Combination tumor treatment with drug-loaded, bispecific ligand-targeted minicells and interferon-gamma
Compositions and methods are provided for cancer treatments. The methodology entails, for instance, administering to a cancer patient a first composition comprising a plurality of bacterially derived intact minicells or intact killed bacterial cells, each of which encompasses an anti-neoplastic agent and carries a bispecific ligand on the surface, the ligand having specificity for a mammalian cell component, and a second composition comprising interferon-gamma (IFN-gamma) or an agent that increases the expression of IFN-gamma in the subject. The compositions include the first composition and the second composition as described, optionally with additional anti-neoplastic agents.
1. A package, product, or kit comprising:
(a) a first composition comprising a plurality of intact bacterial minicells or intact killed bacterial cells, each of which(i) encompasses an anti-neoplastic agent selected from the group consisting of a radionucleotide; a chemotherapy drugs; a functional nucleic acid selected from the group consisting of siRNA, miRNA, shRNA, lincRNA, antisense RNA, and ribozyme; and a polynucleotide that transcribes a functional nucleic acid selected from the group consisting of siRNA, miRNA, shRNA, lincRNA, antisense RNA, and ribozyme and (ii) carries a ligand on the surface of the intact minicells or intact killed bacterial cells, wherein the ligand has specificity to a tumor cell antigen; and
(b) a second composition comprising interferon-gamma (IFN-gamma).
2. A composition comprising:
(a) a plurality of intact bacterial minicells or intact killed bacterial cells, each of which(i) encompasses an anti-neoplastic agent selected from the group consisting of a radionucleotide; a chemotherapy drugs; a functional nucleic acid selected from the group consisting of siRNA, miRNA, shRNA, lincRNA, antisense RNA, and ribozyme; and a polynucleotide that transcribes a functional nucleic acid selected from the group consisting of siRNA, miRNA, shRNA, lincRNA, antisense RNA, and ribozyme and (ii) carries a ligand on the surface of the intact minicells or bacterial cells, wherein the ligand has specificity to a non-phagocytic mammalian cell surface receptor, wherein the non-phagocytic mammalian cell surface receptor is a tumor cell antigen; and
(b) interferon-gamma (IFN-gamma).
3. The composition of claim 2 , wherein:
(a) the anti-neoplastic agent is a functional nucleic acid or a polynucleotide from which a functional nucleic acid is transcribed; and
(b) the functional nucleic acid inhibits a gene that promotes resistance to chemotherapy, wherein the gene is ribonucleotide reductase catalytic subunit M1 (RRM1).
4. The package, product, or kit of claim 1 , wherein the second composition comprises purified IFN-gamma protein.
5. The package, product, or kit of claim 1 , wherein the anti-neoplastic agent is a radionuclide.
6. The package, product, or kit of claim 1 , wherein the anti-neoplastic agent is a chemotherapy drug.
7. The package, product, or kit of claim 6 , wherein the chemotherapy drug is a small molecule drug having a molecular weight of less than about 900 Dalton.
8. The package, product, or kit of claim 7 , wherein the small molecule drug is cytotoxic.
9. The package, product, or kit of claim 7 , wherein the small molecule drug is a morpholinyl anthracycline derivative.
10. The package, product, or kit of claim 1 , wherein the functional nucleic acid inhibits a gene that promotes tumor cell proliferation, angiogenesis or resistance to chemotherapy and/or that inhibits apoptosis or cell cycle arrest.
11. The package, product, or kit of claim 1 , wherein the functional nucleic acid is siRNA or miRNA.
12. The package, product, or kit of claim 1 , wherein the functional nucleic acid inhibits the gene ribonucleotide reductase M1 (RRM1).
13. The package, product, or kit of claim 1 , wherein the composition comprises from about 10 9 to about 10 10 minicells or killed bacterial cells.
14. The composition of claim 2 , wherein the interferon-gamma (IFN-gamma) comprises purified IFN-gamma protein.
15. The composition of claim 2 , wherein the anti-neoplastic agent is a radionuclide.
16. The composition of claim 2 , wherein the anti-neoplastic agent is a chemotherapy drug.
17. The composition of claim 16 , wherein the chemotherapy drug is a small molecule drug having a molecular weight of less than about 900 Dalton.
18. The composition of claim 17 , wherein the small molecule drug is cytotoxic.
19. The composition of claim 17 , wherein the small molecule drug is a morpholinyl anthracycline derivative.
20. The composition of claim 2 , wherein the functional nucleic acid inhibits a gene that promotes tumor cell proliferation, angiogenesis or resistance to chemotherapy and/or that inhibits apoptosis or cell cycle arrest.
21. The composition of claim 2 , wherein the functional nucleic acid is siRNA or miRNA.
22. The composition of claim 2 , wherein the composition comprises from about 10 9 to about 10 10 minicells or killed bacterial cells.