Methods and pharmaceutical compositions for enhancing CD8+ T cell-dependent immune responses in subjects suffering from cancer

Patent metadata

Field	Value
Publication number	US-11078277-B2
Application number	US-201716074555-A
Country	US
Kind code	B2
Filing date	Feb 1, 2017
Priority date	Feb 2, 2016
Publication date	Aug 3, 2021
Grant date	Aug 3, 2021

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.

First claim

The invention claimed is:

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.

2. 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.

3. 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).

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.

5. 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.

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.

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.

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

Assignees

• Inst Nat Sante Rech Med
• Univ Toulouse 3 Paul Sabatier
• Ct Hospitalier Universitaire Toulouse

Inventors

• Levade Thierry
• Segui Bruno
• Bertrand Florie
• Rochotte Julia
• Montfort Anne
• Andrieu-Abadie Nathalie
• Colacios Viatge Celine
• Meyer Nicolas

Classifications

• A61K38/465 Primary

  acting on ester bonds (3.1), e.g. lipases, ribonucleases · CPC title

• A61K39/001111

  Immunoglobulin superfamily · CPC title

• G01N2333/70517

  CD8 · CPC title

• C12N9/16

  acting on ester bonds (3.1) · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title