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WO 2016/057705 Al 14 April 2016 (14.04.2016) P O P C T (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 2016/057705 Al 14 April 2016 (14.04.2016) P O P C T (51) International Patent Classification: ical Research, Inc., 250 Massachusetts Avenue, Cam- G01N 33/574 (2006.01) C12N 5/0783 (2010.01) bridge, MA 021 39 (US). (21) International Application Number: (72) Inventor; and PCT/US20 15/054542 (71) Applicant : WILCOX, Nicholas [US/US]; 1904 Country Moss Way, Southlake, TX 76092 (US). (22) International Filing Date: 7 October 2015 (07. 10.2015) (74) Agent: KOYFMAN, Hannah, R.; Lando & Anastasi LLP, Riverfront Office Park, One Main Street, Suite 1100, Cam (25) Filing Language: English bridge, MA 02142 (US). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 62/061,553 8 October 2014 (08. 10.2014) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 62/144,682 8 April 2015 (08.04.2015) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (71) Applicants: NOVARTIS AG [CH/CH]; Lichtstrasse 35, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, CH-4056 Basel (CH). THE TRUSTEES OF THE UNI¬ KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, VERSITY OF PENNSYLVANIA [US/US]; 3160 Chest MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, nut Street, Suite 200, Philadelphia, PA 19104 (US). PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (72) Inventors; and SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (71) Applicants (for US only): BEDOYA, Felipe [CO/US]; TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 3202 Hayes Road, East Norristown, PA 19403 (US). BIT¬ (84) Designated States (unless otherwise indicated, for every TER, Hans [US/US]; Novartis Institutes For Biomedical kind of regional protection available): ARIPO (BW, GH, Research, Inc., 250 Massachusetts Avenue, Cambridge, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, MA 02139 (US). BROGDON, Jennifer [US/US]; N o TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, vartis Institutes For Biomedical Research, Inc., 250 Mas TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, sachusetts Avenue, Cambridge, MA 02139 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventor; and 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, (71) Applicant : DORFMEIER, Corin [US/US]; 2701 Elroy GW, KM, ML, MR, NE, SN, TD, TG). Road Apt 116, Hayfield, PA 19440 (US). (72) Inventors; and Declarations under Rule 4.17 : (71) Applicants (for US only): GARG, Abhishnek [—/US]; — as to applicant's entitlement to apply for and be granted a Novartis Institutes For Biomedical Research, Inc., 250 patent (Rule 4.1 7(H)) Massachusetts Avenue, Cambridge, MA 02139 (US). — as to the applicant's entitlement to claim the priority of the GLASS, David [US/US]; Novartis Institutes For Biomed earlier application (Rule 4.1 7(in)) ical Research, Inc., 100 Technology Square, Cambridge, MA 02139 (US). MANNICK, Joan [US/US]; Novartis In Published: stitutes For Biomedical Research, Inc., 220 Massachusetts — with international search report (Art. 21(3)) Avenue, Cambridge, MA 02139 (US). MELENHORST, Jan, J. [US/US]; 11 Exton Circle, Cherry Hill, MA 08003 — before the expiration of the time limit for amending the (US). MILONE, Michael, C. [US/US]; 314 Surrey Road, claims and to be republished in the event of receipt of Cherry Hill, NJ 08002 (US). MURPHY, Leon [US/US]; amendments (Rule 48.2(h)) Novartis Institutes For Biomedical Research, Inc., 250 — with sequence listing part of description (Rule 5.2(a)) Massachusetts Avenue, Cambridge, MA 02139 (US). OR¬ LANDO, Elena [US/US]; Novartis Institutes For Biomed- © © v o (54) Title: BIOMARKERS PREDICTIVE OF THERAPEUTIC RESPONSIVENESS TO CHIMERIC ANTIGEN RECEPTOR THERAPY AND USES THEREOF (57) Abstract: Cancer biomarkers and methods of using them are disclosed. BIOMARKERS PREDICTIVE OF THERAPEUTIC RESPONSIVENESS TO CHIMERIC ANTIGEN RECEPTOR THERAPY AND USES THEREOF This application claims priority to U.S. Serial No. 62/061,553 filed October 8, 2014 and U.S. Serial No. 62/144,682 filed April 8, 2015, the contents of which are incorporated herein by reference in their entireties. 