# US 2024/0197783 A1 · Methods of treatment and dosing of natural killer cell compositions > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2024/0197783 A1 - Document ID: US20240197783A1 - Status: Published application - Kind: A1 - Application number: 18/556,333 - Filed: 2022-04-20 - Published: 2024-06-20 - Earliest claimed: 2021-04-21 - Assignees: Indapta Therapeutics, Inc. - Applicants: Indapta Therapeutics, Inc. - Inventors: Guy DIPIERRO; Austin BIGLEY - Web page: https://patentgrep.com/patent/US20240197783A1 ## CPC - A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate - A61K 31/7076: containing purines, e.g. adenosine, adenylic acid - A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases - A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum - A61K 40/15: Natural-killer [NK] cells; Natural-killer T [NKT] cells - A61K 40/42: Cancer antigens - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 35/00: Antineoplastic agents - C07K 16/244: {Interleukins [IL]} - A61K 2039/505: {comprising antibodies} - A61K 2039/545: {characterised by the dose, timing or administration schedule} - A61K 2239/31: characterized by the route of administration - A61K 2239/38: characterised by the dose, timing or administration schedule - A61K 2239/48: Blood cells, e.g. leukemia or lymphoma - C07K 2317/21: from primates, e.g. man - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract Provided herein are methods for treatment and uses involving dosing of compositions containing NK cells. Among the provided methods and uses are methods and uses for treating cancer, such as multiple myeloma or lymphoma, including in combination with an antibody therapeutic for the cancer. ## Claims ### Claim 1 A method of treating multiple myeloma, the method comprising administering a composition of Natural Killer (NK) cells deficient in expression of FcRγ chain (g-NK cells) to a subject having multiple myeloma (MM), wherein the composition of g-NK cells is administered once weekly for a predetermined number of doses. ### Claim 2 (depends on 1) The method of claim 1, wherein the method is a monotherapy without combined administration of an exogenous antibody for treating the multiple myeloma. ### Claim 3 (depends on 1) The method of claim 1, wherein the method further comprises administering to the subject an antibody that is directed against a multiple myeloma antigen. ### Claim 4 (depends on 3) The method of claim 3, wherein the multiple myeloma antigen comprises an antigen selected from the group consisting of CD38, SLAMF7, and BCMA. ### Claim 5 (depends on 3, 4) The method of claim 3 or claim 4, wherein the antibody is a full-length antibody. ### Claim 6 (depends on 3, 4, 5) The method of any one of claims 3-5, wherein the antibody is an anti-SLAMF7 antibody. ### Claim 7 (depends on 3, 4, 5) The method of any one of claims 3-5, wherein the antibody is an anti-BCMA antibody. ### Claim 8 (depends on 3, 4, 5) The method of any one of claims 3-5, wherein the antibody is an anti-CD38 antibody. ### Claim 9 (depends on 3) The method of claim 3, wherein the antibody is a bispecific antibody. ### Claim 10 (depends on 9) The method of claim 9, wherein the bispecific antibody is directed against CD16 and a second multiple myeloma antigen selected from the group consisting of BCMA, SLAMF7, and CD38. ### Claim 11 (depends on 9, 10) The method of claim 9 or claim 10, wherein the bispecific antibody is directed against CD16 and CD38. ### Claim 12 (depends on 3, 4, 5, 6, 7, 8, 9, 10, 11) The method of any one of claims 3-11, wherein the antibody is administered once every four weeks, once every three weeks, once every two weeks, once weekly, or twice weekly. ### Claim 13 (depends on 8) The method of claim 8, wherein at least one dose of anti-CD38 antibody has been administered to the subject prior to administration of a dose of the composition of g-NK cells. ### Claim 14 A method of treating multiple myeloma, the method comprising administering a composition of Natural Killer (NK) cells deficient in expression of FcRγ chain (g-NK cells) to a subject having multiple myeloma (MM), wherein the composition of g-NK cells is administered once weekly for a predetermined number of doses, and wherein the subject has received prior administration of at least one dose of an anti-CD38 antibody. ### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14) The