Methods for treating heart disease via redirected T cell immunotherapies
The present invention includes compositions and methods for treating heart disease and/or heart failure. In one embodiment, the treatment includes administering to the subject a cell genetically modified to express a chimeric antigen receptor (CAR), comprising an antigen binding domain specific for fibroblast activation protein (FAP). In another embodiment, the treatment includes administering a cell genetically modified to express a T cell receptor (TCR) specific for an activated fibroblast.
1. A method for treating heart disease and/or heart failure in a subject in need thereof, the method comprising administering to the subject a cell genetically modified to express a chimeric antigen receptor (CAR) or a T cell receptor (TCR), wherein the CAR or the TCR comprises an antigen binding domain that specifically binds fibroblast activation protein (FAP) on cardiac fibroblasts, wherein the antigen binding domain comprises six (6) CDRs of an amino acid sequence encoded by a nucleic acid sequence comprising SEQ ID NO: 2, thereby treating the heart disease and/or the heart failure.
2. The method of claim 1 , wherein the heart disease is selected from the group consisting of cardiac fibrosis, hypertensive heart disease, diastolic dysfunction, heart failure with preserved ejection fraction, myocardial infarction, ischemic cardiomyopathy, hypertrophic cardiomyopathy, arrhythmia, atrial fibrillation, arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, an inherited form of heart disease, muscular dystrophy, infective cardiomyopathy, transplant cardiomyopathy, radiation induced cardiac fibrosis, an autoimmune related heart condition, sarcoid cardiomyopathy, lupus, a toxin related heart condition, a drug related heart condition, amyloidosis, diabetic cardiomyopathy, reactive interstitial fibrosis, replacement fibrosis, infiltrative interstitial fibrosis, and endomyocardial fibrosis.
3. The method of claim 1 , wherein the cell is a T cell.
4. The method of claim 1 , wherein the administering comprises adoptive cell transfer.
5. The method of claim 1 , wherein the CAR comprises an amino acid sequence encoded by a nucleic acid sequence comprising SEQ ID NO: 1.
6. The method of claim 1 , wherein the antigen binding domain comprises the amino acid sequence encoded by the nucleic acid sequence comprising SEQ ID NO: 2.
7. The method of claim 1 , wherein the CAR is a switchable CAR.
8. The method of claim 7 , further comprising administering a second agent to the subject to activate the switchable CAR.
9. The method of claim 1 , wherein the heart disease is cardiac fibrosis.
10. The method of claim 1 , wherein the administering comprises administering the cell genetically modified to express the CAR, and wherein the CAR further comprises an intracellular domain comprising a CD28 or 4-1BB signaling domain and a CD3-zeta signaling domain.
11. The method of claim 10 , wherein the intracellular domain comprises the 4-1BB signaling domain and the CD3-zeta signaling domain, wherein the 4-1BB signaling domain comprises an amino acid sequence encoded by the nucleic acid sequence comprising SEQ ID NO: 4, and wherein the CD3-zeta signaling domain comprises an amino acid sequence encoded by the nucleic acid sequence comprising SEQ ID NO: 5.