# US 10,117,897 B2 · Constitutive expression of costimulatory ligands on adoptively transferred T lymphocytes

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- Number: US 10,117,897 B2
- Document ID: US10117897B2
- Status: Granted
- Kind: B2
- Application number: 14/734,969
- Filed: 2015-06-09
- Published: 2016-01-14
- Granted: 2018-11-06
- Earliest claimed: 2007-03-30
- Assignees: Memorial Sloan Kettering Cancer Center
- Applicants: Memorial Sloan-Kettering Cancer Center
- Inventors: Michel Sadelain; Matthias Stephan
- Web page: https://patentgrep.com/patent/US10117897B2

## CPC

- C12N 5/0636: {T lymphocytes}
- A61K 38/2013: {IL-2}
- A61K 38/217: {IFN-gamma}
- 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 40/4224: {Molecules with a "CD" designation not provided for elsewhere}
- A61K 40/4276: {Prostate specific membrane antigen [PSMA]}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 31/22: for herpes viruses
- A61P 33/00: Antiparasitic agents
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 15/85: for animal cells
- A61K 2035/122: {for inducing tolerance or supression of immune responses}
- A61K 2035/124: {the cells being hematopoietic, bone marrow derived or blood cells}
- A61K 2239/31: characterized by the route of administration
- C12N 2501/25: Tumour necrosing factors [TNF]
- C12N 2501/51: B7 molecules, e.g. CD80, CD86, CD28 (ligand), CD152 (ligand)
- C12N 2501/599: with CD designations not provided for elsewhere
- C12N 2510/00: Genetically modified cells
- C12N 2799/04: in vivo
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention provides immunoresponsive cells, including T cells, cytotoxic T cells, regulatory T cells, and Natural Killer (NK) cells, expressing at least one of an antigen-recognizing receptor and a co-stimulatory ligand and methods of use therefore for the treatment of neoplasia and other pathologies where an increase in an antigen-specific immune response is desired.

## Claims

### Claim 1

An immunoresponsive cell comprising:
a) a receptor that binds to an antigen, and
b) a nucleic acid encoding a recombinant co-stimulatory ligand, wherein the co-stimulatory ligand is a heterologously expressed cytokine, wherein the cytokine is selected from the group consisting of an IL-2, an IL-12 and an IL-21, and wherein the receptor is selected from a group consisting of a chimeric antigen receptor (CAR) and a T cell receptor (TCR).

### Claim 2 (depends on 1)

The immunoresponsive cell of claim 1, wherein the cell is a T cell.

### Claim 3 (depends on 1)

The immunoresponsive cell of claim 1, wherein the cytokine is an IL-12.

### Claim 4 (depends on 2)

The immunoresponsive cell of claim 2, wherein the cell comprises a cytotoxic T lymphocyte.

### Claim 5 (depends on 1)

The immunoresponsive cell of claim 1, wherein the nucleic acid is comprised on a vector.

### Claim 6 (depends on 5)

The immunoresponsive cell of claim 5, wherein the vector is a viral vector.

### Claim 7 (depends on 6)

The immunoresponsive cell of claim 6, wherein the vector is a retroviral vector.

### Claim 8 (depends on 7)

The immunoresponsive cell of claim 7, wherein the retroviral vector is a gamma-retroviral vector or a lentiviral vector.

### Claim 9 (depends on 1)

The immunoresponsive cell of claim 1, wherein the antigen is a tumor antigen.

### Claim 10 (depends on 9)

The immunoresponsive cell of claim 9, wherein the tumor antigen is expressed by a solid tumor.

### Claim 11 (depends on 10)

The immunoresponsive cell of claim 10, wherein the solid tumor is selected from the group consisting of prostate cancer, colon cancer, breast cancer, ovarian cancer, and glioblastoma.

### Claim 12 (depends on 9)

The immunoresponsive cell of claim 9, wherein the tumor antigen is selected from the group consisting of prostate-specific membrane antigen (PSMA), Carcinoembryonic Antigen (CEA), IL13Rα, Her-2, CD19, NY-ESO-1, Lewis Y, Mart-1, gp100, tyrosinase, WT-1, hTERT, and mesothelin.

### Claim 13 (depends on 9)

The immunoresponsive cell of claim 9, wherein the tumor antigen is expressed by a tumor expressing prostate-specific membrane antigen (PSMA), Carcinoembryonic Antigen (CEA), IL13Rα, Her-2, CD19, NY-ESO-1, Lewis Y, Mart-1, gp100, tyrosinase, WT-1, hTERT, or mesothelin.

### Claim 14 (depends on 1)

The immunoresponsive cell of claim 1, wherein the receptor is a chimeric antigen receptor (CAR).

### Claim 15 (depends on 14)

The immunoresponsive cell of claim 14, wherein the CAR comprises a ζ chain signaling domain.

### Claim 16 (depends on 14)

The immunoresponsive cell of claim 14, wherein the CAR further comprises a domain that provides a costimulatory signal.

### Claim 17 (depends on 14)

The immunoresponsive cell of claim 14, wherein the CAR comprises a CD28 signaling element.

### Claim 18 (depends on 17)

The immunoresponsive cell of claim 17, wherein the CAR is P28z.

### Claim 19 (depends on 1)

The immunoresponsive cell of claim 1, wherein the immunoresponsive cell is a T cell, the cytokine comprises an IL-12, and the antigen is expressed by a solid tumor selected from the group consisting of prostate cancer, colon cancer, breast cancer, ovarian cancer, and glioblastoma.

### Claim 20 (depends on 19)

The immunoresponsive cell of claim 19, wherein the receptor is a CAR.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising an effective amount of the immunoresponsive cell of claim 1 and a pharmaceutically acceptable carrier or excipient.

### Claim 22 (depends on 2)

A pharmaceutical composition comprising an effective amount of the T cell of claim 2 and a pharmaceutically acceptable carrier or excipient.

### Claim 23 (depends on 19)

A pharmaceutical composition comprising an effective amount of the T cell of claim 19 and a pharmaceutically acceptable carrier or excipient.

### Claim 24 (depends on 1)

A kit comprising the immunoresponsive cell of claim 1 and instructions for administering the cell to a subject having or at risk of developing a neoplasia.

### Claim 25 (depends on 24)

The kit of claim 24, wherein the neoplasia is a solid tumor.

### Claim 26 (depends on 25)

The kit of claim 25, wherein the solid tumor is selected from the group consisting of prostate cancer, colon cancer, breast cancer, ovarian cancer, and glioblastoma.