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US-20260124242-A1 - EXPANSION OF TUMOR INFILTRATING LYMPHOCYTES FROM LIQUID TUMORS AND THERAPEUTIC USES THEREOF

US20260124242A1US 20260124242 A1US20260124242 A1US 20260124242A1US-20260124242-A1

Abstract

Methods of expanding peripheral blood lymphocytes (PBLs) from blood of patients with hematological malignancies, including lymphomas and leukemias, genetic modifications of expanded PBLs to incorporate chimeric antigen receptors, genetically modified T cell receptors, and other genetic modifications, and uses of such expanded and/or modified PBLs in the treatment of diseases such as cancers and hematological malignancies are disclosed herein.

Inventors

  • Parmeswaran HARI
  • Frederick G. Vogt

Assignees

  • IOVANCE BIOTHERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20231103

Claims (20)

  1. 1 . A method of treating a hematological malignancy in a patient, the method comprising administering, to a patient, a therapeutically effective population of peripheral blood lymphocytes (PBLs) obtained from the patient.
  2. 2 . The method of claim 1 , wherein the patient has been pre-treated with an ITK inhibitor, a BTK inhibitor and/or a BCL2 inhibitor to the patient.
  3. 3 . The method of claim 2 , wherein the ITK inhibitor is an ITK inhibitor that covalently binds to ITK.
  4. 4 . The method of claim 2 or 3 , wherein the BTK inhibitor is optionally a BTK inhibitor that covalently binds to BTK.
  5. 5 . The method of any of claims 2-4 , wherein the BCL2 inhibitor is optionally a BCL2 inhibitor that mimics BH3.
  6. 6 . The method of any of claims 1-5 , wherein the patient is suffering from a leukemia or a chronic lymphocytic leukemia.
  7. 7 . The method of claim 6 , wherein the patient has relapsed after treatment with a BTK inhibitor, a BCL2 inhibitor or a combination of a BTK inhibitor and BCL2 inhibitor.
  8. 8 . The method of claim 6 or 7 , wherein the patient is ineligible for CAR-T therapy or has a 17p deletion.
  9. 9 . The method of any of claims 1-8 , wherein the patient is suffering from small lymphocytic lymphoma.
  10. 10 . The method of claim 9 , wherein the patient has relapsed after treatment with a BTK inhibitor, a BCL2 inhibitor or a combination of a BTK inhibitor and BCL2 inhibitor.
  11. 11 . The method of claim 9 or 10 , wherein the patient is ineligible for CAR-T therapy or has a 17p deletion.
  12. 12 . The method of any of claims 1-11 , wherein the hematological malignancy selected from the group consisting of acute myeloid leukemia (AML), AML without genetic markers or without molecular targets, myelodysplastic syndrome (MDS), MDS without genetic markers or without molecular targets, low grade MDS, hypoplastic MDS, EBV related lymphoproliferative disorder, post-transplant lymphoproliferative disorder, CD123 negative (IL-3R negative) AML, FLT3 mutation negative AML, FLT3 positive AML, Nucleophosmin (NPM1) mutation negative acute myeloid leukemia, and NPM1 positive AML.
  13. 13 . The method of any of claims 1-11 , wherein the hematological malignancy selected from the group consisting of the mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), activated B cell (ABC) DLBCL, and germinal center B cell (GCB) and DLBCL.
  14. 14 . The method of any of claims 1-11 , wherein the hematological malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL), CLL with Richter's transformation (or Richter's syndrome), CLL replased after treatment with BTK inhibitors, CLL relapsed after treatment with BCL2 inhibitors, CLL replased after treatment with BTK and BCL2 inhibitors, Relapsed CLL with 17p deletion, small lymphocytic leukemia (SLL), SLL replased after treatment with BTK inhibitors, SLL relapsed after treatment with BCL2 inhibitors, SLL replased after treatment with BTK and BCL2 inhibitors, and Relapsed SLL with 17p deletion.
  15. 15 . The method of any of claims 1-11 , wherein the hematological malignancy selected from the group consisting of CD19 negative B cell leukemia or lymphoma (including CLL/SLL), CD20 negative B cell leukemia or lymphoma (including CLL/SLL), CD23 negative B cell leukemia or lymphoma (including CLL/SLL), and CD123 negative B cell leukemia or lymphoma (including CLL/SLL).
