an effective amount of a cell (e.g., a population of cells) that expresses a chimeric antigen receptor (CAR) molecule that binds BCMA (a "BCMA CAR-expressing cell"), in combination with a gamma secretase inhibitor (GSI), wherein: the CAR molecule comprises an anti-BCMA binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein: the GSI has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or all) of the following properties: (i) the GSI reduces gamma secretase-mediated cleavage of BCMA; (ii) the GSI, when incubated with BCMA-expressing cells, increases cell surface expression of BCMA, e.g., by at least 2, 4, 6, 8, 10, 15, or 20-fold, e.g., as measured by a method described herein, e.g., a flow cytometry assay, e.g., as measured using methods described in Example 1 with respect to FIG. 1; (iii) the GSI, when incubated with BCMA-expressing cells, changes conformation and/or posttranslational modification of the extracellular domain of cell surface-expressed BCMA; (iv) the GSI, when incubated with BCMA-expressing cells, decreases the level of soluble BCMA in the cell supernatant, e.g., by at least 80, 85, 90, 95, 99, or 99.5%, e.g., as measured by a method described herein, e.g., an ELISA assay, e.g., as measured using methods described in Example 1 with respect to Table 28; (v) the GSI, when administered in vivo, increases cell surface expression of BCMA, e.g., as measured by a method described herein, e.g., a flow cytometry assay; (vi) the GSI, when administered in vivo, changes conformation and/or posttranslational modification of the extracellular domain of cell surface-expressed BCMA; (vii) the GSI, when administered in vivo, decreases the level of soluble BCMA in the serum and/or bone marrow, e.g., as measured by a method described herein, e.g., an ELISA assay; (viii) the GSI is capable of increasing the activity of the BCMA CAR-expressing cell, e.g., increasing the cytotoxicity of the BCMA CAR-expressing cell, e.g., as measured by a method described herein, e.g., as measured using methods described in Example 3 with respect to FIGs. 7B and 7C; (ix) the GSI is capable of increasing the activity of the BCMA CAR-expressing cell, e.g., increasing the anti-tumor activity of the BCMA CAR-expressing cell, e.g., as measured by a method described herein, e.g., as measured using methods described in Example 3 with respect to FIG. 9D; (x) the GSI does not reduce gamma secretase-mediated cleavage of Notch, or reduces gamma secretase-mediated cleavage of Notch less
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