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WO 2017/075478 A2 4 May 20 17 (04.05.2017) W 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 2017/075478 A2 4 May 20 17 (04.05.2017) W P O P C T (51) International Patent Classification: [US/US]; 77 Massachusetts Ave., Cambridge, MA 02142 C12Q 1/68 (2006.01) (US). THE BRIGHAM AND WOMEN'S HOSPITAL, INC. [US/US]; 75 Francis Street, Boston, MA 021 15 (US). (21) International Application Number: PCT/US20 16/059507 (72) Inventors; and (71) Applicants : REGEV, Aviv [IL/US]; 15A Ellsworth Ave, (22) International Filing Date: Cambridge, MA 02139 (US). ANDERSON, Ana, Carri- 28 October 2016 (28.10.201 6) zosa [US/US]; 110 Cypress Street, Unit 3 11, Brookline, (25) Filing Language: English MA 02445 (US). CONG, Le [CN/US]; 100 Memorial Drive, Apt. 8-21B, Cambridge, MA 02142 (US). KU- (26) Publication Language: English CHROO, Vijay, K. [IN/US]; 30 Fairhaven Road, Newton, (30) Priority Data: MA 02149 (US). SINGER, Meromit [US/US]; 10 Bel 62/247,430 28 October 2015 (28. 10.2015) US mont Place, Somerville, MA 02143 (US). WANG, Chao 62/384,597 7 September 2016 (07.09.2016) US [US/US]; 6 Canal Park, Unit 302, Cambridge, MA 02 141 (US). (71) Applicants: THE BROAD INSTITUTE INC. [US/US]; 415 Main Street, Cambridge, MA 02142 (US). MAS¬ (74) Agents: KOWALSKI, Thomas, J. et al; Vedder Price SACHUSETTS INSTITUTE OF TECHNOLOGY P.C., 1633 Broadway, New York, NY 1001 9 (US). [Continued on nextpage] (54) Title: COMPOSITIONS AND METHODS FOR EVALUATING AND MODULATING IMMUNE RESPONSES BY USE OF IMMUNE CELL GENE SIGNATURES (57) Abstract: The present invention provides markers, marker signatures and molecular targets that correlate with dysfunction of immune cells and are ad vantageously independent of the immune cell activation status. The present markers, marker signatures and molecular targets provide for new ways to evaluate and modulate immune responses. Therapeutic methods are also provided to treat a patient in need thereof who would benefit from an in creased immune response. weeks CDS* / \ Tim3 PD1 Tim3 PD1 * Function FIG. A w o 2017/075478 A2 llI II III 111 III III II III III I II» II (81) Designated States (unless otherwise indicated, for every (84) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, kind of regional protection available): ARIPO (BW, GH, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). 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, Published: VN, ZA, ZM, ZW. — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) COMPOSITIONS AND METHODS FOR EVALUATING AND MODULATING IMMUNE RESPONSES BY USE OF IMMUNE CELL GENE SIGNATURES RELATED APPLICATIONS AND INCORPORATION BY REFERENCE [0001] This application claims priority and benefit of U.S. provisional application Serial numbers 62/247,430 filed October 28, 20 5 and 62/384,597 filed September 7, 2016. [0002] Reference is made to PCT Publication No. WO/2014/134351 published on February 27, 2014, PCT Publication No. WO/20 14/1 45631 published on September 18, 2014, PCT Publication No. WO/2014/172606 published on October 23, 2014 and PCT Publication No. WO/2015/130968 published on February 26, 2015. Reference is also made to International application serial number PCT/US20 16/0400 15 filed on June 29, 2016. [0003] The foregoing applications, and all documents cited therein or during their prosecution ("appln cited documents") and all documents cited or referenced in the appln cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or referenced i herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. FEDERAL- FUNDING LEGEND [0004] This invention was made with government support under MH105960, NS045937, AI073748 and CA1 87975 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION [0005] The invention relates to substances, compositions and methods useful in evaluating and modulating immune responses. BACKGROUND OF THE INVENTION [0006] T ceil fitness is closely linked to health and disease. Activated CD8 T lymphocytes have been reported to exist in various functional states characterized by different cytokine secretion potentials, proliferation capabilities and the ability and potential to become long-term memory cells. The types of CD8+ subpopulations and their functional states can vary kinetically in response to different pathogens and are dependent on the status of pathogen clearance. Characterizing