Tumor therapy with high affinity laminin receptor-target vectors and combinations with chemotherapeutic agents

Abstract

The present invention relates to methods and compositions for treating tumors using vectors that preferentially target tumor cells. In particular, the invention relates to alphavirus-based, preferably Sindbis virus-based, vectors and to non-alphavirus-based vectors, which have a preferential affinity for high affinity laminin receptors (HALR). These vectors are efficiently targeted to tumors and have the ability to cause tumor necrosis.

1 - 57 . (canceled) 
     
     
         58 . A method for treating a mammal suffering from a tumor that expresses greater amounts of High Affinity Laminin Receptors (HALRs) than normal cells of the same lineage, which method comprises systemically administering to a mammal harboring such a tumor an amount of a Sindbis virus vector effective to treat the tumor and a chemotherapeutic agent, wherein the vector has not been modified to target a tumor-specific cellular determinant, has a preferential affinity for HALRs, a Sindbis virus E2 HALR binding domain, has genes encoding Sindbis proteins nsp1-4 and does not carry a heterologous anti-tumor gene. 
     
     
         59 . The method according to  claim 58 , wherein the mammal has at least a partially functional immune system. 
     
     
         60 . The method according to  claim 58 , wherein the mammal is a human. 
     
     
         61 . The method according to  claim 58 , wherein the tumor is a solid tumor. 
     
     
         62 . The method according to  claim 61 , wherein the solid tumor is selected from the group consisting of a hepatic carcinoma, melanoma, epidermoid carcinoma, pancreatic cancer, brain malignancy, breast cancer, lung cancer, ovarian adenocarcinoma, colon cancer, prostate cancer, bladder cancer, and renal cancer. 
     
     
         63 . The method according to  claim 58 , wherein the vector is administered parenterally. 
     
     
         64 . The method of  claim 58 , wherein said High Affinity Laminin Receptors are unoccupied. 
     
     
         65 . The method of  claim 58 , wherein the chemotherapeutic agent is a taxoid. 
     
     
         66 . The method of  claim 65 , wherein the chemotherapeutic agent is taxol. 
     
     
         67 . The method of  claim 58 , wherein the chemotherapeutic agent is a nitric oxide inhibitor. 
     
     
         68 . The method of  claim 58 , wherein the chemotherapeutic agent is selected from the group consisting of platin intercalating compounds, etoposide, etoposide phosphate, bleomycin, mitomycin C, CCNU, doxorubicin, daunorubicin, idarubicin, ifosfamide, and derivatives thereof. 
     
     
         69 . The method of  claim 58 , wherein said Sindbis virus vector is replication defective. 
     
     
         70 . The method of  claim 58 , wherein said vector is propagation competent. 
     
     
         71 . The method of  claim 58 , wherein said chemotherapeutic agent is selected from the group consisting of alkalating agents, plant aklatoids, plant terpenoids, monoclonal antibodies, topoisomerase inhibitors and antitumor antibodies. 
     
     
         72 . A method of treating a tumor in a patient which comprises systemically administering to a patient in need of such treatment a Sindbis virus vector and a chemotherapeutic agent. 
     
     
         73 . The method of  claim 71 , wherein said tumor expresses greater amounts of High Affinity Laminin Receptors than normal cells of the same lineage. 
     
     
         74 . The method of  claim 71 , wherein said Sindbis virus vector is replication defective. 
     
     
         75 . The method of  claim 71 , wherein said Sindbis virus vector is propagation competent. 
     
     
         76 . A method for treating a mammal suffering from a tumor that expresses greater amounts of High Affinity Laminin Receptors (HALRs) than normal cells of the same lineage, which method comprises systemically administering to mammal harboring such a tumor an amount of a Sindbis virus vector effective to treat the tumor and radiation, wherein the vector has not been modified to target a tumor-specific cellular determinant, has a preferential affinity for HALRs, a Sindbis virus E2 HALR binding domain, has genes encoding Sindbis proteins nspl-4 and does not carry a heterologous anti-tumor gene. 
     
     
         77 . The method of  claim 76  wherein said Sindbis virus vector is replication defective. 
     
     
         78 . The method of  claim 76  wherein said Sindbis virus vector is propagation competent.