Compositions and methods for tumor-targeted delivery of effector molecules

Abstract

The present application discloses the preparation and use of attenuated tumor-targeted bacteria vectors for the delivery of one or more primary effector molecule(s) to the site of a solid tumor. The primary effector molecule(s) of the invention is used in the methods of the invention to treat a solid tumor cancer such as a carcinoma, melanoma, lymphoma, or sarcoma. The invention relates to the surprising discovery that effector molecules, which may be toxic when administered systemically to a host, can be delivered locally to tumors by attenuated tumor-targeted bacteria with reduced toxicity to the host. The application also discloses to the delivery of one or more optional effector molecule(s) (termed secondary effector molecules) which may be delivered by the attenuated tumor-targeted bacteria in conjunction with the primary effector molecule(s).

1 .- 99 . (Canceled)  
     
     
         100 . A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of one or more chemotherapeutic agents and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria, wherein said attenuated tumor-targeted bacteria is a facultative aerobe or facultative anaerobe.  
     
     
         101 . A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of one or more chemotherapeutic agents and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria comprising one or more nucleic acid molecules encoding one or more primary effector molecules operably linked to one or more promoters, wherein said attenuated tumor-targeted bacteria is a facultative aerobe or facultative anaerobe.  
     
     
         102 . A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of one or more chemotherapeutic agents and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria comprising one or more nucleic acid molecules encoding one or more primary effector molecules and one or more secondary effector molecule operably linked to one or more promoters, wherein said attenuated tumor-targeted bacteria is a facultative aerobe or facultative anaerobe.  
     
     
         103 . A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of mitomycin C, cytoxan or cisplatin and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria, wherein said attenuated tumor-targeted bacteria is  Salmonella.    
     
     
         104 . A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of mitomycin C, cytoxan or cisplatin and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria comprising one or more nucleic acid molecules encoding one or more primary effector molecules operably linked to one or more promoters, wherein said attenuated tumor-targeted bacteria is  Salmonella.    
     
     
         105 . A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of mitomycin C, cytoxan or cisplatin and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria comprising one or more nucleic acid molecules encoding one or more primary effector molecules and one or more secondary effector molecule operably linked to one or more promoters, wherein said attenuated tumor-targeted bacteria is  Salmonella.    
     
     
         106 . The method of  claim 100 ,  101  or  102 , wherein at least one of the chemotherapeutic agents is cisplatin, ifosfamide, a taxane, a topoisomerase I inhibitor, gemcitabine, vinorelbine, oxaliplatin, 5-fluorouracil (5-FU), leucovorin, vinorelbine, temodal, cytochalasin B, gramicidin D, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, a glucocorticoid, a puromycin homolog or cytoxan.  
     
     
         107 . The method of  claim 100 ,  101  or  102 , wherein the attenuated tumor-targeted bacteria is  Escherichia coli, Shigella, Yersinia enterocohtica, Listeria monocytogenies, Mycoplasma hominis  or  Streptococcus.    
     
     
         108 . The method of  claim 103 ,  104  or  105 , wherein the  Salmonella  is an msbB −    Salmonella  mutant.  
     
     
         109 . The method of  claim 101 ,  102 ,  104  or  105 , wherein at least one of the primary effector molecules is a TNF family member, anti-angiogenic factor, a tumor inhibitory enzyme, hemolysin, verotoxin, CNF1, CNF2, PMT, or a bacteriocin family member with the proviso said bacteriocin is not BRP.  
     
     
         110 . The method of  claim 102  or  105 , wherein at least one of the secondary effector molecules is an immunomodulating agent, an anti-tumor protein, a pro-drug converting enzyme, an antisense molecule, a ribozyme, an antigen or a bacteriocin release factor.  
     
     
         111 . The method of  claim 100 ,  101 ,  102 ,  103 ,  104  or  105 , wherein the solid tumor is a tumor of the central nervous system, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, glioma, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma, renal cancer, bladder cancer or mesothelioma.  
     
     
         112 . The method of  claim 100 ,  101 ,  102 ,  103 ,  104  or  105 , wherein the subject is a human.