Methods of treating neoplasia with combination target cell-specific adenovirus, chemotherapy and radiation

Abstract

The invention provides methods of treating neoplasia using combinations of target cell-specific replication competent adenoviral vectors and chemotherapy, radiation therapy or combinations thereof. The adenoviral vectors are target cell-specific for the particular type of neoplasia for which treatment is necessary and the combination with the chemotherapy and/or radiation leads to synergistic treatment over existing adenoviral therapy or traditional chemotherapy and radiation therapy.

1 - 58 . (canceled) 
     
     
         59 . A method for suppressing tumor growth in a mammal comprising administering to said mammal:
 (a) a replication competent, target cell-specific adenovirus, said adenovirus comprising at least one adenoviral gene essential for replication under transcriptional control of a target cell-specific transcriptional regulatory element (TRE) selected from the group consisting of a prostate specific antigen (PSA)-TRE, a probasin (PB)-TRE, an α-fetoprotein (AFP)-TRE, a mucin (MUC1)-TRE, an hKLK2 TRE, a tyrosinase TRE, a carcinoembryonic antigen (CEA)-TRE, an E2F-1 TRE and a human uroplakin II (UPII)-TRE wherein administration of said target cell-specific adenovirus results in virus replication-dependent cytolysis; and   (b) an effective amount of an appropriate course of external radiation therapy to said mammal at a dose less than the effective dose for suppressing tumor growth when radiation is administered alone.   
     
     
         60 . The method of  claim 59  wherein said TRE is a prostate-specific TRE selected from the group consisting of PSA-TRE, PB-TRE and hKLK2-TRE. 
     
     
         61 . The method of  claim 59  wherein said at least one adenoviral gene essential for replication is E1A or E1B. 
     
     
         62 . The method of  claim 61  wherein said E1A or E1B has a mutation or deletion of its endogenous promoter. 
     
     
         63 . The method of  claim 61  wherein said E1B has a mutation or deletion of the 19 kDa region. 
     
     
         64 . The method of  claim 59  wherein said adenovirus further comprises an E3 region. 
     
     
         65 . The method of  claim 59  wherein said adenovirus further comprises co-transcribed first and second genes under transcriptional control of said TRE, wherein the second gene is under translational control of an IRES and wherein at least one of said first and said second genes is an adenovirus gene essential for replication. 
     
     
         66 . The method of  claim 59  wherein said adenovirus is administered by site-specific injection. 
     
     
         67 . A method for suppressing prostate tumor growth in a mammal comprising administering to said mammal:
 (a) a replication competent, prostate cell-specific adenovirus, said adenovirus comprising a prostate-specific antigen (PSA) transcriptional regulatory element (TRE) operably linked to an E1A gene and a probasin (PB)-TRE operably linked to an E1B gene, wherein administration of said prostate cell-specific adenovirus results in virus replication-dependent cytolysis; and   (b) an effective amount of an appropriate course of external radiation therapy to said mammal at a dose less than the effective dose for suppressing tumor growth when radiation is administered alone.   
     
     
         68 . The method of  claim 67  wherein said adenovirus further comprises an E3 region. 
     
     
         69 . The method of  claim 67  wherein said adenovirus is administered by site-specific injection. 
     
     
         70 . The method of  claim 67  further comprising an E1A enhancer. 
     
     
         71 . A method for suppressing prostate tumor growth in a mammal comprising administering to said mammal:
 (a) a replication competent, prostate cell-specific adenovirus, said adenovirus comprising a prostate-specific antigen (PSA) transcriptional regulatory element (TRE) operably linked to an E1A gene, wherein administration of said prostate cell-specific adenovirus results in virus replication-dependent cytolysis; and   (b) an effective amount of an appropriate course of external radiation therapy to said mammal at a dose less than the effective dose for suppressing tumor growth when radiation is administered alone.   
     
     
         72 . The method of  claim 71  further comprising an E A enhancer. 
     
     
         73 . The method of  claim 71  wherein said adenovirus is administered by site-specific injection.