MODIFIED CELLS OF LEUKEMIC ORIGIN AND A PD-L1 ANTIBODY FOR ENHANCING THE EFFICACY OF CANCER CELL THERAPY
Composition and methods for ex vivo expansion of natural killer (NK) cells, and methods for cell-based cancer immunotherapy are disclosed. Leukemic cell-derived dendritic cells and anti-PD-L1 antibodies, and certain embodiments with addition of PBMCs are used for in vivo administration for cancer treatment. Leukemic cell-derived dendritic cells and anti-PD-L1 antibodies are also used for ex vivo expansion of NK cells.
1 . A composition comprising
a modified cell of leukemic origin, and
an anti-PD-L1 antibody,
wherein the modified cell exhibits a mature dendritic cell phenotype.
2 . The composition of claim 1 , wherein the modified cell of leukemic origin comprises at least one tumor antigen selected from the group consisting of WT-1, RHAMM, PRAME, MUC-1, p53, and Survivin.
3 . The composition of claim 1 , wherein the modified cell of leukemic origin is CD34-positive, CD1a-positive, CD83-positive, and CD14-negative.
4 . The composition of claim 1 , wherein the anti-PD-L1 antibody comprises an IgG domain that binds with high affinity to Fc-gamma receptors (FcgRs), including FcgRI (CD64), FcgRII (CD32) and FcgRIIIA (CD16).
5 . The composition of claim 1 , further comprising a plurality of peripheral blood mononuclear cells (PBMCs), natural killer (NK) cell line cells, cord blood stem cells, pluripotent stem cells and any combination thereof.
6 . The composition of claim 5 , wherein a plurality of allogeneic NK cells is derived from the PBMCs, the NK cell line cells, the cord blood stem cells, the pluripotent stem cells and the combination thereof.
7 . The composition of claim 5 , wherein the PBMCs are derived from a patient to treat.
8 . The composition of claim 5 ,
wherein the modified cell of leukemic origin and the anti-PD-L1 antibody have a synergistic effect on activating FCgR-expressing NK cells and myeloid mononuclear cells;
wherein the activation of the FCgR-expressing NK cells and myeloid mononuclear cells results in increased secretion of chemokines and proinflammatory cytokines; and/or
wherein the activation of the NK cells results in increased NK-mediated lysis of tumor cells.
9 . (canceled)
10 . (canceled)
11 . The composition of claim 1 , wherein the anti-PD-L1 antibody is selected from the group consisting of an IgG Fc domain with high affinity to FcgRs, that is optionally avelumab or PDL-GEX.
12 . The composition of claim 1 , wherein the modified cell of leukemic origin further comprises a cell surface marker selected from the group consisting of DC-SIGN, Langerin, CD40, CD70, CD80, CD86, and any combination thereof;
wherein the modified cell of leukemic origin is CD70-positive, CD80-positive, and CD86-positive;
wherein the modified cell of leukemic origin comprises an MHC class I molecule;
wherein the modified cell of leukemic origin comprises an MHC class II molecule; and/or
wherein the modified cell of leukemic origin is non-proliferating.
13 - 16 . (canceled)
17 . A method for activating, stimulating and and/or expanding a population of immune cells, comprising:
(a) obtaining a population of cells comprising immune cells;
(b) contacting the population of cells with a modified cell of leukemic origin and an anti-PD-L1 antibody, wherein the modified cell exhibits a mature dendritic cell phenotype; and
(c) co-culturing the population of cells and the modified cell of leukemic origin and the anti-PD-L1 antibody under conditions suitable to induce activation of the immune cells, thereby expanding the population of immune cells.
