P21 Expressing Monocytes for Cancer Cell Therapy
Identification of effective targets alleviating the programmed cell removal (PrCR) of tumor cells by macrophages is of very high interest. The present inventors have identified that the cyclin-dependent kinase inhibitor p21 protein is a strong regulator of the macrophage-mediated PrCR. Also, they showed that the adoptive transfer of p21 overexpressing monocytes induces macrophage PrCR and transition from an anti-inflammatory to a pro-inflammatory phenotype in vivo, delays cancer progression and increases significantly the overall survival of mice engrafted with cancer cells. The present invention therefore concerns therapeutic compositions comprising monocytes that over-express the cyclin-dependent kinase inhibitor p21 protein, and their use for treating mammals suffering from cancer, especially leukemia.
1 - 15 . (canceled)
16 . A method for treating a mammal suffering from a lymphoid cancer or from a myeloid cancer or from a solid cancer, said method comprising administering to the mammal a pharmaceutical composition comprising a vector coding for cyclin-dependent kinase inhibitor p21 protein (p21) and a pharmaceutically acceptable excipient, wherein the vector produces genetically modified monocytes that overexpress p21 in the mammal.
17 . The method of claim 16 , wherein said mammal is a human.
18 . The method of claim 17 , wherein the vector is a plasmid, viral vector, nonviral vector or mRNA.
19 . The method of claim 17 , wherein the vector is a viral vector, optionally an adenovirus, adeno-associated virus (AAV), herpesvirus, lentivirus, vaccina virus, cytomegalovirus (CMV) or Self inactivated (SIN) lentiviral vector.
20 . The method of claim 19 , wherein the viral vector comprises a transcription promoter sequence, optionally an E2F1 promoter, an EFS promoter, a SFFV promoter, a CMV promoter or an RSV promoter.
21 . The method of claim 17 , wherein the vector is mRNA.
22 . The method of claim 16 , wherein said lymphoid cancer is leukemia.
23 . The method of claim 16 , wherein said cancer is a lymphoma, carcinoma, melanoma, glioblastoma, sarcoma, myeloma or colon rectal tumors.
24 . The method of claim 17 , wherein said p21 protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:2.
25 . The method of claim 17 , wherein the vector comprises the nucleic acid sequence of SEQ ID NO:5.
26 . The method of claim 17 , further comprising administering an effective dose of an agent that increases haematocrit, of a chemotherapeutic agent, of a cell-specific antibody, or of an immune checkpoint inhibitor (ICI).