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Neoepitope vaccine compositions and methods of use thereof

A composition and fusion partner technology, applied in biochemical equipment and methods, drug combinations, chemical instruments and methods, etc., can solve the problem of not being able to trigger therapeutic immunity

Inactive Publication Date: 2019-06-14
埃特彼塞斯公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, clinical vaccination trials targeting tumor-associated autoantigens often fail to elicit therapeutic immunity despite detection of vaccine-induced T-cell responses in the blood

Method used

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  • Neoepitope vaccine compositions and methods of use thereof
  • Neoepitope vaccine compositions and methods of use thereof
  • Neoepitope vaccine compositions and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0497] Multiple neo-epitopes for insertion of Ad5 [E1-, E2b-]

[0498] Construction of vectors (Alkbh6.2, Slit3 and Atxn10.1)

[0499] Construction of Ad5[E1-, E2b-] vector: the about 20kb Xba-BamHI subfragment of pBHG11 (Bett et al., 1994, Institute of Microbiology, Toronto, Ontario, Canada (1994, Microbix, Toronto, Ontario, Canada)) Subcloning into pBluescriptKSII+ (Stratagene, La Jolla, Calif.) generated pAXB. Plasmid pAXB was digested with BspEI, end-stuffed with T4 DNA polymerase, and digested with BamHI to isolate a fragment of approximately 9.0 kb. Plasmid pAXB was also digested with BspHI, T4 DNA polymerase endfill, and BamHI digested, and the approximately 13.7 kb fragment was ligated to a previously isolated 9.0 kb fragment to generate pAXB-Δpol.

[0500] This subcloning strategy deleted a 608 bp (Δpol; Ad5 nucleotide 7274 to nucleotide 7881 ) at the amino terminus of the polymerase gene. This deletion also effectively removed the open reading frame 9.4 present on...

Embodiment 2

[0504] Multiple injections of Ad5[E1-,E2b-]-vectors containing Alkbh6.2, Slit3, and Atxn10.1 generate cell-mediated immune responses against these neoepitopes

[0505] Mice were immunized twice with mutated peptides Alkbh6.2, Slit3 and Atxn10.1 or an empty vector control, two weeks apart. Draining lymph nodes were harvested 7 days after immunization was terminated. Lymph nodes were cultured in vitro, then stimulated or unstimulated with cognate peptides for 20 hours, and then analyzed by ELISpot. Spleens were obtained from individual mice two (2) weeks after the last immunization (vaccination), and the CMI of IFN-secreting splenocytes was assessed using an ELISpot assay (Gabitzsch ES, et al. Cancer Immunity Antigens 2010;59: 1131-35 (Cancer Immunol Immunother. 2010; 59:1131-35); Gabitzsch ES, et al. Cancer Gene Ther. 2011; 18:326-35 (Cancer Gene Ther. 2011; 18:326-35); Jones FR , et al. Vaccinology 2011;29:7020-26 (Vaccine 2011;29:7020-26)).

Embodiment 3

[0507] Vaccination with Ad5[E1-,E2b-]-vector containing Alkbh6.2, Slit3 and Atxn10.1 in

[0508] Generation of cell-mediated immune responses against these neo-epitopes in vivo

[0509] Each group of five (5) mice was subcutaneously administered at two (2) week intervals at a dose of 1 x 10 8 , 1×10 9 or 1×10 10 VP Ad5[E1-, E2b-]-Alkbh6.2, Slit3 and Atxn10.1 or blank control vector. One week later, mice were challenged intradermally with 300,000 live CMS5-FFLuc tumor cells. Tumor growth was monitored using live bioluminescent imaging (PerkinElmer). Blood was collected from mice, T cells were isolated, and stimulated in vitro with cognate peptides, unstimulated or unstimulated with unrelated peptides. Media were analyzed for IFN-γ and IL-2 production. Flow cytometry of mouse T cells for intracellular IFN-γ production.

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Abstract

In certain embodiments, methods and compositions are provided for generating immune responses against tumor neo-antigens or neo-epitopes. In particular embodiments there may be provided methods for constructing and producing recombinant adenovirus-based vector vaccines containing nucleic acid sequences encoding tumor neo-antigens and neo-epitopes that allow for vaccinations in individuals with preexisting immunity to adenovirus. In additional embodiments, methods and compositions are provided for the treatment of cancer using immunotherapy based on recombinant adenovirus-based vectors combinedwith engineered natural killer cells. In some embodiments, the methods and compositions further comprises a nucleic acid encoding for an immunological fusion partner.

Description

[0001] cross reference [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 342,752, filed May 27, 2016, which is hereby incorporated by reference in its entirety. Background technique [0003] Limiting vaccination against cancer by identifying relevant target antigens. Thus, clinical vaccination trials targeting tumor-associated autoantigens have generally failed to elicit therapeutic immunity despite detection of vaccine-induced T-cell responses in the blood. [0004] In retrospect, these failures may be explained by the finding that many of these autoantigens are expressed in the thymus, leading to loss of the hyperreactive T cell repertoire and development of suppressive T regulatory cells. Furthermore, circumvention of thymic tolerance by infusion of genetically engineered T cells targeting such antigens was found to be associated with severe toxicity in vital somatic tissues, illustrating the physiological importance of immune toler...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00C12N15/86C07K14/705
CPCA61K39/0011C07K14/705C12N15/86A61K2039/5154A61K2039/5256A61K2039/545C12N2710/10343C07K14/4748A61P35/00A61P37/04C07K14/5443C07K14/7155A61K39/001193A61K39/001184A61K39/001161A61K39/001176A61K39/001194A61K39/00117A61K39/001188A61K39/001191A61K39/001106A61K39/001151A61K39/001157A61K39/001182A61K39/001102A61K39/001156A61K39/001189A61K39/001192A61K39/001162A61K39/001186A61K39/001195A61K39/04A61K39/102G01N33/57484A61K2039/585A61K38/191A61K38/20A61K39/3955A61K39/39541A61K38/2086A61K35/17C12N7/00C12N2710/10043G01N33/574
Inventor F·R·琼斯A·赖斯P·孙雄K·尼亚兹S·拉比扎德
Owner 埃特彼塞斯公司
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