Furin-knockdown and GM-CSF-augmented (FANG) cancer vaccine
Inventors
Nemunaitis, John J. • Senzer, Neil • Maples, Phillip B. • Rao, Donald
Assignees
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Publication Number
US-9790518-B2
Publication Date
2017-10-17
Expiration Date
Abstract
Compositions and methods for cancer treatment are disclosed herein. More specifically, the present invention describes an autologous cancer vaccine genetically modified for Furin knockdown and GM-CSF expression. The vaccine described herein attenuates the immunosuppressive activity of TGF-β through the use of bi-functional shRNAs to knock down the expression of furin in cancer cells, and to segment tumor antigen expression, presentation, and processing through expression of the GM-CSF transgene.
Core Innovation
The invention provides a furin-knockdown and GM-CSF-augmented autologous whole-cell cancer vaccine concept. It uses genetically modified patient tumor cells expressing GM-CSF and a bi-functional furin-targeting shRNA. The furin-targeting sequence is described as bi-functional shRNA/siRNA+miRNA-like motifs according to SEQ ID NO:2.
The described problem is that immunosuppressive TGF-β activity, including TGF-β1 and TGF-β2, can suppress immune modulation. The invention presents furin knockdown as a strategy to attenuate TGF-β activation and thereby enhance GM-CSF-mediated antigen expression, presentation, and processing.
In the system described, the expression vector architecture includes a CMV promoter, optionally with enhancer/intron, and a picornaviral 2A ribosomal skip peptide positioned between GM-CSF and the shRNA cassettes. The furin-targeting nucleic acid sequence targets furin mRNA coding and/or 3′UTR regions, and the approach includes transfecting tumor cells for administration, with optional γIFN combination therapy and monitoring of TGF-β and GM-CSF levels.
Claims Coverage
One independent claim is identified. The independent claim includes two core inventive elements: an expression vector configured with GM-CSF and a defined furin-targeting insert sequence (SEQ ID NO: 2) introduced into an autologous tumor cell, and administering the transfected tumor cell to treat cancer in an individual.
Autologous tumor cell expressing GM-CSF and SEQ ID NO: 2
The method transfects an autologous tumor cell from the individual with an expression vector comprising a first insert encoding a GM-CSF sequence and a second insert comprising a sequence according to SEQ ID NO: 2.
Administration of transfected autologous tumor cells for cancer treatment
The method administers the transfected tumor cell to the individual to treat the cancer in an individual in need thereof.
Overall claim coverage is directed to treating cancer by transfecting an autologous tumor cell with an expression vector encoding GM-CSF together with a second insert defined by SEQ ID NO: 2, followed by administering the transfected tumor cell to the individual.
Stated Advantages
Attenuating immunosuppressive TGF-β activity to enhance GM-CSF-mediated antigen expression, presentation, and processing.
Documented Applications
Treating cancer in an individual in need thereof using transfected autologous tumor cells expressing GM-CSF and furin-targeting SEQ ID NO: 2.
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