Modified Monocytes/Macrophage Expressing Chimeric Antigen Receptors and Uses Thereof
The present invention includes methods and compositions for treating cancer, whether a solid tumor or a hematologic malignancy. By expressing a chimeric antigen receptor in a monocyte, macrophage or dendritic cell, the modified cell is recruited to the tumor microenvironment where it acts as a potent immune effector by infiltrating the tumor and killing the target cells. One aspect includes a modified cell and pharmaceutical compositions comprising the modified cell for adoptive cell therapy and treating a disease or condition associated with immunosuppression.
1 - 44 . (canceled)
45 . A method of treating a malignancy in a subject, comprising:
administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a modified cell comprising a chimeric antigen receptor (CAR),
wherein the CAR comprises an antigen binding domain, a transmembrane domain and an intracellular domain of a stimulatory and/or co-stimulatory molecule,
wherein the antigen binding domain targets a tumor antigen, and
wherein the modified cell is a human macrophage or human monocyte.
46 . The method of claim 45 , wherein the tumor antigen is Receptor tyrosine-protein kinase ERBB2 (HER2), prostate-specific membrane antigen (PSMA), CD19, or mesothelin.
47 . The method of claim 45 , wherein the malignancy is or comprises: carcinoma, blastoma, sarcoma, leukemia, a lymphoid malignancy, or melanoma.
48 . The method of claim 45 , wherein the antigen binding domain of the CAR comprises an antibody selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a synthetic antibody, human antibody, humanized antibody, single domain antibody, single chain variable fragment, and antigen-binding fragments thereof.
49 . The method of claim 45 , wherein the transmembrane domain of the CAR comprises a CD8 or CD28 transmembrane domain.
50 . The method of claim 45 , wherein the intracellular domain of the CAR comprises dual signaling domains.
51 . The method of claim 45 , wherein the intracellular domain of the CAR comprises a CD3 zeta intracellular domain.
52 . The method of claim 45 , wherein the modified cell exhibits targeted effector activity.
53 . The method of claim 52 , wherein the targeted effector activity is directed against a target cell comprising the tumor antigen.
54 . The method of claim 52 , wherein the targeted effector activity is selected from the group consisting of phagocytosis, targeted cellular cytotoxicity, antigen presentation, and cytokine secretion.
55 . The method of claim 52 , wherein the targeted effector activity is enhanced by inhibition of CD47 or SIRPα activity.
56 . The method of claim 45 , wherein the pharmaceutical composition further comprises an agent selected from the group consisting of a nucleic acid, an antibiotic, an anti-inflammatory agent, an antibody or antibody fragments thereof, a growth factor, a cytokine, an enzyme, a protein, a peptide, a fusion protein, a synthetic molecule, an organic molecule, a carbohydrate or the like, a lipid, a hormone, a microsome, a derivative or a variation thereof, and any combination thereof.
57 . The method of claim 45 , wherein the modified cell exhibits reduced SIRPα activity relative to an unmodified cell.
58 . The method of claim 45 , wherein at least 35% of the modified cells in the pharmaceutical composition express the CAR.
59 . The method of claim 45 , wherein the modified cell comprises an Ad5f35 adenoviral component.
60 . The method of claim 45 , wherein the modified cell is autologous or allogeneic to the patient.
61 . The method of claim 45 , wherein the modified cells are administered by injection, aerosol inhalation, ingestion, transfusion, implantation or transplantation.
62 . The method of claim 45 , wherein the modified cells are administered transarterially, subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, intravenously, or intraperitoneally.
63 . The method of claim 45 , wherein the modified cell is administered to a patient in conjunction with at least one other treatment modality.
64 . The method of claim 63 , wherein the at least one other treatment modality is or comprises antiviral therapy, chemotherapy, radiation, an immunosuppressive agent, and/or an antibody therapy.