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 . A method for killing a cancer cell in a mammal suffering from cancer, comprising contacting the cancer cell in the mammal with a monocyte genetically modified to overexpress cyclin-dependent kinase inhibitor p21 protein, wherein the genetically modified monocyte comprises an exogenous nucleic acid coding for cyclin-dependent kinase inhibitor p21 protein.
2 . 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 genetically modified monocytes that overexpress cyclin-dependent kinase inhibitor p21 protein, and a pharmaceutically acceptable excipient, wherein the genetically modified monocytes comprise an exogenous nucleic acid coding for cyclin-dependent kinase inhibitor p21 protein.
3 . The method of claim 2 , wherein said lymphoid cancer is leukemia.
4 . The method of claim 2 , wherein said pharmaceutical composition comprises 50×10 6 monocytes per injection dose and is administered each week until progression of the disease is reduced.
5 . The method of claim 2 , wherein said mammal is a human.
6 . The method of claim 2 , 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).
7 . The method of claim 6 , wherein said mammal is a human.
8 . The method of claim 2 , wherein said monocytes comprise a replication defective recombinant virus encoding cyclin-dependent kinase inhibitor p21 under control of regulatory elements permitting its expression.
9 . The method of claim 2 , wherein said monocytes comprise a replication defective recombinant lentivirus encoding cyclin-dependent kinase inhibitor p21 under control of regulatory elements permitting its expression.
10 . The method of claim 2 , wherein said monocytes comprise a HIV-1 based self inactivated (SIN) lentiviral vector encoding cyclin dependent kinase inhibitor p21 under control of regulatory elements permitting its expression.
11 . The method of claim 2 , wherein the composition is formulated in an intravenous injectable form or in a perfusion form.
12 . The method of claim 2 , wherein the composition contains 30×10 6 to 10 9 of modified monocytes.
13 . The method of claim 2 , wherein said monocytes comprise a synthetic transposon system encoding cyclin-dependent kinase inhibitor p21 under control of regulatory elements permitting its expression.
14 . The method of claim 2 , wherein said p21 protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:2.
15 . The method of claim 2 , wherein said monocytes comprise a replication defective recombinant virus comprising the nucleic acid according to SEQ ID NO:5.
16 . The method of claim 2 , wherein said monocytes comprise a replication defective recombinant virus comprising the nucleic acid according to SEQ ID NO:5 under control of a SFFV promoter.