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WO 2018/067991 Al 12 April 2018 (12.04.2018) W !P O PCT

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WO 2018/067991 Al 12 April 2018 (12.04.2018) 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 2018/067991 Al 12 April 2018 (12.04.2018) W !P O PCT (51) International Patent Classification: achusetts 021 15 (US). THE BROAD INSTITUTE, A61K 51/10 (2006.01) G01N 33/574 (2006.01) INC. [US/US]; 415 Main Street, Cambridge, Massachu C07K 14/705 (2006.01) A61K 47/68 (2017.01) setts 02142 (US). MASSACHUSETTS INSTITUTE OF G01N 33/53 (2006.01) TECHNOLOGY [US/US]; 77 Massachusetts Avenue, Cambridge, Massachusetts 02139 (US). (21) International Application Number: PCT/US2017/055625 (72) Inventors; and (71) Applicants: KUCHROO, Vijay K. [IN/US]; 30 Fairhaven (22) International Filing Date: Road, Newton, Massachusetts 02149 (US). ANDERSON, 06 October 2017 (06.10.2017) Ana Carrizosa [US/US]; 110 Cypress Street, Brookline, (25) Filing Language: English Massachusetts 02445 (US). MADI, Asaf [US/US]; c/o The Brigham and Women's Hospital, Inc., 75 Francis (26) Publication Language: English Street, Boston, Massachusetts 021 15 (US). CHIHARA, (30) Priority Data: Norio [US/US]; c/o The Brigham and Women's Hospital, 62/405,835 07 October 2016 (07.10.2016) US Inc., 75 Francis Street, Boston, Massachusetts 021 15 (US). REGEV, Aviv [US/US]; 15a Ellsworth Ave, Cambridge, (71) Applicants: THE BRIGHAM AND WOMEN'S HOSPI¬ Massachusetts 02139 (US). SINGER, Meromit [US/US]; TAL, INC. [US/US]; 75 Francis Street, Boston, Mass c/o The Broad Institute, Inc., 415 Main Street, Cambridge, (54) Title: MODULATION OF NOVEL IMMUNE CHECKPOINT TARGETS CD4 FIG. 1A (57) Abstract: Dysfunctional or exhausted T cells arise in chronic diseases including chronic viral infections and cancer, and express high levels of co-inhibitory receptors. Therapeutic blockade of these receptors has clinical efficacy in the treatment of cancer. While co- inhibitory receptors are co-expressed, the triggers that induce them and the transcriptional regulators that drive their co-expression have not been identified. The immunoregulatory cytokine IL-27 induces a gene module in T cells that includes several known co- inhibitory receptors (Tim-3, Lag-3, and TIGIT). The present invention provides a novel immunoregulatory network and novel cell © surface molecules that have an inhibitory function in the tumor microenvironment. The present invention further provides the novel 00 discovery that the transcription factors Prdml and c-Maf cooperatively regulate the expression of the co-inhibitory receptor module. o This critical molecular circuit underlies the expression of co- inhibitory receptors such as ILT-3 in dysfunctional T cells and identifies [Continued on nextpage] WO 2018/067991 Al llll II II 11III II I II II III 11II il II I II Massachusetts 02142 (US). ZHANG, Huiyuan [CN/US]; 400 Brookline Ave, Apt 13F, Boston, Massachusetts 02215 (US). (74) Agent: TALAPATRA, Sunit et al; Foley & Lardner LLP, 3000 K Street, N.W., Suite 600, Washington, District of Co¬ lumbia 20007-5 143 (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, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) novel regulators of T cell dysfunction. MODULATION OF NOVEL IMMUNE CHECKPOINT TARGETS CROSS REFERENCE TO RELATED APPLICATION [0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/405,835, filed on October 7, 2016, the contents of which are hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present disclosure relates to the modulation of T cell dysfunction and Thl7 balance. FEDERAL FUNDING LEGEND [0003] This invention was made with government support under grant numbers NS076410, AI0562999, NS045937, AI039671, AI045757, AI073748, CA187975 and awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION [0004] The following discussion is merely provided to aid the reader in understanding the disclosure and is not admitted to describe or constitute prior art thereto. [0005] T cell dysfunction or exhaustion is a state of T cell differentiation that arises in chronic disease settings such as chronic viral infections and cancer. Dysfunctional T cells exhibit diverse deficits in effector functions, including impaired proliferative