Oncolytic adenoviruses coding for bi-specific antibodies 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 of humans. More specifically, the present invention relates to an oncolytic adenoviral vector encoding a bispecific monoclonal antibody. Furthermore, the present invention relates to methods and uses utilizing the oncolytic adenoviral vectors, also together with adoptive cell therapies.

1 . A method of treating cancer in a subject, wherein the method comprises administration of an oncolytic adenoviral vector to a subject, wherein the oncolytic adenoviral vector comprises:
 i) an adenovirus serotype 5 (Ad5) nucleic acid backbone comprising a 5/3 chimeric fiber knob;   ii) an E2F1 promoter for tumor specific expression of E1A;   iii) a 24 bp deletion (D24) in the Rb binding constant region 2 of adenoviral E1;   iv) a nucleic acid sequence deletion of viral gp19k and 6.7k reading frames; and   v) a nucleic acid sequence encoding a bispecific monoclonal antibody in the place of the deleted gp19k and 6.7k nucleic acid sequence in the E3 region,   wherein the bispecific monoclonal antibody comprises a single chain variable fragment (scFv) specific for a cell surface molecule on immunological effector cells and a scFv specific for a tumor antigen,   wherein the tumor antigen is EpCAM1 or MUC 1 and the cell surface molecule is CD3, and   wherein, in the presence of tumor cells, the bispecific monoclonal antibody is capable of counteracting tumor immunosuppression and promoting the recruitment of T cells to the tumor cells.   
     
     
         2 . The method according to  claim 1 , wherein the method further comprises administration of adoptive cell therapeutic composition to the subject. 
     
     
         3 . The method according to  claim 2 , wherein the adoptive cell therapeutic composition comprises a cell type selected from a group consisting of a tumor infiltrating lymphocyte (TIL), T-cell receptor modified lymphocytes and chimeric antigen receptor modified lymphocytes. 
     
     
         4 . The method according to  claim 2 , wherein the adoptive cell therapeutic composition comprises a cell type selected from a group consisting of T-cells, CD 8 + cells, CD 4 + cells, NK-cells, delta-gamma T-cells, regulatory T-cells, and peripheral blood mononuclear cells. 
     
     
         5 . The method according to  claim 2 , wherein the adoptive cell therapeutic composition comprises T-cells. 
     
     
         6 . The method according to  claim 2 , wherein the administration(s) of oncolytic viral vectors and an adoptive cell therapeutic composition to a subject is(are) conducted simultaneously or consecutively, in any order. 
     
     
         7 . The method according to  claim 2 , further comprising administration of concurrent or sequential radiotherapy, monoclonal antibodies, chemotherapy or other anti-cancer drugs or interventions to a subject. 
     
     
         8 . The method according to  claim 2 , wherein the method increases the efficacy of adoptive cell therapy in a subject. 
     
     
         9 . The method according to  claim 1 , 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 and tonsil cancer. 
     
     
         10 . The method according to  claim 1 , wherein the tumor antigen is EpCAM1. 
     
     
         11 . The method according to  claim 1 , wherein the tumor antigen is MUC 1. 
     
     
         12 . The method according to  claim 11 , wherein the nucleic acid sequence further encodes for IL-2. 
     
     
         13 . The method according to  claim 1 , wherein the oncolytic adenoviral vector further comprises an IL-2, TNFalpha, or CD40L transgene.