Use of entrained neutrophils to treat metastatic and micrometastatic disease in at risk patients
The present invention relates generally to compositions and methods for treating cancer patients with a poor prognosis, and to therapeutic modalities for improving prognosis by combating metastasis and abrogating chemoresistance in cancer cells. In particular, the invention relates to the role of white blood cells, i.e. neutrophils and neutrophil-like cells, in preventing the spread of cancer from a primary tumor to secondary locations in the body. The invention provides methods for reducing or delaying the spread of metastatic cancer cells in a patient at risk for metastatic tumor development, at risk for metastatic relapse, i.e. prophylactic methods, and treating patients suffering from metastatic tumors.
1. A method, comprising,
a) providing,
i) a patient at risk for developing metastatic cancer, wherein said patient comprises a neutrophil, wherein said neutrophil is capable of being cytotoxic to a tumor cell; and
ii) a chemokine selected from the group consisting of Chemokine (C-C motif) ligand 2, Chemokine (C-C motif) ligand 3, Chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 1, chemokine (C-X-C motif) ligand 12, chemokine (C-X-C motif) ligand 16, capable of increasing said neutrophil cytotoxicity;
b) isolating said neutrophil from said patient; and
c) contacting said neutrophil with said chemokine under conditions for increasing cytotoxic activity of said neutrophil.
2. The method of claim 1 , wherein said contacting further comprises contacting with a transforming growth factor-beta inhibitor.
3. The method of claim 1 , further comprising a test tumor cell, wherein said neutrophil has increased cytotoxicity towards said test tumor cell after said contacting.
4. The method of claim 1 , wherein said increasing cytotoxicity is increasing cytotoxicity for mediating killing of a tumor cell.
5. The method of claim 1 , wherein said increasing cytotoxicity is increasing capability to induce apoptosis in a tumor cell.
6. The method of claim 1 , wherein said increasing cytotoxicity is increasing oxidative activity of said neutrophil for providing an oxidative burst capable of killing a tumor cell.
7. The method of claim 1 , wherein said patient is administered granulocyte colony-stimulating factor prior to said isolation of said neutrophil.
8. The method of claim 1 , wherein said neutrophil comprises a matrix metallopeptidase 9 marker.
9. A method, comprising,
a) providing,
i) a patient comprising at least one tumor cell capable of metastasis, wherein said patient further comprises a neutrophil, wherein said neutrophil is capable of being cytotoxic to said tumor cell;
ii) a chemokine selected from the group consisting of Chemokine (C-C motif) ligand 2, Chemokine (C-C motif) ligand 3, Chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 1, chemokine (C-X-C motif) ligand 12, chemokine (C-X-C motif) ligand 16, capable of increasing cytotoxicity of said neutrophil;
b) isolating said neutrophil from said patient;
c) contacting said neutrophil with said chemokine under conditions for increasing cytotoxic activity of said neutrophil; and
d) administering said contacted neutrophil to said patient under conditions such that said tumor cell is inhibited from metastasis.
10. The method of claim 9 , wherein said contacting further comprises contacting with a transforming growth factor-beta inhibitor.
11. The method of claim 9 , wherein said tumor cell is selected from the group consisting of breast cancer, colon cancer, prostate cancer and lung cancer.
12. The method of claim 9 , wherein said neutrophil comprises a matrix metallopeptidase 9 marker.
13. The method of claim 9 , wherein said increasing cytotoxicity is increasing cytotoxicity for mediating killing of a tumor cell.
14. The method of claim 9 , wherein said increasing cytotoxicity is increasing capability to induce apoptosis in a tumor cell.
15. The method of claim 9 , wherein said increasing cytotoxicity is increasing oxidative activity of said neutrophil for providing an oxidative burst capable of killing a tumor cell.
16. The method of claim 9 , wherein said method further comprises administering a granulocyte colony-stimulating factor to said patient prior to said isolation of said neutrophil.
17. The method of claim 9 , wherein said administering of said neutrophil is prior to detection of said tumor cell metastasis.
18. The method of claim 9 , wherein said administering of said neutrophil is after detection of said metastasis.
19. A method, comprising,
a) providing,
i) a pharmaceutical composition, comprising an agent for increasing the number of neutrophils in a blood sample;
ii) a patient comprising a tumor cell and circulating neutrophils;
iii) a chemokine selected from the group consisting of Chemokine (C-C motif) ligand 2, Chemokine (C-C motif) ligand 3, Chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 1, chemokine (C-X-C motif) ligand 12, chemokine (C-X-C motif) ligand 16, capable of increasing cytotoxicity of a neutrophil;
b) administering said pharmaceutical composition under conditions such that said circulating neutrophils are increased in a blood sample of said patient;
c) isolating said neutrophils from a blood sample of said patient;
d) contacting said neutrophils with said chemokine under conditions for increasing cytotoxic activity of said neutrophil; and
e) administering said contacted neutrophils to said patient under conditions such that said tumor cell is inhibited from metastasis.
20. The method of claim 19 , wherein said agent is granulocyte colony-stimulating factor.