# US 2021/0277480 A1 · Methods for the detection and treatment of classes of hepatocellular carcinoma responsive to immunotherapy

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- Number: US 2021/0277480 A1
- Document ID: US20210277480A1
- Status: Published application
- Kind: A1
- Application number: 16/621,983
- Filed: 2018-06-14
- Published: 2021-09-09
- Earliest claimed: 2017-06-14
- Assignees: Icahn School of Medicine at Mount Sinai
- Applicants: Icahn School of Medicine at Mount Sinai
- Inventors: Daniela Sia; Josep Maria Llovet I Bayer; Augusto Villanueva-Rodriguez
- Web page: https://patentgrep.com/patent/US20210277480A1

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 2039/505: {comprising antibodies}
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/158: Expression markers
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- 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)

## Abstract

The present invention relates to methods for detecting, diagnosing, prognosing, monitoring, and treating a patient with hepatocellular carcinoma. In particular, the invention provides diagnostic markers for the detection and treatment of patients who would benefit from immunotherapy, i.e., patient who would be most responsive to immunotherapy.

## Claims

### Claim at position 1

-6. (canceled)

### Claim 7

A method of treating a subject with hepatocellular carcinoma, comprising
a. assaying gene expression levels of one or more genes in Table 3 in a sample from the subject with hepatocellular carcinoma to obtain a test expression profile;
b. comparing the test expression profile of the genes with a reference expression profile, wherein the reference expression profile comprises a reference expression level of the same genes in a sample from a control;
c. detecting the gene expression levels of one or more genes in the test expression profile are the same as compared to expression level of the same genes in the reference expression profile that is indicative of immunotherapy responsive phenotype; and
d. treating the subject with immunotherapy.

### Claim 8 (depends on 7)

The method of claim 7, wherein the subject has recently been diagnosed with hepatocellular carcinoma (HCC).

### Claim 9 (depends on 7)

The method of claim 7, wherein the sample is from a hepatocellular carcinoma tumor.

### Claim 10 (depends on 7)

The method of claim 7, wherein the control is selected from the group consisting of a subject with hepatocellular carcinoma who has responded favorably to immunotherapy and a subject with another form of cancer who has responded favorably to immunotherapy.

### Claim 11

(canceled)

### Claim 12 (depends on 10)

The method of claim 10, wherein the cancer is lung cancer or melanoma.

### Claim 13 (depends on 7)

The method of claim 7, wherein the immunotherapy is selected from the group consisting of monoclonal antibodies directed against the cytotoxic T-lymphocyte protein (CTLA-4), the programmed cell death protein 1 (PD-1) and its ligand PD-L1, and combinations thereof.

### Claim 14

A method of treating a subject with hepatocellular carcinoma, comprising
a. assaying gene expression levels of one or more genes in Table 3 in a sample from the subject with hepatocellular carcinoma to obtain a first test expression profile;
b. comparing the first test expression profile of the one or more genes in Table 3 with a first reference expression profile, wherein the first reference expression profile comprises a reference expression level of the same genes in a sample from a control;
c. detecting the gene expression levels of one or more genes in the first test expression profile are the same as compared to expression level of the same genes in the first reference expression profile that is indicative of immunotherapy responsive phenotype and further detecting that the subject would be responsive to immunotherapy;
d. assaying the gene expression levels of one or more genes in FIG. 12 in a sample from the subject with hepatocellular carcinoma to obtain a second test expression profile;
e. comparing the second expression profile of the one or more gene pathways in FIG. 12 with a second reference expression profile, wherein the second expression profile comprises a reference expression level of the same genes in a sample from a control;
f. detecting the gene expression levels of one or more genes in the first test expression profile are the same as compared to expression level of the same genes in the second reference expression profile that is indicative of the Exhausted Immune Response class; and
g. treating the subject with a combination of immunotherapy and a second agent.

### Claim 15 (depends on 14)

The method of claim 14, wherein the subject has recently been diagnosed with hepatocellular carcinoma (HCC).

### Claim 16 (depends on 14)

The method of claim 14, wherein the sample is from a hepatocellular carcinoma tumor.

### Claim 17 (depends on 14)

The method of claim 14, wherein the control is selected from the group consisting of a subject with hepatocellular carcinoma who has responded favorably to immunotherapy and a subject with another form of cancer who has responded favorably to immunotherapy.

### Claim 18

(canceled)

### Claim 19 (depends on 17)

The method of claim 17, wherein the cancer is lung cancer or melanoma.

### Claim 20 (depends on 14)

The method of claim 14, wherein the immunotherapy is selected from the group consisting of monoclonal antibodies directed against the cytotoxic T-lymphocyte protein (CTLA-4), the programmed cell death protein 1 (PD-1), and its ligand PD-L1, and combinations thereof.

### Claim 21 (depends on 14)

The method of claim 14, wherein the gene which is increased in step (f) is selected from the group consisting of TGF-β, PMEPA1, LGALS1, LGALS3, a gene from the CTNNB1 signaling pathway and combinations thereof.

### Claim 22 (depends on 14)

The method of claim 14, wherein the second agent is selected from the group consisting of a TGF-β inhibitor and a CTNNB1 signaling pathway inhibitor.

### Claim 23 (depends on 14)

The method of claim 14, wherein the gene from the CTNNB1 signaling pathway is chosen from the group consisting of CCL4, PTK2 and combinations thereof.

### Claim 24 (depends on 14)

The method of claim 14, wherein the second agent is a chemotherapy agent or radiation.

### Claim at position 20

-35. (canceled)

### Claim 36

A kit for the detection of a phenotype that is responsive to immunotherapy in a subject diagnosed with hepatocellular carcinoma, comprising probes for one or more of the genes listed in Table 3, reagents for isolating and purifying nucleic acids from biological tissue or bodily fluid, reagents for performing assays on the isolated and purified nucleic acid, instructions for use, and reference values or the means for obtaining reference values in a control sample for the included genes.

### Claim 37 (depends on 36)

The kit of claim 36, further comprising probes for one or more of the genes listed in FIG. 12.

### Claim 38 (depends on 37)

The kit of claim 37, wherein the probes are attached to a solid state in a microarray format.