  16. 16 . The method of any of claims 1-11 , wherein the hematological malignancy selected from the group consisting of non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, relapsed and/or refractory Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), mature B-ALL, Burkitt's lymphoma, Waldenström's macroglobulinemia (WM), multiple myeloma, myelodysplastic syndromes, myelofibrosis, chronic myelocytic leukemia, follicle center lymphoma, indolent NHL, human immunodeficiency virus (HIV) associated B cell lymphoma, and Epstein-Barr virus (EBV) associated B cell lymphomaEpstein-Barr virus (EBV) associated B cell lymphoma, EBV related lymphoproliferative disorders and post-transplant lymphoproliferative disorders.
  17. 17 . The method of any of claims 1-16 , wherein the patient has been pretreated with a kinase inhibitor selected from the group consisting of imatinib, dasatinib, ibrutinib, bosutinib, nilotinib, erlotinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib, evobrutinib, spebrutinib, remibrutinib, tolebrutinib, olmutinib, branebrutinib, TAK-020, elsubrutinib, rilzabrutinib, vecabrutinib, fenebrutinib, GNE-431, RN-486, BMS935177, BMS-986142, CGI-1746, GDC-0834, G-744, G-278, and a combination thereof, or a BCL2 inhibitor selected from the group consisting of venetoclax, obatoclax, subatoclax, maritoclax, gossypol, apogossypol, TW-37, UMI-77, BDA-366, navitoclax, ABT-737, and a combinationt hereof.
  18. 18 . The method of any of claims 1-17 , wherein the patient has replapsed after treatment with a kinase inhibitor selected from the group consisting of imatinib, dasatinib, ibrutinib, bosutinib, nilotinib, erlotinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib, evobrutinib, spebrutinib, remibrutinib, tolebrutinib, olmutinib, branebrutinib, TAK-020, elsubrutinib, rilzabrutinib, vecabrutinib, fenebrutinib, GNE-431, RN-486, BMS935177, BMS-986142, CGI-1746, GDC-0834, G-744, G-278, and a combination thereof, or a BCL2 inhibitor selected from the group consisting of venetoclax, obatoclax, subatoclax, maritoclax, gossypol, apogossypol, TW-37, UMI-77, BDA-366, navitoclax, ABT-737, and a combinationt hereof.
  19. 19 . The method of any of claims 1-18 , wherein the therapeutically effective population of PBLs comprises from about 2.3×10 10 to about 13.7×10 10 PBLs.
  20. 20 . A method of treating a hematological malignancy in a patient, the method comprising administering a therapeutically effective population of peripheral blood lymphocytes (PBLs) obtained by the steps comprising: a. obtaining a sample of peripheral blood mononuclear cells (PBMCs) from the peripheral blood of a patient suffering from the hematological malignancy, wherein said sample is optionally cryopreserved and the patient is optionally pretreated with an ITK inhibitor, a BTK inhibitor and/or a BCL2 inhibitor; b. optionally washing the PBMCs by centrifugation, c. adding magnetic beads selective for CD3 and CD28 to the PBMCs; d. seeding PBMCs into a gas-permeable container and co-culturing said PBMCs in media comprising about 3000 IU/mL of IL-2 in for about 4 to about 6 days; e. feeding said PBMCs using media comprising about 3000 IU/mL of IL-2, and co-culturing said PBMCs for about 5 days, such that the total co-culture period of steps d and e is about 9 to about 11 days; f. harvesting PBMCs from media; g. removing the magnetic beads selective for CD3 and CD28 using a magnet; h. removing residual B-cells using magnetic-activated cell sorting and CD19 + beads to provide a peripheral blood lymphocyte (PBL) product; i. washing and concentrating the PBL product using a cell harvester; j. formulating and optionally cryopreserving the PBL product; and k. administering a therapeutically effective dose of the PBL product to the patient, wherein the ITK inhibitor is optionally an ITK inhibitor that covalently binds to ITK, wherein the BTK inhibitor is optionally a BTK inhibitor that covalently binds to BTK, and wherein the BCL2 inhibitor is optionally a BCL2 inhibitor that mimics BH3.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63/382,487, filed Nov. 4, 2022, all of which is herein incorporated by reference in its entirety. FIELD OF THE INVENTION Methods of expanding peripheral blood lymphocytes (PBLs) derived from blood and/or bone marrow of a patient with a hematological malignancy, such as a liquid tumor, including lymphomas and leukemias, and compositions comprising populations of PBLs obtained therefrom, are disclosed herein. In addition, therapeutic uses of autologous PBLs expanded from blood of a patient in the treatment of hematological malignancies are disclosed herein. BACKGROUND OF THE INVENTION Treatment of bulky, refractory cancers using adoptive autologous transfer of tumor infiltrating lymphocytes (TILs) represents a powerful approach to therapy for patients with poor prognoses. Gattinoni, et al., Nat. Rev. Immunol. 