Natural killer cells modified to express membrane-bound interleukin 15 and uses thereof
The present invention provides, in certain aspects, a natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15), and methods for producing such cells. The invention further provides methods of using a natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15) to treat cancer in a subject or to enhance expansion and/or survival of NK cells.
1. A method of treating a cancer, the method comprising:
administering to a subject having the cancer a population of Natural Killer (NK) cells that expresses all or a functional portion of interleukin-15 (IL-15), wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein that anchors the expressed IL-15 as a cell membrane-bound polypeptide (mbIL15) of the NK cell, and wherein the all or a functional portion of IL-15 promotes one or more of:
(i) NK cell survival,
(ii) regulation of NK cell and T cell activation and proliferation, and
(iii) support of NK cell development from hematopoietic stem cells.
2. The method of claim 1 , further comprising administering IL-2 to the individual.
3. The method of claim 1 , further comprising administering one or more antibodies directed against the cancer to the individual.
4. The method of claim 1 , wherein the transmembrane protein is selected from the group consisting of CD8α, CD4, CD3ε, CD3γ, CD3δ, CD3ζ, CD28, CD137, glycophorin A, glycophorin D, nicotinic acetylcholine receptor, a GABA receptor, FcεRIγ, and a T-cell receptor.
5. The method of claim 1 , wherein the membrane-bound IL15 activates IL-15 signaling and/or anti-apoptotic signaling in an autocrine manner.
6. The method of claim 1 , wherein the transmembrane protein comprises CD8α, wherein the mbIL15 comprises the amino acid sequence of SEQ ID NO: 4, and wherein the NK cells expressing all or a functional portion of IL-15 as a membrane-bound polypeptide exhibits enhanced expression of one or more activation receptors as compared to NK cells not expressing membrane-bound IL15, wherein the one or more activation receptors are selected from the group consisting of NKG2D, NKp44 (CD336) and NKp30 (CD337), CD16 and CD56.
7. The method of claim 1 , wherein the cancer is selected from the group consisting of leukemia, a myelodysplastic syndrome, a lymphoma, a solid tumor, and a sarcoma.
8. The method of claim 7 , wherein the cancer is a leukemia, and wherein the leukemia is acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, or chronic lymphocytic leukemia.
9. The method of claim 7 , wherein the cancer is a solid tumor, and wherein the solid tumor is a result of hepatocellular carcinoma, colon cancer, breast cancer, prostate cancer, gastric cancer, nasopharyngeal carcinoma, or neuroblastoma, high grade glioma.