the different CDS T cell subpopulations and their underlying driving mechanisms is an active field of research contributing to our understanding of protective immunity in successful pathogen clearance, and of T cell regulation during uncontrolled tumor growth and chronic infections. Recent advances on this front have enabled the development of improved vaccines and novel immune-based therapies for various cancers. It is believed that the breadth of the functional potential of CDS T cells is far from understood, and that gaining a deeper understanding will lead to further advancements. [0007] During persistent immune activation, such as uncontrolled tumor growth or chronic viral infections, the ability of CD8 lvmphocvtes to secrete pro-inflammatory cytokines and elaborate cytotoxic function becomes compromised to different extents (Anderson et al., 2016, Immunity 44, 989-1004; Baitsch et al., 2012, Trends Immunol 33, 364-372; Kim and Ahmed, 2010, Curr Opin Immunol 22, 223-230; Wherry and Kurachi, 2015, Nature reviews Immunology 15, 486-499; Zuniga et al., 2015, Annu Rev Virol 2, 573-597). These CD8+ populations are frequently referred to as "dysfunctional" or "exhausted", and are believed to constitute a barrier to successful anti-tumor and anti-viral immunity. Such dysfunctional or exhausted CD8+ lymphocytes are typically compromised for their ex vivo cytokine secretion capabilities and are present in an environment in which there is persistent antigen. Gaining a clear molecular understanding of the dysfunctional T cell state can thus help develop successful therapeutic interventions. [0008] Dysfunctional CD8+ T cells can be both protective and detrimental against disease control. Attempts to manipulate pathways associated with T cell dysfunction have resulted in different biological consequences to the host. On one hand, blocking co-inhibitory pathways such as PD-1 and Tim3 that frequently coincide with T cell dysfunction has promoted T cell function and is particularly effective in promoting tumor regression in several types of cancer. On the other hand, the targeted deletion of PD-1 at disease onset causes immune pathology and death of the host in a chronic viral infection model, suggesting that T cell dysfunction may have evolved to prevent immunopathology (Barber et al., 2006, Nature, vol. 439, 682-687). Also, current therapies targeting co-inhibitory or immune checkpoint receptors such as CTLA-4 and PD-1 that are highly expressed on dysfunctional T cells are showing promise in the clinic. However, not all patients respond and some cancers remain largely refractory to these therapies. Furthermore, depletion of exhausted T ceils by targeting known regulators such as Tbet and Eomes resulted in high viral load suggesting that dysfunctional T cells provide partially effective immune control (Paley et ai., 2012, Science, vol. 338, 1220-1225). These findings highlight the complex roles of dysfunctional CDS T cells during unsuccessful antigen clearance. The ability to delineate the diverse roles of dysfunctional CDS' T cells at the molecular level can help with more specific targeting of truly exhausted T cells while sparing those dysfunctional T cells that may be still protective. [0009] C T cell function is associated with their cytokine profiles. It has been reported that effector CDS T cells with the ability to simultaneously produce multiple cytokines (polyfunctional CDS ' T cells) are associated with protective immunity in patients with controlled chrome viral infections as well as cancer patients responsive to immune therapy (Spranger et a ., 2014, J . Immunother. Cancer, vol. 2, 3). In the presence of persistent antigen CDS ' T cells were found to have lost cytolytic activity completely over time (Moskophidis et al., 1 93, Nature, vol. 362, 758-761). It was subsequently found that dysfunctional T cells can differentially produce IL-2, TNFa and FNg in a hierarchical order (Wherry et al., 2003, J . Virol., vol. 77, 491 - 4927) Recent studies also suggest that Tbet and Eomes regulate early and terminally exhausted T cells with distinct cytokine profiles (Paley et al., 2012, supra) and that these subpopulations coexist in both murine models and in humans with chronic infections over a long period of time (Buggert et al., 2014, PLoS Pathog., vol.
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