# US 2020/0399355 A1 · Car-t cells and autoimmune diseases

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- Number: US 2020/0399355 A1
- Document ID: US20200399355A1
- Status: Published application
- Kind: A1
- Application number: 16/968,794
- Filed: 2019-02-11
- Published: 2020-12-24
- Earliest claimed: 2018-02-11
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: JEFFREY A. BLUESTONE; CAROLINE RAFFIN
- Web page: https://patentgrep.com/patent/US20200399355A1

## CPC

- A61K 39/0008: {Antigens related to auto-immune diseases; Preparations to induce self-tolerance}
- C07K 16/18: against material from animals or humans
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/22: Immunosuppressive or immunotolerising
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/416: {Antigens related to auto-immune diseases; Preparations to induce self-tolerance}
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70521: {CD28, CD152}
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C12N 5/0636: {T lymphocytes}
- C12N 5/0637: {Immunosuppressive T lymphocytes, e.g. regulatory T cells or Treg}
- A61K 2035/124: {the cells being hematopoietic, bone marrow derived or blood cells}
- C07K 2317/569: Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2319/02: containing a signal sequence
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- C12N 2501/2302: Interleukin-2 (IL-2)
- C12N 2501/51: B7 molecules, e.g. CD80, CD86, CD28 (ligand), CD152 (ligand)
- C12N 2501/515: CD3, T-cell receptor complex
- C12N 2510/00: Genetically modified cells
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Chimeric antigen receptor (CAR)-expressing Tregs specifically target an antigen present in the joint of RA patients to induce a localized and effective immunosuppressive response.

## Claims

### Claim 1

A chimeric antigen receptor (CAR) comprising an antigen specific binding domain, a hinge domain, a transmembrane domain, co-stimulatory domain, and a CD3ζ signaling domain, wherein the antigen specific binding domain specifically binds to antigens comprising vimentin polypeptides or peptides thereof.

### Claim 2 (depends on 1)

The chimeric antigen receptor of claim 1, wherein the vimentin polypeptides or peptides thereof are posttranslationally modified, comprising citrullinated-vimentin (CV) polypeptides or peptides thereof.

### Claim 3 (depends on 1, 2)

The chimeric antigen receptor of claim 1 or 2, wherein the antigen specific binding domain comprises an antibody, antibody fragment, a camelid nanobody or aptamer.

### Claim 4 (depends on 3)

The chimeric antigen receptor of claim 3, wherein the antibody fragment is a single chain fragment.

### Claim 5 (depends on 4)

The chimeric antigen receptor of claim 4, wherein the single chain fragment is a single chain variable fragment (scFv).

### Claim 6 (depends on 1, 2, 3, 4, 5)

The chimeric antigen receptor of any one of claims 1-5, wherein the co-stimulatory domain comprises a CD28 or a 41BB polypeptide.

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

The chimeric antigen receptor of any one of claims 1-6, wherein:
a) the hinge domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 8;
b) the transmembrane domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 11.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6)

The chimeric antigen receptor of any one of claims 1-6, wherein:
a) the hinge domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 8;
b) the transmembrane domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 11.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6)

The chimeric antigen receptor of any one of claims 1-6, wherein:
a) the hinge domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8;
b) the transmembrane domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6)

The chimeric antigen receptor of any one of claims 1-6, wherein:
a) the hinge domain is encoded by the nucleic acid sequence of SEQ ID NO: 8;
b) the transmembrane domain is encoded by the nucleic acid sequence of SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by the nucleic acid sequence of SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 11.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6)

The chimeric antigen receptor of any one of claims 1-6, wherein:
a) the hinge domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 8;
b) the transmembrane domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 12.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6)

The chimeric antigen receptor of any one of claims 1-6, wherein:
a) the hinge domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 8;
b) the transmembrane domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 12.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6)

The chimeric antigen receptor of any one of claims 1-6, wherein:
a) the hinge domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8;
b) the transmembrane domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6)

The chimeric antigen receptor of any one of claims 1-6, wherein:
a) the hinge domain is encoded by the nucleic acid sequence of SEQ ID NO: 8;
b) the transmembrane domain is encoded by the nucleic acid sequence of SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by the nucleic acid sequence of SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 12.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The chimeric antigen receptor of any one of claims 1-14, wherein the CV-CAR specifically binds to a CV peptide having at least a 50% sequence identity to SEQ ID NO: 21 or 22.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The chimeric antigen receptor of any one of claims 1-14, wherein the CV-CAR specifically binds to a CV peptide having at least a 75% sequence identity to SEQ ID NO: 21 or 22.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The chimeric antigen receptor of any one of claims 1-14, wherein the CV-CAR specifically binds to a CV peptide having at least a 95% sequence identity to SEQ ID NO: 21 or 22.

### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The chimeric antigen receptor of any one of claims 1-14, wherein the CV-CAR specifically binds to a CV peptide comprising SEQ ID NO: 21 or 22.

### Claim 19

An isolated T cell that is modified to express: a chimeric antigen receptor (CAR) comprising an antigen binding domain linked to at least one co-stimulatory domain and a CD3ζ signaling domain, wherein the antigen binding domain comprises a single chain variable fragment (scFv) which specifically binds to citrullinated-vimentin (CV).

### Claim 20 (depends on 19)

The isolated T cell of claim 19, wherein the co-stimulatory domain comprises a CD28 or a 41BB polypeptide.

### Claim 21 (depends on 19, 20)

The isolated T cell of claim 19 or 20, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 11.

### Claim 22 (depends on 19, 20)

The isolated T cell of claim 19 or 20, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 11.