2006, 6, 383-393. TILs are dominated by T cells, and IL-2-based TIL expansion followed by a “rapid expansion process” (REP) has become a preferred method for TIL expansion because of its speed and efficiency. Dudley, et al., Science 2002, 298, 850-54; Dudley, et al., J Clin. Oncol. 2005, 23, 2346-57; Dudley, et al., J. Clin. Oncol. 2008, 26, 5233-39; Riddell, et al., Science 1992, 257, 238-41; Dudley, et al., J. Immunother. 2003, 26, 332-42. A number of approaches to improve responses to TIL therapy in melanoma and to expand TIL therapy to other tumor types have been explored with limited success, and the field remains challenging. Goff, et al., J. Clin. Oncol. 2016, 34, 2389-97; Dudley, et al., J. Clin. Oncol. 2008, 26, 5233-39; Rosenberg, et al., Clin. Cancer Res. 2011, 17, 4550-57. Earlier approaches to expansions of TILs from B cell lymphomas yielded poor results, with only 2 of 12 attempts at TIL growth providing for potential activity against tumors. Schwartzentruber, et al., Blood 1993, 82, 1204-1211. There is an urgent need to provide for more efficacious therapies in many hematological malignancies, including chronic lymphocytic leukemia (CLL). There is also an urgent need to provide such therapies using whole blood as a source of lymphocytes with TIL functionality, such as PBLs, to treat patients refractory to other therapies or that have relapsed. Because of the burden of apheresis and the large blood volumes taken from critically ill cancer patients, there is also an urgent need to use as little as patient blood as possible. The present invention provides the surprising finding that PBLs expansion processes using low volumes of blood as a source of PBLs can result in efficacious PBL populations obtained from hematological malignancies, such as liquid tumors, including lymphomas or leukemias. SUMMARY OF THE INVENTION In an embodiment, a method of treating a hematological malignancy in a patient is disclosed. The method comprises administering a therapeutically effective population of peripheral blood lymphocytes (PBLs) obtained from a patient pre-treated with an ITK inhibitor, a BTK inhibitor and/or a BCL2 inhibitor to the patient. The ITK inhibitor maybe an ITK inhibitor that covalently binds to ITK. The BTK inhibitor maybe a BTK inhibitor that covalently binds to BTK. The BCL2 inhibitor maybe a BCL2 inhibitor that mimics BH3. The patient may be suffering from a leukemia or a chronic lymphocytic leukemia. The patient may have relapsed after treatment with a BTK inhibitor, a BCL2 inhibitor or a combination of a BTK inhibitor and BCL2 inhibitor. The patient may be ineligible for CAR-T therapy. The patient may be suffering from small lymphocytic lymphoma. The patient may have relapsed after treatment with a BTK inhibitor, a BCL2 inhibitor or a combination of a BTK inhibitor and BCL2 inhibitor. The patient is ineligible for CAR-T therapy. The patient may have been pretreated with a kinase inhibitor selected from the group consisting of imatinib, dasatinib, ibrutinib, bosutinib, nilotinib, erlotinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib, evobrutinib, spebrutinib, remibrutinib, tolebrutinib, olmutinib, branebrutinib, TAK-020, elsubrutinib, rilzabrutinib, vecabrutinib, fenebrutinib, GNE-431, RN-486, BMS935177, BMS-986142, CGI-1746, GDC-0834, G-744, G-278, and a combination thereof, or a BCL2 inhibitor selected from the group consisting of venetoclax, obatoclax, subatoclax, maritoclax, gossypol, apogossypol, TW-37, UMI-77, BDA-366, navitoclax, ABT-737, and a combination hereof. The patient may have replapsed after treatment with a kinase inhibitor selected from the group consisting of imatinib, dasatinib, ibrutinib, bosutinib, nilotinib, erlotinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib, evobrutinib, spebrutinib, remibrutinib, tolebrutinib, olmutinib, branebrutinib, TAK-020, elsubrutinib, rilzabrutinib, vecabrutinib, fenebrutinib, GNE-431, RN-486, BMS935177, BMS-986142, CGI-1746, GDC-0834, G-744, G-278, and a combination thereof, or a BCL2 inhibitor select