Cell-mediated transient delivery of immune-enhancing molecules into the tumor microenvironment
A recombinant natural killer (NK) cell or T-cell composition is transfected with a nucleic acid encoding i) a homing receptor; ii) an antigen binding protein (ABP) or a chimeric antigen receptor (CAR) that specifically binds a target antigen; iii) an Fc Receptor; and/or iv) a secreted immune modulator selected from a TGFβ inhibitor and/or IL-12, where the recombinant cell is gamma (γ)-irradiated conferring inhibition of cell proliferation with transient activity of the transfected molecules including the secreted immune modulators for up to 72 hours.
1 . A method of treating a cancer or a tumor in a subject, the method comprising:
administering to the subject a therapeutically effective amount of irradiated recombinant NK-92 cells, wherein the irradiated recombinant NK-92 cells are transfected with one or more nucleic acids that encode
i) a homing receptor;
ii) an antigen binding protein (ABP) or a chimeric antigen receptor (CAR) that specifically binds a target antigen;
iii) an Fc Receptor; and
iv) a secreted immune modulator selected from a TGFβ inhibitor and/or IL-12,
wherein the nucleic acid is operably linked to a promoter, and wherein the transfected recombinant NK-92 cell is irradiated with 2.5 to 15 Gy; and
administering the irradiated transfected recombinant NK-92 cell to the subject.
2 . The method of claim 1 , wherein the recombinant NK-92 cells are transfected with a vector.
3 . The method of claim 1 , wherein the recombinant NK-92 cells are transfected with a quadri-cistronic recombinant nucleic acid.
4 . The method of claim 1 , wherein the homing receptor is a G protein-coupled receptor, a cytokine receptor, a selectin, or an integrin.
5 . The method of claim 1 , wherein the homing receptor is selected from the group consisting of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, CX3CR1, XCR1, CCXCKR, D6, DARC, or a receptor for CXCL14.
6 . The method of claim 1 , wherein the nucleic acid encodes the antigen binding protein.
7 . The method of claim 6 , wherein the ABP is selected from a protein or antibody that binds to CD19, CD20, GD2, HER-2, CD30, EGFR, FAP, CD33, CD123, PD-L1, IGFIR, CSPG4, or B7-H4.
8 . The method of claim 6 , wherein the ABP is selected from a protein or antibody that binds to PD-L1.
9 . The method of claim 1 , wherein the nucleic acid encodes the CAR.
10 . The method of claim 1 , wherein the CAR specifically binds PD-L1.
11 . The method of claim 1 , wherein the Fc Receptor is CD16 or a high affinity CD16.
12 . The method of claim 1 , wherein the secreted immune modulator is IL-12.
13 . The method of claim 12 , wherein the IL-12 is a single chain IL-12.
14 . The method of claim 1 , wherein the secreted immune modulator is a TGFβ inhibitor.
15 . The method of claim 1 , wherein the TGFβ inhibitor comprises a single chain dimer of a TGF-beta Receptor II ectodomain.
16 . The method of claim 1 , wherein from 1×10 3 to 1×10 10 , per m 2 of the irradiated recombinant NK-92 cells are administered to the subject.
17 . The method of claim 1 , wherein the recombinant NK-92 cells are administered parenterally, intravenously, peritumorally, or by infusion.
18 . The method of claim 1 , further comprising administering to the subject a therapeutic drug.
19 . The method of claim 1 , wherein the recombinant NK-92 cells, after irradiation, maintain transient activity of the secreted immune modulator.
20 . The method of claim 19 , wherein the recombinant NK-92 cells, after irradiation, are inhibited from replication.