### Claim 23 (depends on 19, 20)

The isolated T cell of claim 19 or 20, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11.

### Claim 24 (depends on 19, 20)

The isolated T cell of claim 19 or 20, wherein:
a) the CAR comprises a hinge domain encoded by the nucleic acid sequence of SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by the nucleic acid sequence of SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by the nucleic acid sequence of SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 11.

### Claim 25 (depends on 19, 20)

The isolated T cell of claim 19 or 20, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 12.

### Claim 26 (depends on 19, 20)

The isolated T cell of claim 19 or 20, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 12.

### Claim 27 (depends on 19, 20)

The isolated T cell of claim 19 or 20, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12.

### Claim 28 (depends on 19, 20)

The isolated T cell of claim 19 or 20, wherein:
a) the CAR comprises a hinge domain encoded by the nucleic acid sequence of SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by the nucleic acid sequence of SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by the nucleic acid sequence of SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 12.

### Claim 29 (depends on 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The isolated T cell of any one of claims 19-28, wherein the T cell is a mammalian regulatory T cell (Treg).

### Claim 30 (depends on 29)

The isolated T cell of claim 29, wherein the Treg cell is CD4+CD25+CD127−FOXP3+.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

An expression vector encoding the chimeric antigen receptor (CAR) of any one of claims 1-18.

### Claim 32 (depends on 31)

A host cell comprising the expression vector of claim 31.

### Claim 33

A method of treating a subject diagnosed with rheumatoid arthritis, comprising:
isolating T lymphocytes from a biological sample obtained from the subject;
separating CD4+ T regulatory Cells (Treg) from conventional T cells (Tconv), wherein the Treg cells are CD4+CD25+CD127− and the Tconv are CD4+CD25−CD127+;
transducing the Treg cells with an expression vector encoding a chimeric antigen receptor (CAR) which specifically binds to a citrullinated-vimentin (CV) antigen;
expanding the transduced Treg with anti-CD3/CD28 beads at least once ex vivo to obtain expanded Treg cells specific for the CV antigen; and
reinfusing the Treg into the subject, thereby treating the subject.

### Claim 34 (depends on 33)

The method of claim 33, wherein the Treg cells are autologous cells.

### Claim 35 (depends on 33, 34)

The method of claim 33 or 34, wherein the CAR comprises an antigen binding domain linked to at least one co-stimulatory domain and a CD3 signaling domain, wherein the antigen binding domain comprises a single chain variable fragment (scFv) which specifically binds to citrullinated-vimentin (CV).

### Claim 36 (depends on 35)

The method of claim 35, wherein the co-stimulatory domain comprises a CD28 or a 41BB polypeptide.

### Claim 37 (depends on 35, 36)

The method of claim 35 or 36, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 11.

### Claim 38 (depends on 35, 36)

The method of claim 35 or 36, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 11.

### Claim 39 (depends on 35, 36)

The method of claim 35 or 36, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 11.

### Claim 40 (depends on 35, 36)

The method of claim 35 or 36, wherein:
a) the CAR comprises a hinge domain encoded by the nucleic acid sequence of SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by the nucleic acid sequence of SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by the nucleic acid sequence of SEQ ID NO: 10; and/or;
d) the CD28 co-stimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 11.

### Claim 41 (depends on 35, 36)

The method of claim 35 or 36, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by a nucleic acid sequence having at least 50% sequence identity to SEQ ID NO: 12.

### Claim 42 (depends on 35, 36)

The method of claim 35 or 36, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by a nucleic acid sequence having at least 75% sequence identity to SEQ ID NO: 12.

### Claim 43 (depends on 35, 36)

The method of claim 35 or 36, wherein:
a) the CAR comprises a hinge domain encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by a nucleic acid sequence having at least 95% sequence identity to SEQ ID NO: 12.

### Claim 44 (depends on 35, 36)

The method of claim 35 or 36, wherein:
a) the CAR comprises a hinge domain encoded by the nucleic acid sequence of SEQ ID NO: 8;
b) the CAR comprises a transmembrane domain encoded by the nucleic acid sequence of SEQ ID NO: 9;
c) the CD3ζ signaling domain is encoded by the nucleic acid sequence of SEQ ID NO: 10; and/or;
d) the 41BB co-stimulatory domain is encoded by the nucleic acid sequence of SEQ ID NO: 12.

### Claim 45 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The method of any one of claims 33-44, further comprising administering to the subject one or more anti-inflammatory agents and/or therapeutic agents.

### Claim 46 (depends on 45)

The method of claim 45, wherein the anti-inflammatory agents comprise one or more antibodies which specifically bind to pro-inflammatory cytokines.

### Claim 47 (depends on 46)

The method of claim 46, wherein the antibodies are anti-TNFα, anti-IL-6 or combinations thereof.

### Claim 48

A chimeric antigen receptor (CAR) comprising an antigen binding domain, a hinge domain, a transmembrane domain, co-stimulatory domain, and a CD3ζ signaling domain, wherein the antigen specific domain comprises an antibody or antibody fragment.

### Claim 49 (depends on 48)

The chimeric antigen receptor of claim 48, wherein the antibody fragment is a single chain variable fragment (scFv) which specifically binds to post-translationally modified antigens.

### Claim 50 (depends on 48, 49)

The chimeric antigen receptor of claim 48 or 49, wherein the co-stimulatory domain comprises a CD28 or a 41BB polypeptide.

### Claim 51 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 48, 49, 50)

A pharmaceutical composition comprising the chimeric antigen receptor (CAR) of any one of claims 1-18 and 48-50, the isolated T cell of any one of claims 19-30, the expression vector of claim 31, or the host cell of claim 32.