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

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.

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.

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.

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.