method of any of claims 1-14, wherein the g-NK cell composition is administered as two doses in a 14-day cycle, wherein the 14-day cycle is repeated one to three times. ### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) The method of any of claims 1-15, wherein the g-NK cell composition is administered as six total doses. ### Claim 17 (depends on 8, 13, 14, 15, 16) The method of any of claims 8 and 13-16, wherein the anti-CD38 antibody is daratumumab. ### Claim 18 (depends on 13, 14, 15, 16, 17) The method of any of claims 13-17, wherein administration of the at least one dose of the anti-CD38 antibody is initiated within one month prior to administration of the composition of g-NK cells. ### Claim 19 (depends on 13, 14, 15, 16, 17) The method of any of claims 13-17, wherein administration of the at least one dose of the anti-CD38 antibody is initiated within three weeks prior to administration of the composition of g-NK cells. ### Claim 20 (depends on 13, 14, 15, 16, 17) The method of any of claims 13-17, wherein administration of the at least one dose of the anti-CD38 antibody is initiated within two weeks prior to administration of the composition of g-NK cells. ### Claim 21 (depends on 8, 13, 14, 15, 16, 17, 18, 19, 20) The method of any of claims 8 and 13-20, wherein the anti-CD38 antibody is administered intravenously. ### Claim 22 (depends on 8, 13, 14, 15, 16, 17, 18, 19, 20, 21) The method of any of claims 8 and 13-21, wherein the anti-CD38 antibody is administered as a once weekly dose, optionally for one or two 28-day cycles. ### Claim 23 (depends on 8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22) The method of any of claims 8 and 13-22, wherein each dose of the anti-CD38 antibody (e.g. daratumumab) is administered in an amount that is from or from about 8 mg/kg to about 32 mg/kg, optionally at or about 16 mg/kg. ### Claim 24 (depends on 8, 13, 14, 15, 16, 17, 18, 19, 20) The method of any of claims 8 and 13-20, wherein the anti-CD38 antibody is administered subcutaneously. ### Claim 25 (depends on 8, 13, 14, 15, 16, 17, 18, 19, 20) The method of any of claims 8, 13-20, and 24, wherein the anti-CD38 antibody (e.g. daratumumab) is administered in an anti-CD38 antibody composition comprising a hyaluronidase, optionally wherein the anti-CD38 antibody composition comprises daratumumab and recombinant human hyaluronidase PH20 (e.g. hyaluronidase-fihj). ### Claim 26 (depends on 25) The method of claim 25, wherein the anti-CD38 antibody composition is administered as a once weekly dose, optionally for one or two 28-day cycles. ### Claim 27 (depends on 25, 26) The method of claim 25 or claim 26, wherein each dose of the anti-CD38 antibody composition comprises from at or about 1200 mg to about 2400 mg anti-CD38 antibody (e.g. daratumumab) and from at or about 15,000 Units (U) to about 45,000 U hyaluronidase (e.g. hyaluronidase-fihj). ### Claim 28 (depends on 24, 25, 26, 27) The method of any of claims 24-27, wherein each dose of the anti-CD38 antibody composition comprises about 1800 mg anti-CD38 antibody (e.g. daratumumab) and about 30,000 U hyaluronidase (e.g. hyaluronidase-fihj). ### Claim 29 (depends on 8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) The method of any of claims 8 and 13-28, wherein the method comprises administering the anti-CD38 antibody, optionally the anti-CD38 antibody composition, once weekly for 8 total doses and administering the g-NK cell composition once weekly for 6 total doses, wherein one dose or two doses of the anti-CD38 antibody is administered prior to administration of the composition comprising g-NK cells. ### Claim 30 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29) The method of any of claims 1-29, wherein the multiple myeloma is relapsed/refractory multiple myeloma. ### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) The method of any of claims 1-30, wherein the g-NK cells have low or no expression of CD38, optionally wherein less than 25% of the cells in the g-NK cell composition are positive for surface CD38. ### Claim 32 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31) The method of any of claims 1-31, wherein the cells in the g-NK cell composition are not engineered to reduce or eliminate CD38 expression. ### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32) The method of any of claims 1-32, wherein the g-NK cell composition exhibits minimal anti-CD38-induced fratricide, optionally wherein less than 10% of cells in the g-NK cell composition exhibit anti-CD38 induced fratricide. ### Claim 34 A method of treating lymphoma, the method comprising administering a composition of Natural Killer (NK) cells deficient in expression of FcRγ chain (g-NK cells) to a subject having lymphoma, wherein the composition of g-NK cells is administered once weekly for a predetermined number of doses. ### Claim 35 (depends on 34) The method of claim 34, wherein the method is a monotherapy without combined administration of an exogenous antibody for treating the lymphoma. ### Claim 36 (depends on 34) The method of claim 34, wherein the method further comprises administering to the subject an antibody that is directed against a lymphoma antigen. ### Claim 37 (depends on 36) The method of claim 36, wherein the lymphoma antigen comprises an antigen selected from the group consisting of CD19, CD20, and CD30. ### Claim 38 (depends on 36, 37) The method of claim 36 or claim 37, wherein the antibody is a full-length antibody. ### Claim 39 (depends on 36, 37, 38) The method of any one of claims 36-38, wherein the antibody is an anti-CD19 antibody. ### Claim 40 (depends on 36, 37, 38) The method of any one of claims 36-38, wherein the antibody is an anti-CD30 antibody. ### Claim 41 (depends on 36, 37, 38) The method of any one of claims 36-38, wherein the antibody is an anti-CD20 antibody. ### Claim 42 (depends on 36) The method of claim 36, wherein the antibody is a bispecific antibody. ### Claim 43 (depends on 42) The method of claim 42, wherein the bispecific antibody is directed against CD16 and a second antigen selected from the group consisting of CD19, CD20, and CD30. ### Claim 44 (depends on 43) The method of claim 43, wherein the bispecific antibody is directed against CD16 and CD20. ### Claim 45 (depends on 36, 37, 38, 39, 40, 41, 42, 43, 44) The method of claim 36-44, wherein the antibody is administered once every four weeks, once every three weeks, once every two weeks, once weekly, or twice weekly. ### Claim 46 (depends on 41) The method of claim 41, wherein at least one dose of anti-CD20 antibody has been administered to the subject prior to administration of a dose of the composition of g-NK cells. ### Claim 47 A method of treating lymphoma, the method comprising administering a composition of Natural Killer (NK) cells deficient in expression of FcRγ chain (g-NK cells) to a subject having lymphoma, wherein the composition of g-NK cells is administered once weekly for a predetermined number of doses, and wherein the subject has received prior administration of at least one dose of an anti-CD20 antibody. ### Claim 48 (depends on 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47) The method of any of claims 34-47, wherein the lymphoma is a Non-Hodgkin's Lymphoma (NHL). ### Claim 49 (depends on 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48) The method of any of claims 34-48, wherein the g-NK cell composition is administered as two doses in a 14-day cycle, wherein the 14-day cycle is repeated one to three times. ### Claim 50 (depends on 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49) The method of any of claims 34-49, wherein the g-NK cell composition is administered as six total doses. ### Claim 51 (depends on 41, 45, 46, 47, 48, 49, 50) The method of any of claims 41 and 45-50, wherein the anti-CD20 antibody is rituximab. ### Claim 52 (depends on 41, 45, 46, 47, 48, 49, 50, 51) The method of any of claims 41 and 45-51, wherein administration of the at least one dose of the anti-CD20 antibody is initiated within one month prior to administration of the composition of g-NK cells. ### Claim 53 (depends on 41, 45, 46, 47, 48, 49, 50, 51, 52) The method of any of claims 41 and 45-52, wherein administration of the at least one dose of the anti-CD20 antibody is initiated within three weeks prior to administration of the composition of g-NK cells. ### Claim 54 (depends on 41, 45, 46, 47, 48, 49, 50, 51, 52, 53) The method of any of claims 41 and 45-53, wherein administration of the at least one dose of the anti-CD20 antibody is initiated within two weeks prior to administration of the composition of g-NK cells. ### Claim 55 (depends on 41, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54) The