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EP-4735011-A1 - DOSING REGIMENS FOR TREATMENT OF CANCER

EP4735011A1EP 4735011 A1EP4735011 A1EP 4735011A1EP-4735011-A1

Abstract

Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to express cytotoxic chimeric receptors and various dosing regimens for administering such cells. In several embodiments, the immune cells express a chimeric receptor that targets ligands of NKG2D on tumor cells. In several embodiments, the cancer is a blood cancer, for example, acute myeloid leukemia (e.g., relapsed/refractory acute myeloid leukemia) or myelodysplastic syndrome. In several embodiments, the tumor is a solid tumor.

Inventors

  • SHOOK, David, Richard
  • KOTHARI, Nishi

Assignees

  • Nkarta, Inc.

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. 1 . A method of treating a cancer in a subject comprising administering to a subject having a cancer a population of Natural Killer (NK) cells genetically engineered to express a chimeric receptor that binds a ligand of natural killer cell group 2D (NKG2D), wherein the genetically engineered NK cells are administered in a dosing cycle comprising: (i) a first dose of the genetically engineered NK cells; (ii) a second dose of the genetically engineered NK cells administered to the subject 2-4 days after administration of the first dose of the genetically engineered cells; and (iii) a third dose of genetically engineered NK cells administered to the subject 2-4 days after administration of the second dose of the genetically engineered NK cells, wherein each dose of the genetically engineered NK cells comprises at least about 1 x 10 9 genetically engineered NK cells, and wherein prior to administration of the first dose of the genetically engineered NK cells to the subject, the subject is administered a lymphodepleting therapy.
  2. 2. A method of treating a cancer in a subject comprising administering to a subject having a cancer a population of Natural Killer (NK) cells genetically engineered to express a chimeric receptor that binds a ligand of natural killer cell group 2D (NKG2D), wherein the genetically engineered NK cells are administered in a dosing cycle comprising: (i) a first dose of the genetically engineered NK cells; (ii) a second dose of the genetically engineered NK cells administered to the subject 2-4 days after administration of the first dose of the genetically engineered cells; and (iii) a third dose of genetically engineered NK cells administered to the subject 2-4 days after administration of the second dose of the genetically engineered NK cells, wherein each dose of the genetically engineered NK cells comprises at least about 2 x 10 9 genetically engineered NK cells, and wherein prior to administration of the first dose of the genetically engineered NK cells to the subject, the subject is administered a lymphodepleting therapy.
  3. 3. The method of claim 1 , wherein: all three doses of the genetically engineered NK cells are administered to the subject within about 14 days of conclusion of administration of the lymphodepleting therapy.
  4. 4. A method of treating a cancer in a subject comprising administering to a subject having a cancer a population of Natural Killer (NK) cells genetically engineered to express a chimeric receptor that binds a ligand of natural killer cell group 2D (NKG2D), wherein: the genetically engineered NK cells are administered in a dosing cycle comprising a first dose of the genetically engineered NK cells, a second dose of the genetically engineered NK cells and a third dose of genetically engineered NK cells; each dose of the genetically engineered NK cells comprises at least about 1 x 10 9 genetically engineered NK cells; prior to administration of the first dose of the genetically engineered NK cells to the subject, the subject is administered a lymphodepleting therapy; and all three doses of the genetically engineered NK cells are administered to the subject within about 14 days of conclusion of administration of the lymphodepleting therapy.
  5. 5. A method of treating a cancer in a subject comprising administering to a subject having a cancer a population of Natural Killer (NK) cells genetically engineered to express a chimeric receptor that binds a ligand of natural killer cell group 2D (NKG2D), wherein: the genetically engineered NK cells are administered in a dosing cycle comprising a first dose of the genetically engineered NK cells, a second dose of the genetically engineered NK cells and a third dose of genetically engineered NK cells; each dose of the genetically engineered NK cells comprises at least about 2 x 10 9 genetically engineered NK cells; prior to administration of the first dose of the genetically engineered NK cells to the subject, the subject is administered a lymphodepleting therapy; and all three doses of the genetically engineered NK cells are administered to the subject within about 14 days of conclusion of administration of the lymphodepleting therapy.
  6. 6. The method of claim 4, wherein the second dose of the genetically engineered NK cells is administered to the subject 2-4 days after administration of the first dose of the genetically engineered cells; and the third dose of the genetically engineered NK cells is administered to the subject 2-4 days after administration of the second dose of the genetically engineered NK cells.
  7. 7. The method of claim 1 , wherein the second dose of the genetically engineered NK cells is administered to the subject about 3 days after administration of the first dose of the genetically engineered cells.
  8. 8. The method of claim 1 , wherein the third dose of genetically engineered NK cells is administered to the subject about 4 days after administration of the second dose of the genetically engineered NK cells.
  9. 9. The method of claim 1 , wherein each dose of the genetically engineered NK cells comprises between about 1 x 10 9 and about 5x 10 9 genetically engineered NK cells.
  10. 10. The method of claim 1 , wherein each dose of the genetically engineered NK cells comprises about 1 .5 x 10 9 genetically engineered NK cells.
  11. 1 1 . The method of claim 1 , wherein each dose of the genetically engineered NK cells comprises about 2 x 10 9 genetically engineered NK cells.
  12. 12. The method of claim 1 , wherein each dose of the genetically engineered NK cells comprises about 2.5 x 10 9 genetically engineered NK cells.
  13. 13. The method of claim 1 , wherein all three doses of the genetically engineered NK cells are administered to the subject within about 10 days of conclusion of administration of the lymphodepleting therapy.
  14. 14. The method of claim 1 , wherein the lymphodepleting therapy comprises administration of fludarabine (Flu).
  15. 15. The method of claim 14, wherein each dose of Flu comprises between about 10 mg/m 2 and about 40 mg/m 2 .
  16. 16. The method of claim 1 wherein the lymphodepleting therapy comprises administration of five doses of Flu.
  17. 17. The method of claim 1 , wherein the lymphodepleting therapy comprises administration cytosine arabinoside (Ara-C).
  18. 18. The method of claim 17, wherein each dose of Ara-C comprises between about 1 g/m 2 and about 4 g/m 2 .
  19. 19. The method of claim 1 , wherein the lymphodepleting therapy comprises administration of five doses of Ara-C.
  20. 20. The method of claim 19, wherein the first doses of Flu and Ara-C are each given 7 days prior to initiation of the dosing cycle; the second doses of Flu and Ara-C are each given 6 days prior to initiation of the dosing cycle; the third doses of Flu and Ara-C are each given 5 days prior to initiation of the dosing cycle; the fourth doses of Flu and Ara-C are each given 4 days prior to initiation of the dosing cycle; and the fifth doses of Flu and Ara-C are each given 3 days prior to initiation of the dosing cycle.

