Methods and compositions to induce antitumor response

Abstract

The present invention provides compositions which are engineered to induce killing of tumor cells and concomitantly mobilize differentiate, activate and attract dendritic cells through the expression of cytokines and dendritic cell chemoattractants. The present invention invention is induces multiple stages of dendritic cell differentiation, activation and migration in vivo using gene therapy delivery systems. Moreover, this invention describes the rational design of utilizing viral vectors (preferred vector is rAd) for multiple administrations of targeted delivery to dendritic cells which can promote differentiation and activation of the transduced dendritic cells (thus augmenting in vivo stimulation of T cells, NK cells and B cells. The present invention provides a method to induce an antitumor immune response through the use of such compositions.

1 . A recombinant adenoviral vector, the vector comprising a polynucleotide encoding a dendritic cell chemoattractant.  
   
   
       2 . The vector of  claim 1 , wherein the vector further comprises a polynucleotide encoding a tumor-associated antigen.  
   
   
       3 . The vector of  claim 1 , wherein the dendritic cell chemoattractant is MIP-3-a.  
   
   
       4 . The vector of  claim 2 , wherein the tumor-associated antigen is p53.  
   
   
       5 . The vector of  claim 4 , wherein the dendritic cell chemoattractant is MIP-3-α and the polynucleotide encoding p53 and the polynucleotide encoding MIP-3-α are linked by an IRES element.  
   
   
       6 . The vector of  claim 5 , wherein the polynucleotides encoding p53 and MIP-3-a are operably linked to the CMV promoter.  
   
   
       7 . The vector of  claim 1 , wherein the vector is capable of selective replication in tumor cells.  
   
   
       8 . The vector of  claim 7 , wherein the vector is deleted in the E1a region so as to reduce binding of the E1 g gene products to p300 and pRb protein family members.  
   
   
       9 . The vector of  claim 8 , wherein the vector is deleted so as to not encode amino acids 4-25 and amino acids 111-123 of the E1a 243R and 289R proteins.  
   
   
       10 . The vector of  claim 8 , wherein the vector further comprises a p53 or TGF-β pathway responsive promoter driving expression of an inhibitor of viral replication.  
   
   
       11 . The vector of  claim 10 , wherein the inhibitor of viral replication is E2F-Rb.  
   
   
       12 . The vector of  claim 11 , wherein a polynucleotide encoding an E1a gene product is operably linked to an E2F pathway responsive promoter.  
   
   
       13 . A pharmaceutical formulation comprising the vector of  claim 1  a pharmaceutically acceptable carrier.  
   
   
       14 . The formulation of  claim 13 , wherein the vector comprises an expression cassette comprising the CMV promoter operably linked to a polynucleotide encoding p53 and a polynucleotide encoding MIP-3-α, wherein the polynucleotide encoding p53 and MIP-3-α are linked by an IRES element.  
   
   
       15 . A method of inducing the migration of dendritic cells to the site of a tumor in a mammal, the method comprising administering to the mammal the vector of  claim 1 .  
   
   
       16 . The method of  claim 15 , wherein the vector further comprises a polynucleotide encoding a tumor-associated antigen.  
   
   
       17 . The method of  claim 16 , wherein the tumor-associated antigen is p53 and the dendritic cell chemoattractant is MIP-3-α.