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 October 7, 2015, is named N2067-7057WO_SL.txt and is 219,221 bytes in size. FIELD OF THE INVENTION The invention relates to cancer biomarkers and uses thereof. 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 the goal of clinical effectiveness difficult to achieve. 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)). For example, the clinical results of a CART that binds to CD19 (i.e., "CTL019") have shown promise in establishing complete remissions in patients suffering with chronic lymphocytic leukemia (CLL), as well as in childhood acute lymphocytic leukemia (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, to persist over time, and to further monitor for leukemic cell escapees. The variable phenotypic state of T cells, whether it is in a state of anergy, suppression or exhaustion, will have effects on CAR-transformed T cells' efficacy. To be effective, CAR transformed patient T cells need to persist and maintain the ability to proliferate in response to the CAR' s antigen. A need, therefore, exists for a method of using biomarkers for use in connection with the differential diagnosis and treatment of cancer with CAR-expressing cell (e.g., T cell, NK cell) therapy. In particular, there is an unmet need for effective predictors of therapeutic response in subjects having a hematological cancer, such as CLL and ALL, to a CAR-expressing cell therapy, e.g., with CTL019 or other CD19 CAR-expressing cells. SUMMARY OF THE INVENTION The present disclosure relates to the identification and use of analytes, analyte profiles, or markers (e.g., gene expression, flow cytometry and/or protein expression profiles) with clinical relevance to cancer (e.g., a hematological cancer such as chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL)). In some embodiments, the disclosure provides the identity of genes, whose expression, at the transcriptional and protein levels, are correlated with CLL and ALL progression, e.g., as a way of predicting a response to a Chimeric Antigen Receptor (CAR)-expressing cell therapy (e.g., a therapy comprising a cell (e.g., an immune effector cell or population of cells) that expresses a CAR that binds to CD19 (also referred to herein as a "CAR19" or "CD19 CAR" -expressing cell). In certain embodiments, one or more of a CD19 CAR-expressing cell gene set signature, a biomarker listed in Table 1A, Table IB, Table 7A, Table 7B, Table 8, Table 9, Table 10, Table 14, Table 15, Table 16 (e.g., CCL20, IL-17a and/or IL-6), Table 17, Table 18, Table 20, a CD27 biomarker, a CD45RO biomarker, a PD-1 biomarker, a LAG-3 biomarker, a TIM-3 biomarker, an IL2RA biomarker, an IL21 biomarker, a CD4 biomarker, a CD8 biomarker, a TH1+ helper T cell gene set signature, a TH2+ helper T cell gene set signature, a memory T cell (e.g., a CD8+ memory T cell, e.g., a naive T cell (TN), e.g. a memory stem cell (TSCM), e.g. a central memory T cell (TCM), e.g. an effector memory T cell (TEM)) gene set signature, and combinations thereof) are evaluated. These gene expression profiles may be applied to the diagnosis and/or prognosis of a cancer, e.g., a hematological cancer such as CLL and ALL, and are particularly useful in predicting whether a subject will respond favorably to a CAR therapy (e.g., a CD19 CAR therapy as described here, e.g., a CTL019 therapy) in a subject diagnosed with a cancer, e.g., a hematological cancer such as CLL or ALL. Compared to clinical parameters or biochemical markers used in existing prognosis methods, the expression profiles of the genes disclosed herein constitute a more robust signature of hematological cancer progression (e.g., CLL and ALL progression) and provide a more reliable, non-subjective basis for the selection of appropriate therapeutic regimens.
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