18 . The method of claim 17 , wherein:
the modified cell of leukemic origin comprises at least one tumor antigen selected from the group consisting of WT-1, RHAMM, PRAME, MUC-1, p53, and Survivin;
the modified cell of leukemic origin is CD34-positive, CD1a-positive, CD83-positive, and CD14-negative;
the modified cell of leukemic origin further comprises a cell surface marker selected from the group consisting of DC-SIGN, Langerin, CD40, CD70, CD80, CD86, and any combination thereof;
the modified cell of leukemic origin is CD70-positive, CD80-positive, and CD86-positive;
the modified cell of leukemic origin comprises an MHC class I molecule;
the modified cell of leukemic origin comprises an MHC class II molecule;
the modified cell of leukemic origin is non-proliferating;
the population of cells comprises PBMCs; and/or
surface expression of CD25 and CD137 increases in natural killer cells after the co-culturing step.
19 - 26 . (canceled)
27 . A method for treating a disease or disorder in a subject in need thereof, comprising
administering intratumorally to the subject a first composition comprising a modified cell of leukemic origin and an anti-PD-L1 antibody, wherein the modified cell exhibits a mature dendritic cell phenotype, optionally wherein the anti-PD-L1 antibody is a bispecific or multi-specific antibody; or
A method for treating a disease or disorder in a subject in need thereof, comprising
administering intratumorally to the subject a composition comprising:
a modified cell of leukemic origin, wherein the modified cell exhibits a mature dendritic cell phenotype;
anti-PD-L1 antibody; and
autologous or allogeneic PBMCs.
28 . (canceled)
29 . The method of claim 27 ,
wherein the modified cell of leukemic origin:
comprises at least one tumor antigen selected from the group consisting of WT-1, RHAMM, PRAME, MUC-1, p53, and Survivin;
is CD34-positive, CD1a-positive, CD83-positive, and CD14-negative;
further comprises a cell surface marker selected from the group consisting of DC-SIGN, Langerin, CD40, CD70, CD80, CD86, and any combination thereof;
is CD70-positive, CD80-positive, and CD86-positive;
comprises an MHC class I molecule;
comprises an MHC class II molecule; and/or
is non-proliferating; and/or
wherein the anti-PD-L1 antibody is a bispecific or multi-specific antibody.
30 - 36 . (canceled)
37 . The method of claim 27 , wherein surface expression of CD25 and CD137 both increases in the natural killer cells after being administered to the subject.
38 . The method of claim 27 , wherein the disease or disorder is a cancer, optionally wherein the cancer is a semi-solid tumor, a solid tumor, acute myeloid leukemia (AML), or lymphoma.
39 - 41 . (canceled)
42 .
1) A method of making a composition, comprising adding an anti-PD-L1 antibody to a modified cell of leukemic origin, wherein the modified cell of leukemic origin exhibits a mature dendritic cell phenotype, optionally wherein the anti-PD-L1 antibody is a bispecific or multi-specific antibody; or
2) A composition comprising ex vivo expanded immune cells, comprising a population of immune cells, a modified cell of leukemic origin, and an anti-PD-L1 antibody, wherein the modified cell exhibits a mature dendritic cell phenotype.
43 . The composition claim 1 , wherein the anti-PD-L1 antibody is a bispecific or multi-specific antibody.
44 . The method of claim 17 , wherein the anti-PD-L1 antibody is a bispecific or multi-specific antibody.
45 . (canceled)
46 . The composition of claim 42 , wherein:
the modified cell of leukemic origin comprises at least one tumor antigen selected from the group consisting of WT-1, RHAMM, PRAME, MUC-1, p53, and Survivin;
the modified cell of leukemic origin is CD34-positive, CD1a-positive, CD83-positive, and CD14-negative,
the modified cell of leukemic origin further comprises a cell surface marker selected from the group consisting of DC-SIGN, Langerin, CD40, CD70, CD80, CD86, and any combination thereof;
the modified cell of leukemic origin is CD70-positive, CD80-positive, and CD86-positive;
the modified cell of leukemic origin comprises an MHC class I molecule;
the modified cell of leukemic origin comprises an MHC class II molecule;
the modified cell of leukemic origin is non-proliferating;
the population of immune cells comprises PBMCs; and/or
surface expression of CD25 and CD137 increases in natural killer cells after the co-culturing step.
47 - 54 . (canceled)