method of any of claims 41 and 45-54, wherein the anti-CD20 antibody is administered intravenously. ### Claim 56 (depends on 41, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55) The method of any of claims 41 and 45-55, wherein the anti-CD20 antibody is administered as a once weekly dose, optionally for 4 or 8 doses. ### Claim 57 (depends on 41, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56) The method of any of claims 41 and 45-56, wherein each dose of the anti-CD20 antibody is administered in an amount that is from or from about 250 mg/m2 to 500 mg/m2, optionally at or about 375 mg/m2. ### Claim 58 (depends on 41, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54) The method of any of claims 41 and 45-54, wherein the anti-CD20 antibody is administered subcutaneously. ### Claim 59 (depends on 41, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54) The method of any of claims 41, 45-54, and 58, wherein the anti-CD20 antibody (e.g. rituximab) is administered in an anti-CD20 antibody composition comprising a hyaluronidase, optionally wherein the anti-CD20 antibody composition comprises rituximab and a human recombinant hyaluronidase PH20. ### Claim 60 (depends on 59) The method of claim 59, wherein the anti-CD20 antibody composition is administered as a once weekly dose, optionally for 4 or 8 doses or optionally for 3 or 7 doses following a once weekly dose of the anti-CD20 antibody intravenously. ### Claim 61 (depends on 59, 60) The method of claim 59 or claim 60, wherein each dose of the anti-CD20 antibody composition comprises from at or about 1200 mg to about 2400 mg anti-CD20 antibody (e.g. rituximab) and from at or about 15,000 Units (U) to about 45,000 U hyaluronidase. ### Claim 62 (depends on 59, 60, 61) The method of any of claims 59-61, wherein each dose of the anti-CD20 antibody composition comprises about 1400 mg anti-CD20 antibody (e.g. rituximab) and about 23,400 U hyaluronidase. ### Claim 63 (depends on 59, 60, 61) The method of any of claims 59-61, wherein each dose of the anti-CD20 antibody composition comprises about 1600 mg anti-CD20 antibody (e.g. rituximab) and about 26,800 U hyaluronidase. ### Claim 64 (depends on 41, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63) The method of any of claims 41 and 45-63, wherein the method comprises administering the anti-CD20 antibody, optionally the anti-CD20 antibody composition, once weekly for 8 total doses and administering the g-NK cell composition once weekly for 6 total doses, wherein one dose or two doses of the anti-CD20 antibody is administered prior to administration of the composition comprising g-NK cells. ### Claim 65 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64) The method of any of claims 1-64, wherein, among cells in the g-NK cell composition, greater than at or about 60% of the cells are g-NK cells, greater than at or about 70% of the cells are g-NK cells, greater than at or about 80% of the cells are g-NK cells, greater than at or about 90% of the cells are g-NK cells, or greater than at or about 95% of the cells are g-NK cells. ### Claim 66 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64) The method of any of claims 1-64, wherein at least at or about 50% of the cells in the g-NK cell composition are FcRγ-deficient (FcRγneg) NK cells (g-NK), wherein greater than at or about 70% of the g-NK cells are positive for perforin and greater than at or about 70% of the g-NK cells are positive for granzyme B. ### Claim 67 (depends on 65, 66) The method of claim 65 or claim 66, wherein (i) greater than at or about 80% of the g-NK cells are positive for perforin and greater than at or about 80% of the g-NK cells are positive for granzyme B, (ii) greater than at or about 90% of the g-NK cells are positive for perforin and greater than at or about 90% of the g-NK cells are positive for granzyme B, or (iii) greater than at or about 95% of the g-NK cells are positive for perforin and greater than at or about 95% of the g-NK cells are positive for granzyme B. ### Claim 68 (depends on 66, 67) The method of claim 66 or claim 67, wherein: among the cells positive for perforin, the cells express a mean level of perforin as measured by intracellular flow cytometry that is, based on mean fluorescence intensity (MFI), at least at or about two times the mean level of perforin