# US 11,078,277 B2 · Methods and pharmaceutical compositions for enhancing CD8+ T cell-dependent immune responses in subjects suffering from cancer

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- Number: US 11,078,277 B2
- Document ID: US11078277B2
- Status: Granted
- Kind: B2
- Application number: 16/074,555
- Filed: 2017-02-01
- Published: 2019-01-31
- Granted: 2021-08-03
- Earliest claimed: 2016-02-02
- Assignees: Inserm (Institut National De La Sante Et De La Recherche Medicale); Universite Paul Sabatier Toulouse III; Centre Hospitalier Universitaire De Toulouse
- Applicants: Inserm (Institut National De La Sante Et De La Recherche Medicale); Universite Paul Sabatier Toulouse III; Centre Hospitalier Universitaire De Toulouse
- Inventors: Thierry Levade; Bruno Segui; Florie Bertrand; Julia Rochotte; Anne Montfort; Nathalie Andrieu-Abadie; Celine Colacios Viatge; Nicolas Meyer
- Web page: https://patentgrep.com/patent/US11078277B2

## CPC

- C07K 16/2815: {against CD8}
- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/465: {acting on ester bonds (3.1), e.g. lipases, ribonucleases}
- A61K 39/001111: {Immunoglobulin superfamily}
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C12N 9/16: acting on ester bonds (3.1)
- C12Y 301/04012: Sphingomyelin phosphodiesterase (3.1.4.12)
- G01N 33/56972: {White blood cells}
- A61K 2039/505: {comprising antibodies}
- G01N 2333/70517: CD8
- 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)
- C12Y: ENZYMES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to methods and pharmaceutical compositions for enhancing CD8+ T cell-dependent immune responses in subjects suffering from cancer. In particular, the present invention relates to a method of enhancing the CD8+ T cell-dependent immune response in a subject suffering from cancer comprising administering to the subject a therapeutically effective amount of an agent capable of increasing intra-tumoral ceramide content.

## Claims

### Claim 1

A method of enhancing the CD8+ T cell-dependent immune response in a subject suffering from cancer characterized by a low tumor infiltration of CD8+ T cells, said method comprising administering to the subject a therapeutically effective amount of a vector comprising a polynucleotide encoding a neutral sphingomyelinase 2 (nSMase 2) polypeptide, wherein said nSMase 2 polypeptide is capable of increasing intra-tumoral ceramide content, wherein the CD8+ T cell-dependent immune response is enhanced.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject suffers from a cancer selected from the group consisting of neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous; adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; and roblastoma, malignant; Sertoli cell carcinoma; Leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject suffers from a melanoma, a melanoma resistant to BRAF inhibitors, or a melanoma with elevated plasma lactate dehydrogenase (LDH).

### Claim 4

A method of treating cancer characterized by a low tumor infiltration of CD8+ T cells in a subject in need thereof, said method comprising administering to the subject a therapeutically effective combination of an immune checkpoint inhibitor and a vector comprising a polynucleotide encoding a neutral sphingomyelinase 2 (nSMase 2) polypeptide, wherein said nSMase 2 polypeptide is capable of increasing intra-tumoral ceramide content, wherein administration of the combination results in enhanced therapeutic efficacy relative to the administration of the immune checkpoint inhibitor alone, wherein the cancer is treated.

### Claim 5 (depends on 4)

The method of claim 4, wherein the immune checkpoint inhibitor is an antibody selected from the group consisting of anti-CTLA4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies anti-TIM-3 antibodies, anti-LAG3 antibodies, anti-B7H3 antibodies, anti-B7H4 antibodies, anti-BTLA antibodies, and anti-B7H6 antibodies.

### Claim 6

A method of treating cancer in a subject in need thereof comprising i) quantifying the density of CD8+ T cells in a tumor tissue sample obtained from the subject, ii) comparing the density quantified at step i) with a predetermined reference value established by measurement of cell densities in historical patient samples, and iii), and when the density quantified at step i) is lower than the predetermined reference value, administering to the subject a therapeutically effective amount of a vector comprising a polynucleotide encoding a neutral sphingomyelinase 2 (nSMase 2) polypeptide, wherein said nSMase 2 polypeptide is capable of increasing intra-tumoral ceramide content, wherein said cancer is treated.

### Claim 7

A method of treating cancer in a subject in need thereof comprising i) quantifying the density of CD8+ T cells in a tumor tissue sample obtained from the subject ii) comparing the density quantified at step i) with a predetermined reference value established by measurement of cell densities in historical patient samples, and iii) and when the density quantified at step i) is lower than the predetermined reference value, administering to the subject a therapeutically effective combination of an immune checkpoint inhibitor and a vector comprising a polynucleotide encoding a neutral sphingomyelinase 2 (nSMase 2) polypeptide when the density quantified at step i) is lower than the predetermined reference value, wherein said nSMase 2 polypeptide is capable of increasing intra-tumoral ceramide content, wherein administration of the combination results in enhanced therapeutic efficacy relative to the administration of the immune checkpoint inhibitor alone, and wherein said cancer is treated.

### Claim 8

A method of enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen, the method comprising administering a pharmaceutically effective amount of a vector comprising a polynucleotide encoding a neutral sphingomyelinase 2 (nSMase 2) polypeptide and the immune checkpoint inhibitor to a subject, wherein said nSMase 2 polypeptide is capable of increasing intra-tumoral ceramide content, and wherein administration of the combination results in enhanced therapeutic efficacy relative to the administration of the immune checkpoint inhibitor alone.