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BRASTIANOS, Kaliopi Priscilla [US/US]; C/O 55 Fruit Street, Boston, Massachusets 021 14 (US) ( (51) International Patent Classification: (72) Inventors; and C12Q 1/6886 (2018.01) (71) Applicants: BRASTIANOS, Kaliopi Priscilla [US/US]; c/o 55 Fruit Street, Boston, Massachusets 021 14 (US). (21) International Application Number: ALVAREZ-BRECKENRIDGE, Christopher Allen PCT/US20 19/035252 [US/US]; c/o 55 Fruit Street, Boston, Massachusetts 021 14 (22) International Filing Date: (US). 03 June 2019 (03.06.2019) (72) Inventors: SHALEK, Alexander K.; c/o 77 Massa¬ (25) Filing Language: English chusets Avenue, Cambridge, Massachusetts 02139 (US). CARTER, Scott; c/o 450 Brookline Avenue, Boston, (26) Publication Language: English Massachusetts 02215 (US). PRAKADAN, Sanjay; c/o 77 (30) Priority Data: Massachusetts Avenue, Cambridge, Massachusetts 02139 62/679,728 0 1 June 2018 (01.06.2018) US (US). (71) Applicants: MASSACHUSETTS INSTITUTE OF (74) Agent: SCHER, Michael B. et al.; Johnson, Marcou & TECHNOLOGY [US/US]; 77 Massachusets Avenue, Isaacs, LLC, P.O. Box 691, Hoschton, Georgia 30548 (US). Cambridge, Massachusets 02139 (US). THE GENER¬ (81) Designated States (unless otherwise indicated, for every AL HOSPITAL CORPORATION [US/US]; 55 Fruit kind of national protection av ailable) . AE, AG, AL, AM, Street, Boston, Massachusetts 021 14 (US). DANA-FAR- AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, BER CANCER INSTITUTE, INC. [US/US]; 450 Brook¬ CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, line Avenue, Boston, Massachusetts 02215 (US). DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (54) Title: METHODS AND COMPOSITIONS FOR DETECTING AND MODULATING MICROENVIRONMENT GENE SIG¬ NATURES FROM THE CSF OF METASTASIS PATIENTS FIG. 20A (57) Abstract: The subject matter disclosed herein is generally directed to detecting and modulating novel gene signatures for the treatment and prognosis of cancer. The gene signatures can be detected in samples obtained from the extracellular fluid of a subject suffering from cancer. The novel gene signatures can be used to predict and monitor responses to immunotherapy in cancer and can be targeted therapeutically. The immunotherapy can be immune checkpoint inhibition therapy. [Continued on next page] WO 2019/232542 A2 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, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) — with sequence listing part of description (Rule 5.2(a)) METHODS AND COMPOSITIONS FOR DETECTING AND MODULATING MICROENVIRONMENT GENE SIGNATURES FROM THE CSF OF METASTASIS PATIENTS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of ET.S. Provisional Application No. 62/679,728, filed June 1, 2018. 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_2620WP.ST25.txt”; Size is 6,993 bytes and it was created on June 3, 2019) is herein incorporated by reference in its entirety. TECHNICAL FIELD [0003] The subject matter disclosed herein is generally directed to detecting and modulating novel gene signatures for the treatment and prognosis of cancer. BACKGROUND [0004] Brain metastasis presents an important obstacle to cancer survival. With 100,000 new cases annually and a median survival of 4-6 months, brain metastasis research is of paramount importance (Eichler, A . F . et al. The biology of brain metastases - translation to new therapies. Nat Rev Clin Oncol 8, 344-356 (201 1); and Owonikoko, T. K . et al. Current approaches to the treatment of metastatic brain tumours. Nat Rev Clin Oncol 11, 203-222, doi :10.1038/nrclinonc. 20 14.25 (2014)). [0005] Currently, major recourses for patients with brain metastases - whole brain radiation therapy and surgery - are invasive and dangerous. Hence, efforts are needed to realize safer interventions, and to define biomarkers for diagnosis and monitoring. [0006] Two major hurdles exist in characterizing brain metastases. First, tumors are complex cellular mixtures (Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69-80, doi: 10. 101 6/j .cell. 2010. 02. 027 (2010); Spencer, S. L., Gaudet, S., Albeck, J . G , Burke, J . M . & Sorger, P . K . Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459, 428-432, doi:l0.l038/nature080l2 (2009); and Patel, A . P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396-1401, doi: 10. H26/science. 