Myeloid derived suppressor cell inhibiting agents

Abstract

Myeloid derived suppressor cell (MDSC) inhibitory agents and vaccine and/or adjuvant enhancers are provided. Improved vaccine treatment regimens employing these agents are also provided. Cancer vaccines and methods for inhibiting tumor growth and cancer metastases are also presented. The myeloid derived suppressor cell (MDSC) inhibiting agents are described as bisphosphonates (such as liposomal clodronate) and CCR2 inhibitors and/or CCR2 antagonists. Methods for enhancing antibody titer levels in response to an antigen of interest are also provided.

1 . A myeloid derived suppressor cell inhibiting agent therapeutic regimen preparation comprising:
 a first component myeloid derived suppressor cell inhibiting agent; and   a second component vaccine antigen of interest,   
       wherein said therapeutic regimen preparation enhances antibody titer levels to the vaccine antigen of interest in vivo greater than antibody titer levels in vivo with a vaccine treatment regimen in the absence of the myeloid derived suppressor cell inhibiting agent, said myeloid derived suppressor cell inhibiting agent comprising a bisphosphonate or a CCR2 inhibitor. 
     
     
         2 . The myeloid derived suppressor cell inhibiting agent of  claim 1  wherein said agent inhibits inflammation induced migration of myeloid derived suppressor cells to draining lymph nodes in vivo. 
     
     
         3 . The myeloid derived suppressor cell inhibiting agent of  claim 1  wherein the myeloid derived suppressor cell inhibiting agent is a CCR2 inhibitor. 
     
     
         4 . The myeloid derived suppressor cell inhibiting agent of  claim 1  wherein the bisphosphonate is clodronate, zoledronate, palmidronate, etidronate, or other bisphosphonate drug and the CCR2 inhibitor is RS 1028595 or PF-04178903. 
     
     
         5 . A method for enhancing immune response to a vaccine in an animal comprising administering a myeloid derived suppressor cell inhibiting agent to the animal as part of a vaccine treatment regimen. 
     
     
         6 . The method of  claim 5  wherein the immune response is demonstrated as an elevated antibody titer level in vivo, compared to an antibody titer level in response to a vaccine treatment regimen without a myeloid derived suppressor cell inhibiting agent. 
     
     
         7 . The method of  claim 5  wherein the vaccine treatment regimen provides for administration of the myeloid derived suppressor cell inhibiting agent before, at the same time, after or before, during and after the administration of the vaccine. 
     
     
         8 . The method of  claim 5  wherein the myeloid derived suppressor cell inhibiting agent is a bisphosphonate or a CCR2 inhibitor. 
     
     
         9 . The method of  claim 5  wherein the myeloid derived suppressor cell inhibiting agent is a small molecule agent capable of inhibiting inflammatory response induced myeloid derived suppressor cell activity. 
     
     
         10 . The method of  claim 5  comprising the steps of:
 (a) treating an animal in need thereof with a therapeutic amount of a vaccine containing a vaccine antigen of interest and a myeloid derived suppressor cell inhibiting agent; and 
 (b) enhancing immune response in the animal. 
 
     
     
         11 . The method of  claim 10  wherein the myeloid derived suppressor cell inhibiting agent is a bisphosphonate or a CCR2 inhibitor. 
     
     
         12 . The method of  claim 10  wherein the myeloid derived suppressor cell inhibiting agent is administered before, at the same time and after the vaccine is administered. 
     
     
         13 . The method of  claim 10  wherein vaccine contains alum, incomplete Freunds adjuvant, Corrixa MPL adjuvant, liposomal polyI:C adjuvant or cationic liposome-DNA complex adjuvant. 
     
     
         14 . A method for inhibiting tumor growth in an animal comprising:
 (a) administering a therapeutic amount of an anti-tumor preparation containing adjuvant and an amount of myeloid derived suppressor cell inhibiting agent sufficient to inhibit myeloid derived suppressor cell activity; and   (b) inhibiting tumor growth in said animal.   
     
     
         15 . The method of  claim 14  wherein the myeloid derived suppressor cell inhibiting agent is a bisphosphonate or a CCR2 inhibitor. 
     
     
         16 . The method of  claim 15  wherein the bisphosphonate is clodronate, zoledronate, palmidronate, etidronate, or other bisphosphonate drug and the CCR2 inhibitor is RS 1028595 or PF-04178903. 
     
     
         17 . The method of  claim 16  wherein the bisphosphonate is liposomal clodronate. 
     
     
         18 . The method of  claim 14  wherein the myeloid derived suppressor cell inhibiting agent is administered before, at the same time, or after the anti-tumor preparation, or before, at the same time and after the anti-tumor preparation. 
     
     
         19 . The method of  claim 18  wherein the anti-tumor preparation comprises alum, incomplete Freunds adjuvant, Corrixa MPL adjuvant, liposomal polyI:C adjuvant or cationic liposome-DNA complex adjuvant. 
     
     
         20 . The method of  claim 14  wherein the myeloid derived suppressor cell inhibiting agent is RS 1028595.