Methods for stimulating an immune response using bacterial antigen delivery system
The invention relates to the use of the type III secretion system of bacteria to stimulate immune responses against tumor antigen(s) for treating antigen-loss variant tumors. Methods are provided for stimulating and/or increasing an immune response against tumor antigens. The invention also relates to the preparation of antigen presenting cells from peripheral blood mononuclear cells using bacteria having a type III secretion system.
1. A method for stimulating an immune response against a first protein expressed by a tumor, comprising
administering to a subject in need of such treatment avirulent bacteria comprising a type III secretion system and a nucleic acid encoding a fusion protein that comprises an immunogenic second protein or an immunogenic fragment thereof fused to a polypeptide that is delivered by the type III secretion system of the avirulent bacteria,
wherein the immunogenic second protein is an antigen against which the subject has preexisting CD8 + T cells,
wherein the fusion protein stimulates an immune response against the first protein and the immunogenic second protein.
2. A method for stimulating an immune response against a first protein expressed by a tumor, comprising
administering to a subject in need of such treatment an immunogenic second protein or an immunogenic fragment thereof to induce CD8 + T cells against the immunogenic second protein, and
administering subsequently to the subject avirulent bacteria comprising a type III secretion system and a nucleic acid encoding a fusion protein that comprises the immunogenic second protein or immunogenic fragment thereof fused to a polypeptide that is delivered by the type III secretion system of the avirulent bacteria,
wherein the fusion protein stimulates an immune response against the first protein and the immunogenic second protein.
3. The method of claim 1 , wherein the immune response comprises a CD8 + T cell response, a CD4 + T cell response, or a CD8 + T cell response and a CD4 + T cell response.
4. The method of claim 1 , wherein the immunogenic second protein or immunogenic fragment is a tumor antigen protein, a viral antigen protein, a microorganism antigen protein or an immunogenic fragment thereof.
5. The method of claim 1 , wherein the avirulent bacteria are Salmonella spp., optionally Salmonella enterica; Yersinia spp.; Bordetella spp.; Escherichia coli; Shigella spp.; Burkholderia mallei; Burkholderia pseudomallei ; or Pseudomonas aeruginosa.
6. The method of claim 5 , wherein the avirulent S. enterica bacteria are S. typhimurium , optionally S. typhimurium ΔphoP phoQ ΔaroA Δasd.
7. The method of claim 1 , wherein the stimulation of the immune response is an increased pre-existing immune response.
8. The method of claim 7 , wherein the immune response comprises a CD8 + T cell response, a CD4 + T cell response, or a CD8 + T cell response and a CD4 + T cell response.
9. The method of claim 7 , wherein the second immunogenic protein or immunogenic fragment is a tumor antigen protein, a viral antigen protein, a microorganism antigen protein or an immunogenic fragment thereof.
10. The method of claim 9 , wherein more than one tumor antigen, viral antigen protein, microorganism antigen protein or immunogenic fragment thereof is encoded.
11. The method of claim 7 , wherein the avirulent bacteria are Salmonella spp., optionally Salmonella enterica; Yersinia spp.; Bordetella spp.; Escherichia coli; Shigella spp.; Burkholderia mallei; Burkholderia pseudomallei ; or Pseudomonas aeruginosa.
12. The method of claim 11 , wherein the avirulent S. enterica bacteria are S. typhimurium , optionally S. typhimurium ΔphoP phoQ ΔaroA Δasd.
13. The method of claim 2 , wherein the immune response is a CD4 + T cell response, a CD8 + T cell response, or both a CD4 + T cell response and a CD8 + T cell response.
14. The method of claim 2 , wherein the second immunogenic protein or immunogenic fragment is a tumor antigen protein, viral antigen protein, microorganism antigen protein or an immunogenic fragment thereof.
15. The method of claim 14 , wherein more than one tumor antigen protein, viral antigen protein, microorganism antigen protein or immunogenic fragment thereof is encoded.
16. The method of claim 2 , wherein the avirulent bacteria are Salmonella spp., optionally Salmonella enterica; Yersinia spp.; Bordetella spp.; Escherichia coli; Shigella spp.; Burkholderia mallei; Burkholderia pseudomallei ; or Pseudomonas aeruginosa.
17. The method of claim 16 , wherein the avirulent S. enterica bacteria are S. typhimurium , optionally S. typhimurium ΔphoP phoQ ΔaroA Δasd.
18. The method of claim 2 , wherein the avirulent bacteria are administered orally.
19. The method of claim 2 , wherein the immunogenic second protein or an immunogenic fragment thereof is administered parenterally or orally.
20. The method of claim 2 , wherein the stimulation of the immune response is an increased pre-existing immune response.
21. The method of claim 20 , wherein the immune response comprises a CD4 + T cell response, a CD8 + T cell response, or a CD4 + T cell response and a CD8 + T cell response.
22. The method of claim 20 , wherein the second immunogenic protein or immunogenic fragment is a second tumor antigen protein, a viral antigen protein, a microorganism antigen protein or an immunogenic fragment thereof.
23. The method of claim 22 , wherein more than one tumor antigen protein, viral antigen protein, microorganism antigen protein or immunogenic fragment thereof is encoded.
24. The method of claim 20 , wherein the avirulent bacteria are Salmonella spp., optionally Salmonella enterica; Yersinia spp.; Bordetella spp.; Escherichia coli; Shigella spp.; Burkholderia mallei; Burkholderia pseudomallei ; or Pseudomonas aeruginosa.
25. The method of claim 24 , wherein the avirulent S. enterica bacteria are S. typhimurium , optionally S. typhimurium ΔphoP phoQ ΔaroA Δasd.
26. The method of claim 20 , wherein the avirulent bacteria are administered orally.
27. The method of claim 20 , wherein the the second immunogenic protein or immunogenic fragment is administered parenterally or orally.
28. The method of claim 4 , wherein more than one tumor antigen protein, viral antigen protein, microorganism antigen protein or immunogenic fragment thereof is encoded.