Treatment of cancer using a chimeric antigen receptor in combination with an inhibitor of a pro-m2 macrophage molecule
AssigneesNovartis AG, The Trusteesof the University of Pennsylvania
InventorsSaar Gill, Marco Ruella, Michael Klichinsky
Life of this patent
Estimating the term…
Abstract
The invention provides compositions and methods for treating diseases associated with expression of an antigen, e.g., a solid tumor antigen or antigen expressed on a tumor associated with TAMs and/or MDSCs, by administering a recombinant T cell comprising a CAR binding to said antigen, as described herein, in combination with an inhibitor of a pro-M2 macrophage molecule, e.g., described herein. The invention also provides kits and compositions described herein.
Claims67
A CAR therapy comprising a cell, e.g., a population of immune effector cells, comprising, e.g., expressing, a chimeric antigen receptor (CAR) for use in combination with an inhibitor of a pro-M2 macrophage molecule in treating a subject having a disease associated with expression of a tumor antigen, wherein the CAR comprises a tumor antigen binding domain, a transmembrane domain, and an intracellular signaling domain.
A method of treating a subject having a disease associated with expression of a tumor antigen, comprising administering to the subject:
- (i) a CAR therapy comprising a cell, e.g., a population of immune effector cells, comprising, e.g., expressing, a chimeric antigen receptor (CAR), wherein the CAR comprises a tumor antigen binding domain, a transmembrane domain, and an intracellular signaling domain;
- and
- (ii) an inhibitor of a pro-M2 macrophage molecule.
A CAR therapy comprising a cell, e.g., a population of immune effector cells, comprising, e.g., expressing, a chimeric antigen receptor (CAR) for use in combination with a tumor targeting therapy in treating a subject having a disease associated with expression of a tumor antigen, wherein:
- (i) the CAR comprises a tumor antigen binding domain that binds CD123 (CD123 CAR), a transmembrane domain, and an intracellular signaling domain;
- and
- (ii) the tumor targeting therapy comprises a second CAR therapy that comprises a cell, e.g., a population of immune effector cells, compring, e.g., expressing, a CAR comprising a tumor antigen binding domain that binds to a tumor antigen other than CD123 (e.g., a CAR that binds to a solid tumor antigen or a hematologic tumor antigen other than CD123),
- wherein the CD123 CAR is administered in an amount and/or time sufficient to result in inhibition of an M2 macrophage activity.
A method of treating a subject having a disease associated with expression of a tumor antigen, comprising administering to the subject:
- (i) a CAR therapy comprising a cell, e.g., a population of immune effector cells, comprising, e.g., expressing, a chimeric antigen receptor (CAR), wherein the CAR comprises a tumor antigen binding domain that binds CD123 (CD123 CAR), a transmembrane domain, and an intracellular signaling domain;
- and
- (ii) a tumor targeting therapy, wherein the tumor targeting therapy comprises a second CAR therapy that comprises a cell, e.g., a population of immune effector cells, compring, e.g., expressing, a CAR comprising a tumor antigen binding domain that binds to a tumor antigen other than CD123 (e.g., a CAR that binds to a solid tumor antigen or a hematologic tumor antigen other than CD123),
- wherein the CD123 CAR is administered in an amount and/or time sufficient to result in inhibition of an M2 macrophage activity.
The CAR therapy for use or the method of any of the preceding claims, wherein the tumor antigen binding domain of the CAR binds a solid tumor antigen.
The CAR therapy for use or the method of any of the preceding claims, wherein the tumor antigen binding domain of the CAR binds an antigen expressed on a tumor associated with tumor-associated macrophages (TAMs) and/or myeloid derived suppressor cells (MDSCs).
The CAR therapy for use or the method of any of the preceding claims, wherein the intracellular signaling domain comprises a primary signaling domain comprising a CD3-zeta stimulatory domain.
The CAR therapy for use or the method of any of the preceding claims, wherein the intracellular signaling domain comprises a costimulatory domain which is an intracellular domain of a costimulatory protein selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, ICAM-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CDS, CD7, CD287, LIGHT, NKG2C, NKG2D, SLAMF7, NKp80, NKp30, NKp44, NKp46, CD160, B7-H3, and a ligand that specifically binds with CD83.
The CAR therapy for use or the method of any of the preceding claims, wherein the disease associated with expression of a tumor antigen is cancer.
The CAR therapy for use or the method of any of the preceding claims, wherein the cell comprising a CAR comprises a nucleic acid encoding the CAR.
The CAR therapy for use or the method of claims 17-60, wherein the CAR therapy and the tumor targeting therapy are formulated in a pharmaceutical composition.
A pharmaceutical composition comprising (i) a cell, e.g., a population of immune effector cells, comprising, e.g., expressing, a chimeric antigen receptor (CAR), wherein the CAR comprises a tumor antigen binding domain, a transmembrane domain, and an intracellular signaling domain;
- and (ii) an inhibitor of a pro-M2 macrophage molecule.
A pharmaceutical composition comprising (i) a cell, e.g., a population of immune effector cells, comprising, e.g., expressing, a chimeric antigen receptor (CAR), wherein the CAR comprises a tumor antigen binding domain, a transmembrane domain, and an intracellular signaling domain;
- and (ii) an inhibitor of a pro-M2 macrophage molecule for use in treating a disease or disorder.
Dependencies are inferred from the claim text.