capacity, cytotoxicity, and production of pro-inflammatory cytokines ( Pardoll, D . M . (2012) Nature reviews. Cancer 12, 252-264; Wherry and Kurachi, (2015) Nature reviews Immunology 15, 486- 499). Consequently, dysfunctional T cells are poor mediators of both viral and tumor clearance. Dysfunctional T cells express high levels of co-inhibitory receptors, such as Programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and blockade of these receptors is associated with recovery of effector T cell responses in multiple experimental models of chronic viral infection. Exhausted T cells have also been noted to be poor mediators of viral and/or tumor clearance and express high levels of co-inhibitory receptors, such as PD-1 and CTLA-4. Blockade of these receptors has been associated with the recovery of effector T cell responses in experimental models of chronic viral infection and cancer(Leach, D . R., et al., (1996) Science 271, 1734-1736; Barber, D . L . et al,. (2006) Nature 439, 682-687; Mahoney et al., (2015) Nature reviews Drug discovery 14, 561-584; Wherry and Kurachi, 2015). Indeed, therapeutic blockade of CTLA-4 and PD-1 has been successfully translated to the clinic for the treatment several human cancers (Hodi, F. S. et al, (2010) The New England journal of medicine 363, 7 11-723; Robert, C . et al, (201 1) The New England journal of medicine 364, 2517-2526, Hamid, O . et al, (2013) The New England journal of medicine 369, 134-144; Topalian et al., (2012) The New England journal of medicine 366, 2443-2454). [0006] CTLA-4 and PD-1 are not the only co-inhibitory receptors that are expressed by dysfunctional T cells. In fact, as described herein, dysfunctional T cells express multiple co- inhibitory receptors including T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), Lymphocyte-activation gene 3 (Lag-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT), indicating shared regulatory mechanisms driving their expression (Anderson et al., (2016) Immunity 44, 989-1004; Wherry and Kurachi, 2015). Importantly, as dysfunctional T cells accumulate expression of co-inhibitory receptors they develop a "deep" state of dysfunction and begin to produce IL-10, which further contributes to local immune suppression (Wherry, E . J . (201 ) Nature immunology 12, 492-499). Thus, the co-expression of co-inhibitory receptors on dysfunctional T cells has important functional consequences. Indeed, combination therapies that simultaneously target multiple co-inhibitory pathways, such as CTLA-4 together with PD-1, or PD-1 together with TIM-3, LAG-3, or TIGIT, are more potent at restoring anti-turnor immunity than blockade of single co-inhibitory targets in both humans and in experimental mouse tumor models (Wolchok, J . D . et al. (2013) The New England journal of medicine 369, 122-133; Woo, S. R . et al. (2012) Cancer research 72, 917-927; Johnston, R . J . et al. (2014) Cancer cell 26, 923-937; Fourcade, J . et al. (2014) Cancer research 74, 1045-1055). Together these observations raise the important issue of understanding how co-inhibitory receptors are induced and co- regulated in exhausted or dysfunctional T cells. [0007] The extent of co-inhibitory receptor co-expression is directly correlated to the severity of dysfunctional phenotype (Wherry and Kurachi, 2015). Thus, combination therapies that simultaneously target multiple co-inhibitory pathways, such as PD-1 together with CTLA-4 are more efficacious at restoring anti-tumor immunity than blockade of single co-inhibitory targets in both mouse tumor models and patients (Fourcade et al., 2014; Johnston et al., 2014; Sakuishi et al., (2010) The Journal of experimental medicine 207, 2187-2194; Wolchok et al., 2013; Woo et al., 2012). Unfortunately, even with combination therapy, a substantial number of patients fail to respond to immune checkpoint blockade, highlighting the importance of identifying additional co-inhibitory receptors that could be targeted for cancer immunotherapy. The present disclosure satisfies this need and provides related advantages as well. [0008] The immune system must strike a balance between mounting proper responses to pathogens and avoiding uncontrolled, autoimmune reaction.
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