Adenoviral vectors and methods and uses related thereto

Abstract

The present invention relates to the fields of life sciences and medicine. Specifically, the invention relates to cancer therapies. More specifically, the present invention relates to oncolytic adenoviral vectors and cells and pharmaceutical compositions comprising said vectors. The present invention also relates to a use of said vectors in the manufacture of a medicament for treating cancer in a subject and a method of treating cancer in a subject. Furthermore, the present invention relates to methods of producing GM-CSP in a cell and increasing tumor specific immune response in a subject, as well as uses of the oncolytic adenoviral vector of the invention for producing GM-CSF in a cell and increasing tumor specific immune response in a subject.

1 - 19 . (canceled) 
     
     
         20 . A method of treating cancer in a subject in need thereof, comprising administering an effective amount an oncolytic adenoviral vector or a pharmaceutical composition comprising the oncolytic adenoviral vector to the subject, wherein the oncolytic adenoviral vector comprises an adenovirus serotype 5 (Ad5) nucleic acid backbone; a 24 bp deletion (D24) in the Rb binding constant region 2 of E1; and a nucleic acid sequence encoding a granulocyte-macrophage colony-stimulating factor (GM-CSF) in the place of the deleted gp19k/6.7K in the E3 region. 
     
     
         21 . The method of  claim 20 , wherein the cancer is selected from a group consisting of nasopharyngeal cancer, synovial cancer, hepatocellular cancer, renal cancer, cancer of connective tissues, melanoma, lung cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, brain cancer, throat cancer, oral cancer, liver cancer, bone cancer, pancreatic cancer, choriocarcinoma, gastrinoma, pheochromocytoma, prolactinoma, T-cell leukemia/lymphoma, neuroma, von Hippel-Lindau disease, Zollinger-Ellison syndrome, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, ureter cancer, brain cancer, oligodendroglioma, neuroblastoma, meningioma, spinal cord tumor, bone cancer, osteochondroma, chondrosarcoma, Ewing's sarcoma, cancer of unknown primary site, carcinoid, carcinoid of gastrointestinal tract, fibrosarcoma, breast cancer, Paget's disease, cervical cancer, colorectal cancer, rectal cancer, esophagus cancer, gall bladder cancer, head cancer, eye cancer, neck cancer, kidney cancer, Wilms' tumor, liver cancer, Kaposi's sarcoma, prostate cancer, lung cancer, testicular cancer, Hodgkin's disease, non-Hodgkin's lymphoma, oral cancer, skin cancer, mesothelioma, multiple myeloma, ovarian cancer, endocrine pancreatic cancer, glucagonoma, pancreatic cancer, parathyroid cancer, penis cancer, pituitary cancer, soft tissue sarcoma, retinoblastoma, small intestine cancer, stomach cancer, thymus cancer, thyroid cancer, trophoblastic cancer, hydatidiform mole, uterine cancer, endometrial cancer, vagina cancer, vulva cancer, acoustic neuroma, mycosis fungoides, insulinoma, carcinoid syndrome, somatostatinoma, gum cancer, heart cancer, lip cancer, meninges cancer, mouth cancer, nerve cancer, palate cancer, parotid gland cancer, peritoneum cancer, pharynx cancer, pleural cancer, salivary gland cancer, tongue cancer, tonsil cancer. 
     
     
         22 . The method of  claim 20 , wherein the subject is a human or an animal. 
     
     
         23 . The method of  claim 20 , wherein the administration is conducted through an intratumoral, intramuscular, intra-arterial, intravenous, intrapleural, intravesicular, intracavitary or peritoneal injection, or an oral administration. 
     
     
         24 . The method of  claim 20 , wherein the adenoviral vectors or pharmaceutical compositions is administered several times during a treatment period. 
     
     
         25 . The method of  claim 20 , wherein a oncolytic adenoviral vector having a different fiber knob of the capsid compared to a vector of an earlier treatment, is administered to the subject. 
     
     
         26 . The method of  claim 20 , further comprising administering concurrent radiotherapy to the subject. 
     
     
         27 . The method of  claim 20 , further comprising administering concurrent chemotherapy to the subject. 
     
     
         28 . The method of  claim 20 , further comprising administering administering verapamil or another calcium channel blocker to the subject. 
     
     
         29 . The method of  claim 20 , further comprising administering administering autophagy inducing agents to the subject. 
     
     
         30 . The method of  claim 20 , further comprising administering temozolomide to the subject. 
     
     
         31 . The method of  claim 20 , further comprising administering chemotherapy or anti-CD20 therapy or other approaches for blocking of neutralizing antibodies. 
     
     
         32 . The method of  claim 20 , further comprising administering substances capable to downregulating regulatory T-cells in the subject. 
     
     
         33 . The method of  claim 20 , further comprising administering cyclophosphamide to the subject. 
     
     
         34 - 38 . (canceled) 
     
     
         39 . The oncolytic adenoviral vector according to  claim 20 , further comprising one or more regions selected from the group consisting of E2, E4 and late regions. 
     
     
         40 . The oncolytic adenoviral vector according to  claim 20 , further comprising regions including a left inverted terminal repeat (ITR), a partial E1, a pIX, a pIVa2, a E2, a VA1, a VA2, a L1, a L2, a L3, a L4, a partial E3, a L5, a E4, and a right ITR. 
     
     
         41 . The oncolytic adenoviral vector according to  claim 40 , wherein the regions are in a sequential order in a 5′ to 3′ orientation. 
     
     
         42 . The oncolytic adenoviral vector according to  claim 20 , further comprising a wild type region located upstream of the E1. 
     
     
         43 . The oncolytic adenoviral vector according to  claim 20 , wherein the E1 comprises a viral packaging signal. 
     
     
         44 . The oncolytic adenoviral vector according to  claim 20 , wherein the nucleic acid sequence encoding GM-CSF is of a wild type. 
     
     
         45 . The oncolytic adenoviral vector according to  claim 39 , wherein at least one of the one or more regions is E4 and is of a wild type. 
     
     
         46 . The oncolytic adenoviral vector according to  claim 20 , further comprising at least one expression cassette. 
     
     
         47 . The oncolytic adenoviral vector according to  claim 20 , further comprising only one expression cassette.