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(51) International Patent Classification: Published: C12Q 1/6886 (2018.01) — with international search report (Art. 21(3)) (21) International Application Number: — before the expiration of the time limit for amending the PCT/US2020/046237 claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (22) International Filing Date: — with sequence listing part of description (Rule 5.2(a)) 13 August 2020 (13.08.2020) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/886,261 13 August 2019 (13.08.2019) US (71) Applicants: THE GENERAL HOSPITAL CORPO¬ RATION [US/US]; 55 Fruit Street, Boston, Massachu¬ setts 021 14 (US). PRESIDENT AND FELLOWS OF HARVARD COLLEGE [US/US]; 17 Quincy Street, Cam¬ bridge, Massachusetts 02138 (US). (72) Inventor; and (71) Applicant: HACOHEN, Nir [US/US]; c/o 55 Fruit Street, Boston, Massachusetts 021 14 (US). (72) Inventors: SADE-FELDMAN, Moshe; c/o 55 Fruit Street, Boston, Massachusetts 021 14 (US). FREEMAN, Samuel; c/o 17 Quincy Street, Cambridge, Massachusetts 02138 (US).

(74) Agent: SCHER, Michael B. et al. ; Johnson, Marcou, Isaacs & Nix, LLC, P.O. Box 691, Floschton, Georgia 30548 (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, IT, 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, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, 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).

(54) Title: METHODS FOR PREDICTING OUTCOMES OF CHECKPOINT INHIBITION AND TREATMENT THEREOF (57) Abstract: The present invention provides methods of predicting a patient's response to immunotherapy, in particular checkpoint blockade therapy, and provides for treatments. Disclosed herein are novel combinations of factors identified in tumors used to predict response and provide for treatments. Also, disclosed are methods of treatment that can shift a tumor to a responder phenotype. METHODS FOR PREDICTING OUTCOMES OF CHECKPOINT INHIBITION AND TREATMENT THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/886,261, filed August 13, 2019. The entire contents of the above-identified application are hereby fully incorporated herein by reference.

TECHNICAL FIELD [0002] The subject matter disclosed herein is generally directed to methods of predicting response of cancer patients to checkpoint inhibition therapy and therapeutic methods of treating patients in need thereof with checkpoint inhibition therapy.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0003] The contents of the electronic sequence listing (BROD_4340WP_ST25.txt”; Size is 9 Kilobytes and it was created on August 11, 2020) is herein incorporated by reference in its entirety.

BACKGROUND [0004] Why some patients but not others respond to checkpoint blockade (CPB) therapies, including anti-CTLA-4 and anti-PD-1 or the combination of both, is still not clear. For example, while patients with microsatellite instability (MSI), which have higher indel and mutation burden, have improved response rates compared to non-MSI cases of the same tumor

8 10 2 1 23 type, the predictive value of tumor mutation burden (TMB) is not always strong ’ ’