1254257 (2014)), limiting the utility of bulk profiling and impacting therapeutic efficacy (Tirosh, I . et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189-196, doi:l0.H26/science.aad050l (2016)). The emergence of scRNA-Seq now enables unprecedented deconvolution of this heterogeneity through direct genome-wide examination of individual cells, yielding clinically-relevant, actionable results (Shalek, A . K . et al. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature 498, 236-240, doi:l0.l038/naturel2l72 (2013); and Shalek, A . K . et al. Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature 510, 363-369, doi:l0.l038/naturel3437 (2014)). Second, acquiring metastatic tissue from the brain is difficult. Surgical resections are often “one time” events from late-stage patients, prohibiting longitudinal studies of treatment response. In recent years, liquid biopsies have emerged as a powerful diagnostic; for brain metastases, CSF provides a unique, relevant source of cells (Sevenich, L . et al. Analysis of tumour- and stroma- supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol 16, 876-888, doi:l0.l038/ncb30l l (2014)). [0007] Over the past decade, immunotherapy has emerged as a promising strategy for the treatment of cancer. Unlike conventional tactics which directly target tumor cell viability, this class of approaches instead reinvigorates the immune system to facilitate eradication. As such, it has the potential to be broadly applicable, given the existence of conserved mechanisms for downregulating immune activity against “self’ that are hijacked by many tumors to evade immunity. Among the immunotherapies, one set that has shown particularly striking clinical activity against a range of tumors is checkpoint blockade inhibitors (CBIs). These molecules - typically antibodies - act by binding inhibitory co-receptors on T cells, such as PD-l and CTLA- 4, that are often engaged by tumor cells (or their tumor cell cognates), to restore immune function. In particular, checkpoint blockade inhibitors (CBIs) lead to durable responses in -35% of patients with metastatic melanoma by unleashing T cells from oncogenic suppression (P. Sharma, J . P. Allison, The future of immune checkpoint therapy. Science. 348, 56-61 (2015); and F. S. Hodi, Kluger HM, Sznol M, Durable, long-term survival in previously treated patients with advanced melanoma who received nivolumab monotherapy in a phase I trial. 2016 AACR Annu. Meet. Abstr. CT001 Present. April 17 2016). Yet, despite early successes with CBIs, their broad applicability has been challenged by mounting observations of partial response, acquired resistance, and inconsistent benefit across patients with the same tumor type. Understanding the cellular and molecular mechanisms that result in response or resistance to immunotherapy is critical for realizing its full therapeutic potential. This, in turn, requires a detailed understanding of the changes induced throughout the tumor microenviroment (TME) upon CBI introduction, as well as their potential relationship to clinical response. [0008] One of the most direct means by which to achieve this knowledge is to extensively profile a tumor before and after introduction of CBIs. Given potentially confounding differences between patients in disease etiology and response dynamics, this would ideally be done within an individual to decouple the effects of CBI introduction from other axes of uncontrolled variation - both known and unknown - and guided by clinical observations of contemporaneous patient state. Similarly, to avoid sampling artifacts, this profiling would be done within the same TME in a manner that could resolve the unique contributions of the myriad constituent cells to overall response. Unfortunately, given the invasiveness of conventional sampling methods (e.g., resections or core biopsies) or the paucity of material recovered via their alternatives (e.g., needle aspirates), it has been challenging to comprehensively characterize the TME before and after treatment. [0009] Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention. SUMMARY [0010] Immunotherapies, such as checkpoint blockade inhibitors (CBIs) produce durable responses in some cancer patients, yet most patients derive no clinical benefit. The molecular underpinnings of CBI resistance (ICR) are elusive. It is an objective of the present invention to identify molecular signatures for diagnosis, prognosis and treatment of subjects suffering from cancer. It is a further objective to understand tumor immunity and to leverage this knowledge for treating subjects suffering from cancer.
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