Description

DOSING REGIMENS FOR TREATMENT OF CANCER CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to United States Provisional Patent Application Nos. 63/523,604, filed June 27, 2023; 63/535,240 filed August 29, 2023, the entire contents of each of which are incorporated by reference herein. FIELD [0002] Several embodiments disclosed herein relate to methods and compositions comprising genetically engineered cells for cancer immunotherapy. In several embodiments, the present disclosure relates to cells engineered to express cytotoxic receptor complexes and administration of such cells in accordance with certain dosing regimens to achieve successful cancer immunotherapy. BACKGROUND [0003] As further knowledge is gained about various cancers and what characteristics a cancerous cell has that can be used to specifically distinguish that cell from a healthy cell, therapeutics are under development that leverage the distinct features of a cancerous cell. Immunotherapies that employ engineered immune cells are one approach to treating cancers. INCORPORATION BY REFERENCE OF MATERIAL IN SEQUENCE LISTING FILE [0004] This application incorporates by reference the material contained in the Sequence Listing XML file being submitted concurrently herewith: File name: NKT.109WO_ST26.xml; created on June 18, 2024 and is 46,527 bytes in size. SUMMARY [0005] Immunotherapy presents a new technological advancement in the treatment of disease, wherein immune cells are engineered to express certain targeting and/or effector molecules that specifically identify and react to diseased or damaged cells. This represents a promising advance due, at least in part, to the potential for specifically targeting diseased or damaged cells, as opposed to more traditional approaches, such as chemotherapy, where all cells are impacted, and the desired outcome is that sufficient healthy cells survive to allow the patient to live. One immunotherapy approach is the recombinant expression of chimeric receptors in immune cells to achieve the targeted recognition and destruction of aberrant cells of interest. [0006] Provided herein is a method of treating a cancer in a subject comprising administering to a subject having a cancer a population of Natural Killer (NK) cells genetically engineered to express a chimeric receptor that binds a ligand of natural killer cell group 2D (NKG2D), wherein the genetically engineered NK cells are administered in a dosing cycle. In some embodiments, the dosing cycle comprises a first dose of the genetically engineered NK cells, a second dose of the genetically engineered NK cells, and a third dose of the genetically engineered NK cells. In some embodiments, all three doses are administered to the subject within between about 4 days and about 10 days. In some embodiments, the second dose is administered to the subject between 2-4 days after administration of the first dose to the subject; the third dose is administered to the subject between 2-4 days after administration of the second dose to the subject. [0007] In some embodiments, the dosing cycle comprises: (I) a first dose of the genetically engineered NK cells; (ii) a second dose of the genetically engineered NK cells administered to the subject 2-4 days after administration of the first dose of the genetically engineered NK cells; and (Hi) a third dose of genetically engineered NK cells administered to the subject 2-4 days after administration of the second dose of the genetically engineered NK cells. In some embodiments, each dose of the genetically engineered NK cells comprises at least about 1 x 109 genetically engineered NK cells. In some embodiments, each dose of the genetically engineered NK cells comprises at least about 1 .5 x 109 genetically engineered NK cells. In some embodiments, each dose of the genetically engineered NK cells comprises at least about 2 x 109 genetically engineered NK cells. In some embodiments, each dose of the genetically engineered NK cells comprises about 1 x 109 genetically engineered NK cells. In some embodiments, each dose of the genetically engineered NK cells comprises about 1 .5 x 109 genetically engineered NK cells. In some embodiments, each dose of the genetically engineered NK cells comprises about 2 x 109 genetically engineered NK cells. In some embodiments, each dose of the genetically engineered NK cells comprises about 2.5 x 109 genetically engineered NK cells. In some embodiments, prior to administration of the first dose of the genetically engineered NK cells to the subject, the subject is administered a lymphodepleting therapy. In some embodiments, all three doses of the genetically engineered NK cells are administered to the subject within about 14 days of conclusion of administration of the lymphodepleting therapy. In some embodiments, all three doses of the genetically engineered NK cells are administered to the subject within about 10 days of conclusion of administration