expressed by cells that are FcRγpos; and/or. among the cells positive for granzyme B, the cells express a mean level of granzyme B as measured by intracellular flow cytometry that is, based on mean fluorescence intensity (MFI), at least at or about two times the mean level of granzyme B expressed by cells that are FcRγpos. ### Claim 69 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68) The method of any of claims 1-68, wherein greater than 10% of the cells in the g-NK cell composition are capable of degranulation against tumor target cells, optionally as measured by CD107a expression, optionally wherein the degranulation is measured in the absence of an antibody against the tumor target cells. ### Claim 70 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69) The method of any of claims 1-69, wherein, among the cells in the g-NK cell composition, greater than at or about 15%, greater than at or about 20%, greater than at or about 30%, greater than at or about 40% or greater than at or about 50% exhibit degranulation, optionally as measured by CD107a expression, in the presence of cells expressing a target antigen (target cells) and an antibody directed against the target antigen (anti-target antibody). ### Claim 71 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70) The method of any of claims 1-70, wherein greater than 10% of the cells in the g-NK cell composition are capable of producing interferon-gamma or TNF-alpha against tumor target cells, optionally wherein the interferon-gamma or TNF-alpha is measured in the absence of an antibody against the tumor target cells. ### Claim 72 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71) The method of any of claims 1-71, wherein, among the cells in the g-NK cell composition, greater than at or about 15%, greater than at or about 20%, greater than at or about 30%, greater than at or about 40% or greater than at or about 50% produce an effector cytokine in the presence of cells expressing a target antigen (target cells) and an antibody directed against the target antigen (anti-target antibody). ### Claim 73 (depends on 72) The method of claim 72, wherein the effector cytokine is IFN-gamma or TNF-alpha. ### Claim 74 (depends on 72, 73) The method of claim 72 or claim 73, wherein the effector cytokine is IFN-gamma and TNF-alpha. ### Claim 75 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74) The method of any of claims 1-74, wherein the g-NK cell composition has been produced by ex vivo expansion of CD3−/CD57+ cells cultured with irradiated HLA-E+ feeder cells, wherein the CD3−/CD57+ cells are enriched from a biological sample from a donor subject. ### Claim 76 (depends on 75) The method of claim 75, wherein the donor subject is CMV-seropositive. ### Claim 77 (depends on 75, 76) The method of claim 75 or claim 76, wherein the donor subject has the CD16 158V/V NK cell genotype or the CD16 158V/F NK cell genotype, optionally wherein the biological sample is from a human subject selected for the CD16 158V/V NK cell genotype or the CD16 158V/F NK cell genotype. ### Claim 78 (depends on 75, 76, 77) The method of any of claims 75-77, wherein at least at or about 20% of natural killer (NK) cells in a peripheral blood sample from the donor subject are positive for NKG2C (NKG2Cpos) and at least 70% of NK cells in the peripheral blood sample are negative or low for NKG2A (NKG2Aneg). ### Claim 79 (depends on 75, 76, 77) The method of any of claims 75-77, wherein the irradiated feeder cells are deficient in HLA class I and HLA class II. ### Claim 80 (depends on 75, 76, 77, 78, 79) The method of any of claims 75-79, wherein the irradiated feeder cells are 221.AEH cells. ### Claim 81 (depends on 75, 76, 77, 78, 79, 80) The method of any of claims 75-80, wherein the culturing is performed in the presence of two or more recombinant cytokines, wherein at least one recombinant cytokine is interleukin (IL)-2 and at least one recombinant cytokine is IL-21. ### Claim 82 (depends on 81) The method of claim 81, wherein the recombinant cytokines are IL-21 and IL-2. ### Claim 83 (depends on 81) The method of claim 81, wherein the recombinant cytokines are IL-21, IL-2, and IL-15. ### Claim 84 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83) The method of any of claims 1-83, wherein the g-NK cells in the composition are from a single donor subject that