Tumor associated vaccines and compositions for disrupting tumor-derived immunosuppression for use in combination cancer immunotherapy
In one embodiment, a single modality cancer immunotherapy regimen that includes a therapeutic composition is provided. Such a therapeutic composition may include a Salmonella strain comprising a plasmid that expresses an shRNA molecule that suppresses the expression of an immunosuppressive target and suppresses tumor growth. In some aspects, the Salmonella strain is an attenuated Salmonella typhimurium strain. In other aspects, the immunosuppressive target is STAT3, IDO1, IDO2, Arginase 1, iNOS, CTLA-4, TGF-β, IL-10, pGE2 or VEGF. In one embodiment, the immunosuppressive target is IDO1 or Arg1 and the shRNA molecule is any one of SEQ ID NO:5-14.
1. A composition comprising:
a Salmonella strain comprising a plasmid that expresses an shRNA molecule that suppresses the expression of an immunosuppressive target and suppresses tumor growth;
wherein the shRNA molecule is STAT3, (ARG1), or iNOS; and wherein the Salmonella strain is selected from the group consisting of YS1646 (ATCC #202165), RE88, SL7207, x8429, x8431 and x8468 IDO1.
2. The composition of claim 1 , wherein the shRNA is an shSTAT3 molecule selected from SEQ ID NO: 1-4.
3. The composition of claim 1 , further comprising a second Salmonella strain comprising a plasmid that expresses survivin.
4. The composition of claim 3 , wherein the plasmid that expresses survivin comprises codon-optimized survivin.
5. The composition of claim 4 , wherein the second Salmonella strain is an MVP728 strain.
6. The composition of claim 1 , wherein the shRNA is an shARG1 molecule selected from SEQ ID NO: 10-14.
7. The composition of claim 1 , wherein the shRNA is a shiNOS molecule selected from SEQ ID NO: 15-19.
8. A composition comprising:
a first Salmonella strain comprising a plasmid that expresses an shRNA molecule that suppresses the expression of an immunosuppressive target and suppresses tumor growth;
wherein the shRNA molecule comprises an shSTAT3 molecule selected from SEQ ID NO: 1-4; an shIDO molecule selected from SEQ ID NO:5-9; an shARG1 molecule selected from SEQ ID NO: 10-14; or an shiNOS molecule selected from SEQ ID NO: 15-19, and
wherein the first Salmonella strain is selected from the group consisting of YS1646 (ATCC #202165), RE88, SL7207, x8429, X8431 and x8468 IDO1.
9. The composition of claim 8 , further comprising a second Salmonella strain comprising a plasmid that expresses survivin.
10. The composition of claim 9 , wherein the plasmid that expresses survivin comprises codon-optimized survivin.
11. The composition of claim 10 , wherein the second Salmonella strain is an MVP728 strain.
12. A method of suppressing tumor growth comprising:
administering a therapeutically effective amount of a first composition to a subject, the first composition comprising an anti-immunosuppressive vector that disrupts tumor-derived immune suppression and suppresses tumor growth,
wherein the anti-immunosuppressive vector comprises a Salmonella typhimurium strain comprising a plasmid that expresses an shRNA molecule that suppresses the expression of an immunosuppressive target which suppresses tumor growth;
wherein the shRNA molecule is STAT3, ARG1 or iNOS; and wherein the Salmonella strain is selected from the group consisting of YS1646 (ATCC #202165), RE88, SL7207, x8429, x8431 and x8468 IDO1.
13. The method of claim 12 , wherein the shRNA is a shSTAT3 molecule selected from SEQ ID NO: 1-4.
14. The method of claim 12 , wherein the first composition further comprises a second Salmonella strain comprising a plasmid that expresses codon-optimized survivin.
15. The method of claim 14 , wherein the second Salmonella strain is an MVP728 strain.
16. The method of claim 12 , wherein the shRNA is a shArgI molecule selected from SEQ ID NO: 10-14.
17. The method of claim 12 , wherein the shRNA is a shiNOS molecule selected from SEQ ID NO: 15-19.
18. The method of claim 12 , further comprising administering a therapeutically effective amount of a second composition to a subject, the second composition comprising a second Salmonella strain comprising a plasmid that expresses survivin.
19. The method of claim 18 , wherein the Salmonella strain is administered intravenously.