# US 10,548,930 B2 · Use of MVA or MVAΔE3L as immunotherapeutic agents against solid tumors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,548,930 B2
- Document ID: US10548930B2
- Status: Granted
- Kind: B2
- Application number: 15/565,609
- Filed: 2016-04-18
- Published: 2018-03-22
- Granted: 2020-02-04
- Earliest claimed: 2015-04-17
- Assignees: Memorial Sloan Kettering Cancer Center
- Applicants: Memorial Sloan Kettering Cancer Center
- Inventors: Liang Deng; Jedd Wolchok; Taha Merghoub; Stewart Shuman; Peihong Dai; Weiyi Wang
- Web page: https://patentgrep.com/patent/US10548930B2

## CPC

- A61K 35/768: Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
- A61K 39/12: Viral antigens
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/525: {Virus}
- A61K 2039/5254: {avirulent or attenuated}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/57: {characterised by the type of response, e.g. Th1, Th2}
- C12N 2710/24122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2710/24132: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- C12N 2710/24134: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2710/24171: Demonstrated in vivo effect
- 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
- 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)
- 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 disclosure relates to modified vaccinia Ankara (MVA) virus or MVAAE3L delivered intratumorally or systemically as an anticancer immunotherapeutic agent, alone, or in combination with one or more immune checkpoint blocking agents for the treatment of malignant solid tumors. Particular embodiments relate to mobilizing the host's immune system to mount an immune response against the tumor.

## Claims

### Claim 1

A method for treating a malignant solid tumor in a subject in need thereof, the method comprising delivering to the cells of the tumor a therapeutically effective amount of a modified vaccinia Ankara virus with deletion of vaccinia virulence factor E3 (MVAΔE3L), thereby resulting in the treatment of the tumor, wherein the tumor is melanoma or colon carcinoma.

### Claim 2 (depends on 1)

The method of claim 1, wherein the treatment comprises one or more of the following:
inducing the immune system of the subject to mount an immune response against the tumor or enhance an ongoing response by the immune system against the tumor;
reducing the size of the tumor;
eradicating the tumor;
inhibiting growth of the tumor;
inhibiting metastasis of the tumor;
reducing or eradicating metastatic tumor;
inducing apoptosis of the tumor cells; and
prolonging survival of the subject
as compared to an untreated control subject.

### Claim 3 (depends on 1)

The method of claim 1, wherein the delivery of MVAΔE3L elicits an antitumor immune response comprising one or more of the following:
increasing at least one of antitumor cytotoxic CD8+ T cells and effector CD4+ T cells within the tumor and/or in tumor-draining lymph nodes;
inducing maturation of dendritic cells infiltrating the tumor through induction of type I IFN;
reducing immune suppressive (regulatory) CD4+ T cells within the tumor;
reducing immune suppressive tumor-associated macrophages (TAMs) within the tumor; and
inducing type I IFN, inflammatory cytokine and chemokine production in immune cells and stromal fibroblasts
as compared to an untreated control subject.

### Claim 4 (depends on 1)

The method of claim 1, wherein the MVAΔE3L is not harboring nucleic acid encoding or expressing a tumor antigen.

### Claim 5 (depends on 1)

The method of claim 1, wherein the tumor includes tumor located at the site MVAΔE3L delivery, or tumor located elsewhere in the body of the subject, or tumor located both at the site and elsewhere in the body of the subject.

### Claim 6 (depends on 1)

The method of claim 1, wherein the MVAΔE3L delivered to the cells is effective to recruit and activate CD4+ effector T cells accompanied by a reduction of regulatory CD4+ cells in the tumor.

### Claim 7 (depends on 1)

The method of claim 1, wherein the MVAΔE3L is delivered parenterally, intratumorally, intravenously, or intraperitoneally.

### Claim 8 (depends on 1)

The method of claim 1, wherein the MVAΔE3L is delivered at a dosage per administration of about 105 to about 1010 plaque-forming units (pfu).

### Claim 9 (depends on 1)

The method of claim 1, wherein the delivery is repeated with a frequency within the range from once per month to once per week or more, and continues for several weeks, months, or years, or indefinitely until a maximum tolerated dose is reached.

### Claim 10 (depends on 1)

The method of claim 1, wherein the MVAΔE3L induces type I interferon in infected tumor cells.

### Claim 11

A method for treating a malignant tumor in a subject in need thereof, the method comprising delivering to tumor cells of the subject a therapeutically effective amount of a modified vaccinia Ankara virus with deletion of vaccinia virulence factor E3 (MVAΔE3L), and conjointly administering to the subject a therapeutically effective amount of an immune checkpoint blocking agent or an immune checkpoint agonist, wherein the tumor is melanoma or colon carcinoma.

### Claim 12 (depends on 11)

The method of claim 11, wherein the MVAΔE3L is delivered parenterally, intratumorally, intravenously, and/or intraperitoneally to the subject, and wherein the immune checkpoint blocking agent or immune checkpoint agonist is administered parenterally, intratumorally, intravenously, and/or intraperitoneally to the subject.

### Claim 13 (depends on 11)

The method of claim 11, wherein the immune checkpoint blocking agent is selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, inhibitory antibodies against LAG-3 (lymphocyte activation gene 3), TIM3 (T cell Immunoglobulin and Mucin-3), B7-H3, and TIGIT (T-cell immunoreceptor with Ig and ITIM domains); and the immune checkpoint agonist is selected from the group consisting of anti-ICOS antibody, anti-OX40 antibody, agonist antibody against 4-1BB (CD137), and agonist antibody against GITR.

### Claim 14 (depends on 11)

The method of claim 11, wherein the virus is delivered to the subject separately, sequentially, or simultaneously with the immune checkpoint blocking agent or immune checkpoint agonist.

### Claim 15 (depends on 11)

The method of claim 11, wherein one or both of the virus and the immune checkpoint blocking agent or immune checkpoint agonist are respectively delivered and administered during a period of time of several weeks, months, or years, or indefinitely as long as benefits persist or a maximum tolerated dose is reached.

### Claim 16 (depends on 11)

The method of claim 11, wherein the virus is delivered at a dosage per administration of about 105 to about 1010 plaque-forming units (pfu).

### Claim 17

A composition for use in treating a solid tumor in a subject in need thereof comprising a therapeutically effective amount of a modified vaccinia Ankara virus with deletion of vaccinia virulence factor E3 (MVAΔE3L), and a pharmaceutically acceptable carrier or diluent, wherein the MVAΔE3L does not comprise a heterologous nucleic acid encoding or expressing a tumor antigen, wherein the tumor is melanoma or colon carcinoma.

### Claim 18 (depends on 11)

The method of claim 11, wherein the MVAΔE3L does not comprise a heterologous nucleic acid encoding or expressing a tumor antigen.