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US-20260124240-A1 - DRUG RESISTANT IMMUNE CELLS

US20260124240A1US 20260124240 A1US20260124240 A1US 20260124240A1US-20260124240-A1

Abstract

Compositions and method of prevention and treatment for a subject in need comprising drug-resistant natural killer (NK) cells, which are effective for treating cancer when administered in conjunction with cytotoxic therapies. A method of treatment comprising administering to a subject in need thereof an effective amount of modified NK cells and a cytotoxic therapy. A purified cell composition comprising modified NK cells. A pharmaceutical composition comprising an effective amount of G101V mutated NK cells and venetoclax.

Inventors

  • Dan S. Kaufman
  • Davide Bernareggi
  • Benjamin H. Goldenson

Assignees

  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Dates

Publication Date
20260507
Application Date
20231024

Claims (20)

  1. 1 . A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of cytotoxic-resistant modified natural killer (NK) cells and a cytotoxic therapy.
  2. 2 . The method of claim 1 , wherein the cytotoxic therapy is venetoclax.
  3. 3 . The method of claim 1 , wherein the modified NK cells are BCL2 G101V mutated NK cells.
  4. 4 . The method of claim 3 , wherein the BCL2 G101V mutated cells are effective to mediate a resistance to the cytotoxic therapy.
  5. 5 . The method of claim 1 , wherein the disease or disorder is cancer.
  6. 6 . The method of claim 5 , wherein the cancer is acute myeloid leukemia (AML).
  7. 7 . The method of claim 6 , wherein the AML is resistant or refractory to venetoclax.
  8. 8 . The method of claim 1 , wherein administering the effective amount of modified NK cells and the cytotoxic therapy is effective to treat the disease or disorder without inhibiting cell product activity.
  9. 9 . The method of claim 1 , wherein the modified NK cells are derived from induced pluripotent stem cell (iPSC)-derived immune cells.
  10. 10 . A purified cell composition comprising cytotoxic-resistant modified NK cells.
  11. 11 . The purified cell composition of claim 10 , wherein the modified NK cells are BCL2 G101V mutated NK cells.
  12. 12 . The purified cell composition of claim 11 , wherein the modified NK cells comprise homozygous BCL2 G101V mutations.
  13. 13 . The purified cell composition of claim 11 , wherein the modified NK cells comprise heterozygous BCL2 G101V mutations.
  14. 14 . The purified cell composition of claim 10 , wherein the modified NK cells are induced pluripotent stem cell (iPSC)-derived natural killer cells.
  15. 15 . The purified cell composition of claim 10 , wherein the modified NK cells comprise homozygous inactivating mutations in a cytokine-inducible SH2-containing protein (CISH) gene.
  16. 16 . The purified cell composition of claim 10 , wherein the modified NK cells comprise a chimeric antigen receptor.
  17. 17 . A pharmaceutical composition comprising an effective amount of BCL2 G101V mutated NK cells and venetoclax.
  18. 18 . The pharmaceutical composition of claim 17 , wherein the composition is effective for treating cancer.
  19. 19 . A pharmaceutical composition comprising the purified cell composition of claim 10 , and a pharmaceutically acceptable carrier.
  20. 20 . The pharmaceutical composition of claim 19 , further comprising venetoclax.

Description

CROSS REFERENCE This application claims the priority benefit of U.S. Provisional Application No. 63/380,698, filed Oct. 24, 2022, the entirety of which is hereby incorporated by reference herein in its entirety. GOVERNMENT SPONSORSHIP This invention was made with government support under Grant No. U01CA217885 awarded by National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING This application contains a computer readable Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “24978-0854_Sequence Listing” was created on Oct. 23, 2023, and is 13000 bytes in size. TECHNICAL FIELD The present invention relates generally to cellular therapies for treating cancer and other diseases. BACKGROUND Acute myeloid leukemia (AML) is an often fatal malignancy with few good curative options. The incidence of AML increases with age, and older patients are typically less able to tolerate more aggressive therapies, typically “7+3” treatment that consists of cytarabine continuously for 7 days, along with infusions of an anthracycline (daunorubicin or idarubicin). Venetoclax in combination with hypomethylating agents (azacytidine or decitabine) is approved for treatment of older patients with AML who cannot tolerate this 7+3 regimen. While the venetoclax-based regimen can be effective to induce remissions, as noted, these patients will inevitably relapse. NK cells have also been shown in clinical trials to be effective to induce remissions for relapsed or refractory AML. However, this treatment is also not typically curative. Additionally, NK cells cannot be given at the same time as cytotoxic therapies, such as venetoclax, as the treatment would kill off the NK cells. Thus, a treatment for more aggressively treating AML (or other malignancies) by administering venetoclax and NK cells is desirable. SUMMARY OF THE INVENTION Disclosed herein are compositions and method of prevention and treatment for a subject in need comprising drug-resistant immune cells, such as natural killer (NK) cells, which may be effective for treating cancer when administered in conjunction with cytotoxic therapies. In embodiments, a method of treatment is provided, the method comprising administering to a subject in need thereof an effective amount of cytotoxic-resistant modified NK cells and a cytotoxic therapy. In some embodiments, the modified NK cells are BCL2 G101V mutated NK cells, and the cytotoxic therapy is venetoclax. In some embodiments, the modified NK cells are derived from induced pluripotent stem cell (iPSC)-derived immune cells. In certain aspects, provided herein is a method of treating or preventing a disease or disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of cytotoxic-resistant modified natural killer (NK) cells and a cytotoxic therapy. In some embodiments, the cytotoxic therapy is venetoclax. In some embodiments, the disease or disorder is cancer. In some the modified NK cells are BCL2 G101V mutated NK cells. In some embodiments, the BCL2 G101V mutated cells are effective to mediate a resistance to the cytotoxic therapy. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the AML is resistant or refractory to venetoclax. In some embodiments, administering the effective amount of modified NK cells and the cytotoxic therapy is effective to treat the disease or disorder without inhibiting cell product activity. In some embodiments, administering the effective amount of modified NK cells with the cytotoxic therapy is effective to treat cancer without inhibiting cell product activity. In embodiments, a purified cell composition comprising modified NK cells is provided. In embodiments, a purified cell composition comprising cytotoxic-resistant modified NK cells is provided. In some embodiments, the modified NK cells are BCL2 G101V mutated NK cells. In some embodiments, the modified NK cells comprise homozygous BCL2 G101V mutations. In some embodiments, the modified NK cells comprise heterozygous BCL2 G101V mutations. In some embodiments, the modified NK cells are induced pluripotent stem cell (iPSC)-derived natural killer cells. In some embodiments, the modified NK cells comprise homozygous inactivating mutations in a cytokine-inducible SH2-containing protein (CISH) gene. In some embodiments, the modified NK cells comprise a chimeric antigen receptor. In embodiments, a pharmaceutical composition comprising an effective amount of BCL2 G101V mutated NK cells and venetoclax is provided. In some embodiments, the pharmaceutical composition is effective for treating cancer. In another aspect, provided herein is a pharmaceutical composition comprising the purified cell