Methods of treatment with natural killer cells matched for killer immunoglobulin receptor type
The present invention concerns methods of treating a disease such as leukemia in a subject by administering natural killer (NK) cells. In particular aspects, HLA-C1-licensed KIR2DL2/3 and KIR2DS2 NK cells are administered to a subject with an HLA-C genotype either homozygous or heterozygous for the C1 allele, or HLA-C2 licensed cells are administered to a subject with an HLA-C genotype homozygous for the C2 allele. In further aspects, the NK cells are genetically modified to express a chimeric antigen receptor and interleukin 15.
1. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of natural killer (NK) cells, wherein
(a) the subject has been determined to have an HLA-C genotype either homozygous or heterozygous for the C1 allele and the NK cells express HLA-C1-licensed KIR2DL2/3 and KIR2DS2; or
(b) the subject has been determined to have an HLA-C genotype that is homozygous for the C2 allele and the NK cells express HLA-C2-licensed KIR2DL1 and KIR2DS1, wherein the disease or disorder is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), or myelodysplastic syndrome (MDS) and the subject is a human.
2. The method of claim 1 , wherein the subject has been determined to have an HLA-C genotype either homozygous or heterozygous for the C1 allele and the NK cells express HLA-C1-licensed KIR2DL2/3 and KIR2DS2.
3. The method of claim 1 , wherein the subject has been determined to have an HLA-C genotype that is homozygous for the C2 allele and the NK cells express HLA-C2-licensed KIR2DL1 and KIR2DS1.
4. The method of claim 1 , wherein the NK cells are derived from umbilical cord blood (CB) or peripheral blood.
5. The method of claim 1 , wherein the NK cells are genetically modified to express interleukin-15 (IL-15).
6. The method of claim 1 , wherein the NK cells are genetically modified to express a recombinant chimeric antigen receptor (CAR) comprising an intracellular signaling domain, a transmembrane domain, and an extracellular domain comprising an antigen binding region.
7. The method of claim 6 , wherein the antigen binding region is an F(ab′)2, Fab′, Fab, Fv, or scFv.
8. The method of claim 6 , wherein the intracellular signaling domain comprises CD3ξ, CD28, OX40/CD134, 4-1BB/CD137, FcεRIγ, ICOS/CD278, ILRB/CD122, IL-2RG/CD132, DAP molecules, CD70, cytokine receptor, CD40, or a combination thereof.
9. The method of claim 6 , wherein the transmembrane domain comprises CD28 transmembrane domain, IgG4Fc hinge, Fc regions, CD4 transmembrane domain, the CD3ξ transmembrane domain, cysteine mutated human CD3ξ domain, CD16 transmembrane domain, CD8 transmembrane domain, or erythropoietin receptor transmembrane domain.
10. The method of claim 1 , wherein NK cells are genetically modified to express an inducible suicide gene.
11. The method of claim 10 , wherein the suicide gene is caspase 9.
12. The method of claim 10 , further comprising administering AP20187 to the subject to induce apoptosis of the NK cells.
13. The method of claim 1 , further comprising administering a second therapeutic agent.
14. The method of claim 13 , wherein the second therapeutic agent comprises T cells, an immunomodulatory agent, a monoclonal antibody, or a chemotherapeutic agent.
15. The method of claim 14 , wherein the immunomodulatory agent is lenalidomide.
16. The method of claim 14 , wherein the monoclonal antibody is rituximab, ofatumumab, or lumiliximab.
17. The method of claim 14 , wherein the chemotherapeutic agent is fludarabine or cyclophosphamide.
18. The method of claim 1 , wherein the disease or disorder is acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML).