DISRUPTING TUMOR TISSUES BY TARGETING FIBROBLAST ACTIVATION PROTEIN (FAP)

1 . A chimeric antigen receptor (CAR) comprising an antigen-binding domain capable of binding Fibroblast Activation Protein (FAP), a transmembrane domain, and an intracellular domain, wherein the antigen-binding domain comprises:

a heavy chain variable region that comprises three heavy chain complementarity determining regions (HCDRs), wherein HCDR1 comprises the amino acid sequence YTJTSYSLH (SEQ ID NO: 1), HCDR2 comprises the amino acid sequence EINPANGDHNFSEKFEIK (SEQ ID NO: 2), and HCDR3 comprises the amino acid sequence LDDSRFHWYFDV (SEQ ID NO: 3); and

a light chain variable region that comprises three light chain complementarity determining regions (LCDRs), wherein LCDR1 comprises the amino acid sequence TASSSVSYMY (SEQ ID NO: 4), a LCDR2 comprises the amino acid sequence LTSNLA (SEQ ID NO: 5), and LCDR3 comprises the amino acid sequence QQWSGYPPIT (SEQ ID NO: 6).

2 . The CAR of claim 1 , wherein the antigen-binding domain comprises:

(a) a heavy chain variable region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 7; and/or

(b) a light chain variable region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 9.

3 . The CAR of claim 1 , wherein the CAR further comprises a CD8 alpha hinge domain.

4 . The CAR of claim 1 , wherein the transmembrane domain:

is an artificial hydrophobic sequence, a transmembrane domain of a type I transmembrane protein, an alpha, beta, or zeta chain of a T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, OX40 (CD134), 4-1BB (CD137), ICOS (CD278), CD154, or a killer immunoglobulin-like receptor (KIR).

5 . The CAR of claim 1 , wherein the intracellular domain

comprises a costimulatory signaling domain and an intracellular signaling domain;

wherein the costimulatory domain is of a protein in the TNFR superfamily, CD28, 4-1BB (CD137), OX40 (CD134), PD-1, CD7, LIGHT, CD83L, DAP10, DAP12, CD27, CD2, CD5, ICAM-1, LFA-1, Lck, TNFR-I, TNFR-II, Fas, CD30, CD40, ICOS (CD278), NKG2C, B7-H3 (CD276), or a killer immunoglobulin-like receptor (KIR); and wherein the intracellular domain is a cytoplasmic signaling domain of a human CD3 zeta chain (CD3ζ), FcγRIII, FcsRI, a cytoplasmic tail of an Fc receptor, an immunoreceptor tyrosine-based activation motif (ITAM) bearing cytoplasmic receptor, TCR zeta, FcR gamma, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, or CD66d.

6 . The CAR of claim 1 , wherein the CAR comprises an amino acid sequence at least 95% identical to SEQ ID NO: 23 or 25.

7 .- 18 . (canceled)

19 . A method of treating a disease in a subject in need thereof, comprising administering to the subject an effective amount of a modified cell comprising the CAR of claim 1 .

20 . The method of claim 19 , wherein

the disease is selected from the group consisting of an immunological disease, a hematological disease, an autoimmune disease, fibrosis, and cancer.

21 . The method of 20, wherein the disease is cancer, wherein the cancer comprises a FAP-expressing cancer-associated cell, and wherein:

(a) the FAP-expressing cancer-associated cell is a cancer-associated fibroblast (CAF);

(b) the FAP-expressing cancer-associated cell is a FAP-expressing adipocyte;

(c) the FAP-expressing cancer-associated cell is a tumor-associated macrophage (TAM);

(d) the FAP-expressing cancer-associated cell is a tumor-associated neutrophil (TAN);

(e) the FAP-expressing cancer-associated cell is a myeloid-derived suppressor cell (MDSC); or

(f) the FAP-expressing cancer-associated cell is a cancer-initiating cell.

22 . The method of claim 20 , wherein the disease is cancer, and wherein the CAR comprises:

a heavy chain variable region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 7; and

a light chain variable region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 9.

23 . The method of claim 20 , wherein the disease is cancer, wherein

(a) the cancer is associated with fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts;

(b) the cancer is associated with fibroblast activation protein (FAP)-expressing cancer-associated macrophages; or

(c) the cancer is associated with fibroblast activation protein (FAP)-expressing cancer-associated neutrophils,

and wherein the CAR comprises:

a heavy chain variable region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 7; and

a light chain variable region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 9.

24 . The method of claim 20 , wherein the disease is cancer, wherein

(a) the cancer is associated with fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts;

(b) the cancer is associated with fibroblast activation protein (FAP)-expressing cancer-associated macrophages; or

(c) the cancer is associated with fibroblast activation protein (FAP)-expressing cancer-associated neutrophils,

and wherein the CAR comprises an amino acid sequence at least 95% identical to SEQ ID NO: 23 or 25.

25 . The method of claim 23 , wherein the cancer comprises a solid tumor.

26 . The method of claim 19 , further comprising administering an immune checkpoint inhibitor, tumor antigen vaccine, or neoplastic cell targeted therapies.

27 . The method of claim 19 , wherein the subject is a human or a non-human animal.

28 . The method of claim 21 , wherein the cancer-associated fibroblast (CAF) is a stromal fibroblast.