Cancer combination therapy and recombinant vectors
This disclosure relates to a combination therapy of chemotherapeutics and/or radiosensitizing agents with a replication competent viral vectors for treating cell proliferative disorders and chemotherapeutic treatments. The disclosure further relates to the use of such replication competent viral vectors for delivery and expression of a heterologous nucleic acid in normal and diseased tissues and methods and compositions that facilitate such delivery and expression to tissues in vivo and in vitro. The disclosure further relates to replication competent retroviral vectors for these uses and in conjunction with methods and compositions that facilitate in vivo therapeutics.
1. A method of treating a cancer, said method comprising administering to the cancer a replication competent mammalian oncoretroviral vector containing a therapeutic cassette, the therapeutic cassette comprising a gene encoding a polypeptide having prodrug-activating activity, wherein the vector infects the cancer cells and wherein the cancer cells expresses the gene encoding the polypeptide; and within about 5 days to about 12 weeks after administering the vector administering a prodrug and administering separately temozolomide, wherein the prodrug is 5-fluorocytosine.
2. A method of treating a cancer in a subject, comprising administering to the subject that is free of any chemotherapeutic agents a replication competent mammalian oncoretroviral vector containing a therapeutic cassette, the therapeutic cassette comprising a gene encoding a polypeptide having cytosine deaminase activity, allowing the vector to infect cancer cells of the cancer and spread, wherein the cancer cells expresses the gene encoding the polypeptide; and within about 5 to about 20 days after administering the vector administering 5-fluorocytosine and one or more chemotherapeutic radio-sensitizing agents.
3. The method of claim 1 or 2 , wherein the cancer is glioblastoma multiforme.
4. The method of claim 3 , wherein the glioblastoma multiforme is recurrent glioblastoma multiforme.
5. The method of claim 1 , wherein temozolomide is administered in a plurality of 28-day cycles, each cycle comprising administration of a dose of about 50 to 150 mg/m 2 per day each day for at least days 1-5.
6. The method of claim 1 or 2 , wherein prior to administration of the vector, the cancer is resected.
7. The method of claim 1 , further comprising administering radiation to the subject at the cancer site within 1-5 days of administration of 5-FC and/or temozolomide.
8. The method of claim 1 or 2 , wherein the subject has not been treated with an agent that inhibits a mis-match repair process in the subject's cells.
9. The method of claim 1 or 2 , wherein the cancer is selected from the group consisting of lung cancer, colon-rectum cancer, breast cancer, prostate cancer, urinary tract cancer, uterine cancer, brain cancer, head and neck cancer, pancreatic cancer, melanoma, stomach cancer and ovarian cancer.
10. The method of claim 1 or 2 , wherein replication competent retrovirus comprises:
a retroviral GAG protein;
a retroviral POL protein;
a retroviral envelope;
a retroviral polynucleotide comprising Long-Terminal Repeat (LTR) sequences at the 3′ end of the retroviral polynucleotide sequence, a promoter sequence at the 5′ end of the retroviral polynucleotide, said promoter being suitable for expression in a mammalian cell, a gag nucleic acid domain, a pol nucleic acid domain and an env nucleic acid domain;
a therapeutic cassette comprising a regulatory domain operably linked to a heterologous gene encoding a polypeptide having cytosine deaminase activity, wherein the cassette is positioned 5′ to the 3′ LTR and 3′ to the env nucleic acid domain encoding the retroviral envelope; and
cis-acting sequences necessary for reverse transcription, packaging and integration in a target cell.
11. The method of claim 10 , wherein the retroviral polynucleotide sequence is derived from murine leukemia virus (MLV), Moloney murine leukemia virus (MoMLV), Feline leukemia Virus or Gibbon ape leukemia virus (GALV).
12. The method of claim 11 , wherein the MLV is an amphotropic MLV.
13. The method of claim 10 , wherein the retrovirus is a gammaretrovirus.
14. The method of claim 1 , wherein the polypeptide has cytosine deaminase activity.