T cells for use in treating relapsed or refractory acute myeloid leukemia

Abstract

The present disclosure provides, among other things, methods for treating relapsed or refractory acute myeloid leukemia by administering to a subject in need thereof a therapeutically effective amount of an allogeneic composition comprising VDelta1+ (Vδ1+) gamma delta (γδ) T cells such that one or more symptoms or biomarkers is improved after treatment. The present disclosure also provides suitable doses of compositions comprising allogeneic Vδ1+gamma delta (γδ) T cells for administration to a subject suffering from relapsed or refractory AML. In some embodiments, the Vδ1+gamma delta (γδ) T cells are untransduced.

Description

W O 2 0 2 4 / 2 0 9 4 24 2 9 A 1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date 10 October 2024 (10.10.2024) (10) International Publication Number WO 2024 / 209429 A1 WIPO PCT (51) International Patent Classification: Declarations under Rule 4.17: A61K 35 / 17 (2015.01) A61P 35 / 02 (2006.01) A61K 39 / 00 (2006.01) - as to applicant's entitlement to apply for and be granted a patent (Rule 4.17(ii)) (21) International Application Number: Published: PCT / IB2024 / 053367 with international search report (Art. 21(3)) (22) International Filing Date: 05 April 2024 (05.04.2024) - 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)) (25) Filing Language: English (26) Publication Language: English - in black and white; the international application as filed contained color or greyscale and is available for download from PATENTSCOPЕ (30) Priority Data: 63 / 457,937 07 April 2023 (07.04.2023) US (71) (72) (81) (84) Applicant: TAKEDA PHARMACEUTICAL COMPA- NY LIMITED [JP / JP]; 1-1, Doshomachi 4-chome, Chuo- ku, Osaka-shi, Osaka 541-0045 (JP). Inventors: ABIKOFF, Cori; c / o Millennium Pharmaceu- ticals, Inc., 40 Landsdowne Street, Cambridge, Massa- chusetts 02139 (US). ATKURI, Kondala: c / o Millenni- um Pharmaceuticals, Inc., 40 Landsdowne Street, Cam- bridge, Massachusetts 02139 (US). LIU, Yue; c / o Millen- nium Pharmaceuticals, Inc., 40 Landsdowne Street, Cam- bridge, Massachusetts 02139 (US). 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. CV. CZ, DE, DJ, DK, DM. DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT. HN, HR, HU, ID, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, MG, MK, MN, MU, 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. Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, CV, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, 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, ME, 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). (54) Title: T CELLS FOR USE IN TREATING RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA (57) Abstract: The present disclosure provides, among other things, methods for treating relapsed or refractory acute myeloid leukemia by administering to a subject in need thereof a therapeutically effective amount of an allogeneic composition comprising VDeltal+ (V61+) gamma delta (y5) T cells such that one or more symptoms or biomarkers is improved after treatment. The present disclosure also provides suitable doses of compositions comprising allogeneic Vô1+gamma delta (yo) T cells for administration to a subject suffering from relapsed or refractory AML. In some embodiments, the Vô1+gamma delta (yô) T cells are untransduced. WO 2024 / 209429 PCT / IB2024 / 053367 T CELLS FOR USE IN TREATING RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA CROSS-REFERENCE TO RELATED APPLICATIONS [1] This application claims priority to U.S. Provisional Patent Application No. 63 / 457,937 filed on April 7, 2023, the contents of which are herein incorporated by reference in entirety, for all purposes. BACKGROUND [2] Acute myeloid leukemia (AML) is a type of blood cancer that affects adults and children, and is characterized by infiltration of bone marrow and other tissues by clonally proliferative immature myeloid cells. About 20,050 cases of acute myeloid leukemia are diagnosed annually (NCI Surveillance Epidemiology and End Results Program, SEER). Current therapeutic strategies include chemotherapy, allogeneic stem cell transplantation and select targeted therapies, however, treating AML remains a clinical challenge due to resistance to chemotherapy and a significant proportion of treated patients developing relapsed or refractory disease. [3] AML has a poor survival rate among the elderly (age 65 or older), and an average overall 5-year survival rate of approximately 30%, mostly due to resistance to standard treatment. For example, chemotherapy with a combination of cytarabine with an anthracyclin drug, although effective at inducing complete remissions, ultimately selects for chemoresistant clones that drive refractory relapses. The median cumulative incidence of relapse is 29.4% after stem cell transplant and 46.8% after induction chemotherapy and a substantial portion of patients develop refractory or relapsed AML with poor prognosis. (Esther N.O. et al. (2021), Am J Blood Res, 11(4):325-360). [4] The presence of gamma delta T cells have been shown to have a positive correlation with prognosis in a number of solid and haematological cancers (Deniger, D.C. et al., Clin. Cancer Res. (2014), 20(22): 5708-19; Gentles A.J. et al., Nat. Med. (2015), 21(8): 938-945). There is a need in the field for a treatment option for AML, in particular relapsed or refractory AML, that is both safe and effective. 1 WO 2024 / 209429 PCT / IB2024 / 053367 SUMMARY OF THE INVENTION [5] The present disclosure provides, among other things, methods of treating relapsed or refractory acute myeloid leukemia by administering to a subject in need thereof a therapeutically effective amount of a composition (e.g., an allogeneic composition) comprising V81+ gamma delta (y8) T cells such that one or more symptoms or biomarkers is improved after treatment. The present disclosure also provides suitable doses of compositions comprising allogeneic V81+ gamma delta (y8) T cells for administration to a subject suffering from relapsed or refractory AML. [6] V81+ ү8 T cells are an enriched subset of yo T cells, that predominantly comprise V81+ ү8 T cells that recognize malignant cells through expression of a diverse repertoire of natural cytotoxicity receptors (NCRs) that interact with stress ligands, pAgs, lipid Ags and many other non-peptide molecules specifically upregulated on diseased cells. While aß T cells require the MHC-antigen axis for activation to occur, gamma delta T lymphocytes do not require major histocompatibility complex (MHC)-mediated antigen presentation to exert their cytotoxic effect, thus the initial responsiveness of yô T cells precede that of aß T cells as they can directly recognize and are activated by molecular patterns of dysregulation on cancer cells. Without wishing to be bound by any particular theory, it is contemplated that non-MHC-restricted immunomodulating and antineoplastic activity of V81+ y8 T cells (GDX012) of the present disclosure provides a novel allogeneic cell therapy for treatment of relapsed or refractory AML, which are particularly challenging to treat. The inventors of the present application have developed an 'off-the-shelf immunotherapy for relapsed or refractory AML which is not resolved by other modes of treatment. GDX012 therapy has also been described in WO2021 / 186137, the contents of which are incorporated by reference herein in their entirety. [7] When administered systemically, for example, by intravenous infusion, GDX012 shows homing to the bone marrow and is detected for at least 28 days. Without wishing to be bound by any particular theory, it is contemplated that in addition to high cytotoxic activity against AML blasts, GDX012 also has the capacity to home to and persist in peripheral blood and the bone marrow, exhibiting prolonged cytotoxic effect within target tissue with a single dose in treating relapsed or refractory AML. The V81+ y8 T cells (GDX012) of the present disclosure thus provide safe and efficacious therapy for relapsed or 2 本揭露內容包括多種治療復發或難治性急性髓性白血病的方法，具體而 言，是將治療有效量的包含 Vδ1+ (Vδ1+) γδ (γδ) T 細胞的同種異體組合物施用於有需 要的受試者，以改善㇐種或多種症狀或生物標誌物。本公開內容也提供了用於治療復 發或難治性急性髓性白血病患者的包含同種異體 Vδ1+γδ (γδ) T 細胞的組合物的合適劑 量。在㇐些實施例中，Vδ1+γδ (γδ) T 細胞未經轉導。 摘要