have been expanded from the same biological sample. ### Claim 85 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84) The method of any of claims 1-84, wherein the g-NK cell composition is formulated in a serum-free cryopreservation medium comprising a cryoprotectant, optionally wherein the cyroprotectant is DMSO and the cryopreservation medium is 5% to 10% DMSO (v/v). ### Claim 86 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85) The method of any of claims 1-85, wherein the g-NK cells are not engineered with an antigen receptor, optionally wherein the antigen receptor is a chimeric antigen receptor. ### Claim 87 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86) The method of any of claims 1-86, wherein the g-NK cells are not engineered with a secretable cytokine, optionally a cytokine receptor fusion protein, such as IL-15 receptor fusion (IL-15RF) ### Claim 88 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87) The method of any of claims 1-87, wherein the method does not include exogenous cytokine administration to the subject to support NK cell survival or expansion, wherein the exogenous cytokine is one or more of IL-2, IL-7, IL-15 or IL-21. ### Claim 89 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88) The method of any of claims 1-88, each dose of g-NK cells is from at or about from at or about 1×108 cells to at or about 50×109 cells of the g-NK cell composition. ### Claim 90 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89) The method of any of claims 1-89, wherein each dose of g-NK cells is or is about 5×108 cells of the g-NK cell composition. ### Claim 91 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89) The method of any of claims 1-89, wherein each dose of g-NK cells is or is about 5×109 cells of the g-NK cell composition. ### Claim 92 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89) The method of any of claims 1-89, wherein each dose of g-NK cells is or is about 10×109 cells of the g-NK cell composition. ### Claim 93 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92) The method of any of claims 1-92, wherein prior to the administration of the dose of g-NK cells, the subject has received a lymphodepleting therapy. ### Claim 94 (depends on 93) The method of claim 93, wherein the lymphodepleting therapy comprises fludarabine and/or cyclophosphamide. ### Claim 95 (depends on 93, 94) The method of claim 93 or claim 94, wherein the lymphodepleting comprises the administration of fludarabine at or about 20-40 mg/m2 body surface area of the subject, optionally at or about 30 mg/m2, daily, for 2-4 days, and/or cyclophosphamide at or about 200-400 mg/m2 body surface area of the subject, optionally at or about 300 mg/m2, daily, for 2-4 days. ### Claim 96 (depends on 94, 95) The method of claim 94 or claim 95, wherein the lymphodepleting therapy comprises fludarabine and cyclophosphamide. ### Claim 97 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96) The method of any of claims 1-96, wherein the lymphodepleting therapy comprises the administration of fludarabine at or about 30 mg/m2 body surface area of the subject, daily, and cyclophosphamide at or about 300 mg/m2 body surface area of the subject, daily, each for 2-4 days, optionally 3 days. ### Claim 98 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97) The method of any of claims 1-97, wherein administration of a dose of g-NK cells is initiated within two weeks or at or about two weeks after initiation of the lymphodepleting therapy. ### Claim 99 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97) The method of any of claims 1-97, wherein administration of a dose of g-NK cells is initiated within 7 days or at or about 7 days after initiation of the lymphodepleting therapy. ### Claim 100 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99) The method of any one of claims 1-99, wherein the individual is a human. ### Claim 101 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100) The method of any one of claims 1-100, wherein the NK cells in the composition are allogenic to the individual. ### Claim 102 (depends on 1, 101) The method of any one of claims 1-101, further comprising administering exogenous cytokine support to facilitate expansion or persistence of the g-NK cells in vivo in the subject, optionally wherein the exogenous cytokine is or comprises IL-15.