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WO 2017/210617 A2 O (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 2017/210617 A2 07 December 2017 (07.12.2017) W !P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C07K 16/28 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, (21) International Application Number: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US2017/035778 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 02 June 2017 (02.06.2017) 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. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Langi English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 62/344,958 02 June 20 16 (02.06.2016) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/381,163 30 August 2016 (30.08.2016) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 62/429,294 02 December 20 16 (02.12.20 16) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 62/434,974 15 December 2016 (15.12.2016) US MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 62/455,547 06 February 2017 (06.02.2017) US TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, 62/490,91 1 27 April 2017 (27.04.2017) US KM, ML, MR, NE, SN, TD, TG). 62/492,784 0 1 May 2017 (01 .05.2017) US Published: (71) Applicants (for US only): PORTER, David, L. [US/US]; — without international search report and to be republished = 82 1Crum Creek Road, Springfield, PA 19064 (US) . FREY, upon receipt of that report (Rule 48.2(g)) = Noelle [US/US] ; 312 Chestnut Avenue, Narberth, PA 19072 = (US). JUNE, Carl, H. [US/US]; 409 Baird Road, Meri- = on Station, PA 19066 (US). LACEY, Simon [US/US]; 15 = Brandywine Drive, Media, PA 19063 (US). CHEN, Fang Ξ [US/US]; 2 11 Cobblestone Dr, Ardmore, PA 19003 (US). = MELENHORST, Jan, J. [US/US]; 11 Exton Circle, Cher- = ry Hill, NJ 08003 (US). S (71) Applicants: NOVARTIS AG [CH/CH]; Lichtstrasse = 35, 4056 Basel (CH). THE TRUSTEES OF THE ≡ UNIVERSITY OF PENNSYLVANIA [US/US]; 3160 Chesnut Street, Suite 200, Philadelphia, Pennsylvania ≡ 19104 (US). — (72) Inventors; and = (71) Applicants: MUELLER, Karen Thudium [US/US]; No- s vartis Pharmaceuticals Corporation, One Health Plaza, East = Hanover, NJ 07936 (US). WOOD, Patricia [US/US]; ~ Novartis Pharmaceuticals Corporation, One Health Plaza, = East Hanover, NJ 07936 (US). ZHANG, Yiyun (Michael) = [US/US]; Novartis Pharmaceuticals Corporation, One = Health Plaza, East Hanover, NJ 07936 (US). TARAN, = Tetiana [US/US]; Novartis Pharmaceuticals Corporation, = One Health Plaza, East Hanover, NJ 07936 (US). = (74) Agent: COLLAZO, Diana, M. et al; Lando & Anastasi, LLP, Riverfront Office Park, One Main Street, Suite 1100, Cambridge, MA 02 142 (US) . (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, o AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (54) Title: THERAPEUTIC REGIMENS FOR CHIMERIC ANTIGEN RECEPTOR (CAR)- EXPRESSING CELLS © (57) Abstract: The invention provides a method of treating an adult subject having a hematological cancer, comprising administering to the subject selected dosage regimens comprising a plurality of immune effector cells expressing a CAR molecule. THERAPEUTIC REGIMENS FOR CHIMERIC ANTIGEN RECEPTOR (CAR)- EXPRESSING CELLS This application claims priority to U.S. Serial No. 62/344,958 filed June 2, 2016, U.S. Serial No. 62/381,163 filed August 30, 2016, U.S. Serial No. 62/429,294 filed December 2, 2016, U.S. Serial No. 62/434,974 filed December 15, 2016, U.S. Serial No. 62/455,547 filed February 6, 2017, U.S. Serial No. 62/490,911 filed April 27, 2017, and U.S. Serial No. 62/492,784 filed May 1, 2017, the contents of all of which are incorporated herein by reference in their entireties. FIELD OF THE INVENTION The present invention relates, at least in part, to dosage regimens for immune cells engineered to express a Chimeric Antigen Receptor (CAR). BACKGROUND OF THE INVENTION Many patients with B cell malignancies are incurable with standard therapy. In addition, traditional treatment options often have serious side effects. Attempts have been made in cancer immunotherapy, however, several obstacles render this a very difficult goal to achieve clinical effectiveness. Although hundreds of so-called tumor antigens have been identified, these are generally derived from self and thus are poorly immunogenic. Furthermore, tumors use several mechanisms to render themselves hostile to the initiation and propagation of immune attack. Recent developments using chimeric antigen receptor (CAR) modified autologous T cell (CART) therapy, which relies on redirecting T cells to a suitable cell-surface molecule on cancer cells such as B cell malignancies, show promising results in harnessing the power of the immune system to treat B cell malignancies and other cancers (see, e.g., Sadelain et al., Cancer Discovery 3:388-398 (2013)). The clinical results of the murine derived CART 19 (i.e., "CTL019") have shown promise in establishing complete remissions in patients suffering with CLL as well as in childhood ALL (see, e.g., Kalos et al., Sci Transl Med 3:95ra73 (2011), Porter et al., NEJM 365:725-733 (2011), Grupp et al., NEJM 368:1509-1518 (2013)). Besides the ability for the chimeric antigen receptor on the genetically modified T cells to recognize and destroy the targeted cells, a successful therapeutic T cell therapy needs to have the ability to proliferate and persist over time, in order to survey for leukemic relapse. The variable quality of T cells, resulting from anergy, suppression, or exhaustion, will have effects on CAR- transformed T cells' performance, over which skilled practitioners have limited control at this time. To be effective, CAR transformed patient T cells need to persist and maintain the ability to proliferate in response to the cognate antigen. It has been shown that ALL patient T cells perform can do this with CART19 comprising a murine scFv (see, e.g., Grupp et al., NEJM 368:1509-1518 (2013)). SUMMARY OF THE INVENTION The disclosure features, at least in part, CAR dosage regimens that maintain efficacy while reducing side effects. In one embodiment, the invention pertains to a method of treating a subject having a cancer (e.g., a hematological cancer), comprising administering to the subject a plurality of cells comprising a CAR molecule. In another embodiment, the plurality of CAR- expressing cells is administered as a single dose, e.g., a single dose as described herein. In other embodiments, the plurality of CAR-expressing cells are administered as multiple doses, e.g., a first dose, a second dose, and optionally a third dose, e.g., as described herein. Additionally disclosed are assays and methods for evaluating responsiveness to a CAR therapy or monitoring a subject undergoing a CAR therapy, e.g., a B cell-targeting CAR therapy, by detecting the level of soluble BCMA; or methods of evaluating the suitability for manufacturing of a CAR therapy. Accordingly, methods and compositions comprising a plurality of CAR-expressing cells, as well as methods of monitoring, or making, a CAR therapy are disclosed. Accordingly, in one aspect, disclosed herein is a plurality of cells that express a chimeric antigen receptor (CAR) molecule for use in the treatment of a subject having hematological cancer. In embodiments, the CAR molecule binds to a B-cell antigen, e.g., a CD19, BCMA, CD20, CD10, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. In one embodiment, the CAR molecule is: (i) a murine CAR molecule that binds to CD19, and wherein the hematological cancer is acute lymphoid leukemia (ALL); (ii) a humanized CAR molecule that binds to CD 19; or (iii) a CAR molecule that binds to BCMA. In one embodiment, the plurality of CAR-expressing cells are administered at a dose of about 0.2 x 106 to 5.0 x 106 (e.g., 0.2 x 106 to 5.0 x 106) viable CAR-expressing cells/kg, e.g., when the subject weighs <50 kg; or at a dose of about 0.1 x 108 to 2.5 x 108 (e.g., 0.1 x 10 8 to 2.5 x 10 ) viable CAR-expressing cells, e.g., when the subject weighs >50 kg. In one aspect, disclosed herein is a method of treating a subject having a hematological cancer, comprising administering to the subject in need thereof a plurality of cells that express a chimeric antigen receptor (CAR) molecule. In embodiments, the CAR molecule binds to a B- cell antigen, e.g., a CD19, BCMA, CD20, CDIO, CD22, CD34, CD123, FLT-3, RORl, CD79b, CD179b, or CD79a. In one embodiment, the CAR molecule is: (i) a murine CAR molecule that binds to CD19, and wherein the hematological cancer is acute lymphoid leukemia (ALL); (ii) a humanized CAR molecule that binds to CD 19; or (iii) a CAR molecule that binds to BCMA. In one embodiment, the plurality of cells is administered at: at a dose of about 0.2 x 106 to 5.0 x 106 (e.g., 0.2 x 106 to 5.0 x 106) viable CAR- expressing cells/kg, e.g., when the subject weighs <50 kg; or at a dose of about 0.1 x 10 to 2.5 x 108 (e.g., 0.1 x 10 8 to 2.5 x 108) viable CAR-expressing cells, e.g., when the subject weighs >50 kg.
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