Claims

ATTORNEY DOCKET NO. MIL-032WO1 CLAIMS What is claimed is:

1. A method of treating acute myeloid leukemia by administering to a subject in need thereof a therapeutically effective amount of an allogeneic composition comprising Vδ1+gamma delta (γδ) T cells, wherein the acute myeloid leukemia is relapsed or refractory.

2. The method of claim 1, wherein one or more symptoms or biomarkers is improved after the administration.

3. The method of claim 1 or 2, wherein the gamma delta T cells are untransduced.

4. The method of any one of the preceding claims, wherein the composition comprises at least about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% gamma delta T cells relative to total live cells.

5. The method of any one of claims 1-3, wherein the composition comprises at least 50% Vδ1+ γδ T cells (e.g., at least 60%) relative to total live cells.

6. The method of claim 4, wherein the composition comprises at least 70% Vδ1+ γδ T cells relative to total live cells.

7. The method of claim 5, wherein the composition comprises at least 90% Vδ1+ γδ T cells relative to total live cells.

8. The method of claim 7, wherein the composition comprises at least 99% Vδ1+ γδ T cells relative to total live cells.

9. The method of claim 1 or 2, wherein the composition comprises less than 5% residual Vδ2+ cells.

10. The method of claim9, wherein the composition comprises less than 0.5% residual Vδ2+ cells.

11. The method of claim 10, wherein the composition comprises less than 0.1% residual Vδ2+ cells.

12. The method of any one of the preceding claims, wherein the subject has previously been treated with chemotherapy.

13. The method of any one of the preceding claims, wherein the subject has received at least two courses of intensive induction chemotherapy.

14. The method of any one of the preceding claims, wherein the subject has 5% or greater than about 5% leukemic blasts in bone marrow.ATTORNEY DOCKET NO. MIL-032WO1 15. The method of any one of the preceding claims, wherein the subject has 5% or greater than about 5% leukemic blasts in peripheral blood.

