# US 11,111,301 B2 · T cell modification and use thereof

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- Number: US 11,111,301 B2
- Document ID: US11111301B2
- Status: Granted
- Kind: B2
- Application number: 15/998,475
- Filed: 2018-08-15
- Published: 2019-04-04
- Granted: 2021-09-07
- Earliest claimed: 2017-08-15
- Assignees: Adaptimmune Limited
- Applicants: Adaptimmune Limited
- Inventors: Garth Hamilton; Jonathan Silk; Claire Gueguen
- Web page: https://patentgrep.com/patent/US11111301B2

## CPC

- C07K 16/2833: {against MHC-molecules, e.g. HLA-molecules}
- A61K 39/0011: {Cancer antigens}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/32: T-cell receptors [TCR]
- A61K 40/4265: {Alpha-feto protein}
- A61K 40/4268: {MAGE}
- A61K 40/4269: {NY-ESO}
- A61K 40/427: {PRAME}
- A61P 35/00: Antineoplastic agents
- C07K 14/4748: {Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE}
- C07K 14/5418: {IL-7}
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 16/244: {Interleukins [IL]}
- C07K 16/30: from tumour cells
- C12N 5/0636: {T lymphocytes}
- A61K 2039/5156: {expressing foreign proteins}
- A61K 2039/5158: {Antigen-pulsed cells, e.g. T-cells}
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- 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)
- 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)
- 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

This invention relates to modified T cells that inducibly express a bioactive molecule, such as IL-7, and constitutively expresses an antigen receptor, such as a T cell receptor or chimeric antigen receptor that binds to a tumour antigen. The modified T cells may comprise a nucleic acid construct that comprises a first nucleotide sequence encoding the bioactive molecule, a second nucleotide sequence encoding the antigen receptor; an inducible promoter operably linked to the first nucleotide sequence and a constitutive promoter operably linked to the second nucleotide. Nucleic acid constructs and vectors are provided, as well as T cells comprising such constructs and vectors and therapeutic methods and uses thereof.

## Claims

### Claim 1

A method of treating cancer using immunotherapy, comprising administering to a patient having cancer a population of modified T cells comprising a nucleic acid construct, wherein the cancer expresses one or more tumor antigens selected from NY-ESO1, PRAME, alpha-fetoprotein (AFP), MAGE A4, MAGE A1, MAGE A10 and MAGE B2; and wherein the nucleic acid construct comprises:
(i) a first nucleotide sequence encoding IL 7,
(ii) a second nucleotide sequence encoding an antigen receptor, wherein the antigen receptor is a chimeric antigen receptor (CAR) that binds to said one or more tumor antigens, or a T cell receptor (TCR) that binds to an MHC-displayed peptide fragment of said one or more tumor antigens;
(iii) an inducible promoter operably linked to the first nucleotide sequence; and
(iv) a constitutive promoter operably linked to the second nucleotide sequence wherein the administration of said modified T cells results in the treatment of the patient's cancer.

### Claim 2 (depends on 1)

The method according to claim 1 wherein expression from the inducible promoter is induced by activation of the modified T cells.

### Claim 3 (depends on 1)

The method according to claim 1 wherein the inducible promoter comprises a nuclear factor of activated T cells (NFAT) transcriptional response element (TRE).

### Claim 4 (depends on 3)

The method according to claim 3 wherein the NFAT TRE has the nucleic acid sequence of SEQ ID NO: 14 or a variant thereof.

### Claim 5 (depends on 3)

The method according to claim 3 wherein the inducible promoter comprises three or more copies of the NFAT TRE.

### Claim 6 (depends on 1)

The method according to claim 1 wherein the nucleic acid construct comprises the sequence of SEQ ID NO: 1.

### Claim 7 (depends on 1)

The method according to claim 1 wherein the constitutive promoter is the Human elongation factor-1 alpha promoter.

### Claim 8 (depends on 1)

The method according to claim 1 wherein the IL-7 is human IL-7.

### Claim 9 (depends on 1)

The method according to claim 1 wherein the TCR comprises the amino acid sequence of any one of SEQ ID NOs: 5, 6 or 11.

### Claim 10 (depends on 1)

The method according to claim 1 wherein the tumour antigen is NY-ESO-1 and the method is for treatment of cancer expressing NY-ESO-1.

### Claim 11 (depends on 1)

The method according to claim 1 wherein the nucleic acid construct is provided in a vector.

### Claim 12 (depends on 11)

The method according to claim 11 wherein the vector is a lentiviral vector.

### Claim 13 (depends on 1)

The method according to claim 1 wherein the cancer is characterized by the presence of one or more cancer cells which bind to said antigen receptor.

### Claim 14 (depends on 1)

The method according to claim 1 wherein the modified T cells are autologous to the patient.

### Claim 15 (depends on 1)

The method according to claim 1 wherein the modified T cells are allogeneic to the patient.

### Claim 16 (depends on 1)

The method according to claim 1 wherein the tumor antigen is MAGE-A10 and the method is for treatment of cancer expressing MAGE-A10.

### Claim 17 (depends on 1)

The method according to claim 1 wherein the tumour antigen is NY-ESO-1 or MAGE-A10.

### Claim 18 (depends on 17)

The method according to claim 17 wherein the method is for treatment of cancer expressing NY-ESO-1 or MAGE-A10.