# US 10,946,045 B2 · Processes for production of tumor infiltrating lymphocytes and uses of same in immunotherapy

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- Number: US 10,946,045 B2
- Document ID: US10946045B2
- Status: Granted
- Kind: B2
- Application number: 16/848,474
- Filed: 2020-04-14
- Published: 2020-09-10
- Granted: 2021-03-16
- Earliest claimed: 2017-03-29
- Assignees: Iovance Biotherapeutics, Inc.
- Applicants: Iovance Biotherapeutics, Inc.
- Inventors: Seth Wardell; James Bender; Michael T. Lotze
- Web page: https://patentgrep.com/patent/US10946045B2

## CPC

- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- A01N 1/162: Temperature processes, e.g. following predefined temperature changes over time
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61K 38/2013: {IL-2}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/428: {Undefined tumor antigens, e.g. tumor lysate or antigens targeted by cells isolated from tumor}
- A61P 35/00: Antineoplastic agents
- C12N 5/0634: {Cells from the blood or the immune system}
- C12N 5/0636: {T lymphocytes}
- C12N 5/0638: {Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]}
- A61K 38/217: {IFN-gamma}
- A61K 39/0011: {Cancer antigens}
- A61K 40/50: characterised by the use of allogeneic cells
- A61K 2039/5154: {Antigen presenting cells [APCs], e.g. dendritic cells or macrophages}
- A61K 2039/5156: {expressing foreign proteins}
- A61K 2039/5158: {Antigen-pulsed cells, e.g. T-cells}
- A61K 2039/55533: {IL-2}
- C12N 2500/90: Serum-free medium, which may still contain naturally-sourced components
- C12N 2501/04: Immunosuppressors, e.g. cyclosporin, tacrolimus
- C12N 2501/2302: Interleukin-2 (IL-2)
- C12N 2501/2315: Interleukin-15 (IL-15)
- C12N 2501/2321: Interleukin-21 (IL-21)
- C12N 2501/24: Interferons [IFN]
- C12N 2501/603: Oct-3/4
- C12N 2502/11: blood or immune system cells
- C12N 2506/30: from cancer cells, e.g. reversion of tumour 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)
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- 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

The present invention provides improved and/or shortened methods for expanding TILs and producing therapeutic populations of TILs, including novel methods for expanding TIL populations in a closed system that lead to improved efficacy, improved phenotype, and increased metabolic health of the TILs in a shorter time period, while allowing for reduced microbial contamination as well as decreased costs. Such TILs find use in therapeutic treatment regimens.

## Claims

### Claim 1

A method for treating a subject with cancer, the method comprising administering to the subject an expanded population of tumor infiltrating lymphocytes (TILs) that exhibit IFN-γ secretion of at least five-fold in vitro as compared to a non-expanded population of TILs.

### Claim 2 (depends on 1)

The method of claim 1, wherein the IFN-γ secretion is measured in vitro by enzyme-linked immunosorbent assay.

### Claim 3 (depends on 1)

The method of claim 1, wherein the expanded population of TILs is capable of increasing IP-10 and/or MCP-1 at least one-fold to at least five-fold in vivo in the treated subject as compared to an untreated subject.

### Claim 4 (depends on 3)

The method of claim 3, wherein the increase in IP-10 is measured as an increase in the blood of the treated subject.

### Claim 5 (depends on 3)

The method of claim 3, wherein the increase in MCP-1 is measured as an increase in the blood of the treated subject.

### Claim 6 (depends on 1)

The method of claim 1, wherein about 1×109 to about 9×1010 TILs are administered to the subject.

### Claim 7 (depends on 1)

The method according to claim 1, wherein prior to administering the expanded population of TILs, a non-myeloablative lymphodepletion regimen has been administered to the subject.

### Claim 8 (depends on 7)

The method according to claim 7, where the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg/m2/day for two days followed by administration of fludarabine at a dose of 25 mg/m2/day for five days.

### Claim 9 (depends on 1)

The method according to claim 1, further comprising the step of treating the subject with a high-dose IL-2 regimen starting on the day after administration of the expanded population of TILs to the subject.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the high-dose IL-2 regimen comprises 600,000 or 720,000 IU/kg administered as a 15-minute bolus intravenous infusion every eight hours until tolerance.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, lung cancer, and head and neck cancer (including head and neck squamous cell carcinoma (HNSCC)).

### Claim 12 (depends on 11)

The method according to claim 11, wherein the cancer is melanoma.

### Claim 13 (depends on 11)

The method according to claim 11, wherein the cancer is cervical cancer.

### Claim 14 (depends on 11)

The method according to claim 11, wherein the cancer is lung cancer.

### Claim 15 (depends on 11)

The method according to claim 11, wherein the cancer is head and neck cancer (including head and neck squamous cell carcinoma (HNSCC)).