16. The method of any one of the preceding claims, wherein the therapeutically effective amount comprises about 8 x 1010, 4 x 1010, 8 x 109, 4 x 109, 2.4 x 109, 1.2 x 109, 8 x 108, 4 x 108, 8 x 107or 4 x 107live T cells.

17. The method of claim 16, wherein the therapeutically effective amount comprises about 8 x 109live T cells.

18. The method of claim 16, wherein the therapeutically effective amount comprises about 4 x 109live T cells.

19. The method of claim 16, wherein the therapeutically effective amount comprises about 2.4 x 109live T cells.

20. The method of claim 16, wherein the therapeutically effective amount comprises about 1.2 x 109live T cells.

21. The method of claim 16, wherein the therapeutically effective amount comprises about 8 x 108live T cells.

22. The method of claim 16, wherein the therapeutically effective amount comprises about 4 x 108live T cells.

23. The method of claim 16, wherein the therapeutically effective amount comprises less than about 4 x 108live T cells.

24. The method of claim 16, wherein the therapeutically effective amount comprises less than about 5 x 104alpha beta T cells / kg.

25. The method of claim 16, wherein the therapeutically effective amount comprises less than about 1 x 104alpha beta T cells / kg.

26. The method of any one of the preceding claims, wherein the gamma delta T cells do not express a chimeric antigen receptor (CAR).

27. The method of any one of the preceding claims, wherein the gamma delta T cells express a chimeric antigen receptor (CAR).

28. The method of any one of the preceding claims, wherein the composition is administered intravenously, transarterially, subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, or intraperitoneally.

29. The method of any one of the preceding claims, wherein the composition is administered intravenously.

30. The method of any one of the preceding claims, wherein the composition is administered in one or more doses.ATTORNEY DOCKET NO. MIL-032WO1 31. The method of claim 30, wherein the composition is administered in one dose.

32. The method of any one of the preceding claims, wherein the composition is administered once a week, once every two weeks, once a month or once in two months.

33. The method of any one of the preceding claims, wherein the composition is administered once a month.

34. The method of any one of the preceding claims, wherein the composition is administered for a period of 1 month, 2 months, 4 months, 6 months, 12 months, 14 months, 18 months or 24 months.

35. The method of any one of the preceding claims, wherein the composition is administered for a period of greater than 24 months.

36. The method of any one of the preceding claims, wherein the chemotherapy comprises administration of mitoxantrone, etoposide, cytarabine or anthracycline.

37. The method of any one of the preceding claims, wherein the chemotherapy comprises administration of 7 days of cytarabine and 3 days of anthracycline.

38. The method of any one of the preceding claims, wherein the cytarabine is administered with venetoclax, fludarabine or other B-cell lymphoma 2 (BCL2) inhibitors.

39. The method of any one of the preceding claims, wherein chemotherapy comprises administration of at least two cycles of hypomethylating agent.

40. The method of any one of the preceding claims, wherein the chemotherapy comprises at least 4 cycles of monotherapy with hypomethylating agents.

41. The method of any one of the preceding claims, wherein the subject is at least 2 years old.

42. The method of any one of the preceding claims, wherein the subject is at least 12 years old.

43. The method of any one of the preceding claims, wherein the subject is at least 18 years old.

44. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is bone marrow blasts are substantially absent.

45. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is bone marrow blasts are less than about 5%.ATTORNEY DOCKET NO. MIL-032WO1 46. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is bone marrow blasts and / or peripheral blood blasts are from between 5% to 25%.

47. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is bone marrow blasts are less than about 10%.

48. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers after treatment that is improved is bone marrow blasts are less than about 15%.

49. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers after treatment that is improved is bone marrow blasts are less than about 20%.

50. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers after treatment that is improved is bone marrow blasts are less than about 25%.

51. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is peripheral blood blasts are substantially absent.

52. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is peripheral blood blasts are less than about 5%.

53. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is peripheral blood blasts are less than about 10%.

54. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is peripheral blood blasts are less than about 15%.

55. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is peripheral blood blasts are less than about 20%.

56. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is peripheral blood blasts are less than about 25%.

57. The method of any one of the preceding claims, wherein the one or more symptoms orATTORNEY DOCKET NO. MIL-032WO1 biomarkers that is improved after treatment is decrease of pretreatment bone marrow blast percentage by at least 50% based on European Leukemia Net (ELN) 2022 response criteria for AML.

58. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is the absence of extramedullary disease.

59. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is absolute neutrophil count (ANC) of 0.5 × 109 / Liters or greater.

60. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is absolute neutrophil count (ANC) of 1.0 × 109 / Liters or greater.

61. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is platelet count of 50 × 109 / Liters or greater.

62. The method of any one of the preceding claims, wherein the one or more symptoms or biomarkers that is improved after treatment is platelet count of 100 × 109 / Liters or greater.

63. The method of any one of the preceding claims, wherein after treatment a Measurable Residual Disease (MRD) is less than about 0.1%.

64. The method of claim 63, wherein MRD is measured by flow cytometry of bone marrow cells and / or blood.