Brachyury protein, non-poxvirus non-yeast vectors encoding Brachyury protein, and their use
Inventors
Schlom, Jeffrey • Palena, Claudia M.
Assignees
US Department of Health and Human Services
Publication Number
US-11357839-B2
Publication Date
2022-06-14
Expiration Date
2033-09-13
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Abstract
Brachyury protein can be used to induce Brachyury-specific CD4+ T cells in vivo and ex vivo. It is also disclosed that Brachyury protein can be used to stimulate the production of both Brachyury-specific CD4+ T cells and Brachyury-specific CD8+ T cells in a subject, such as a subject with cancer. In some embodiments, the methods include the administration of a Brachyury protein. In additional embodiments, the methods include the administration of a nucleic acid encoding the Brachyury protein, such as in a non-pox non-yeast vector. In further embodiments, the method include the administration of host cells expressing the Brachyury protein.
Core Innovation
Brachyury protein and Brachyury polypeptides can be used to induce Brachyury-specific CD4+ T cells in vivo and ex vivo. The invention also discloses that Brachyury protein and polypeptides stimulate the production of both Brachyury-specific CD4+ T cells and Brachyury-specific CD8+ T cells in a subject, including subjects with cancer. Methods include administering Brachyury protein, nucleic acids encoding Brachyury protein (such as in non-pox non-yeast vectors), or host cells expressing Brachyury protein.
Brachyury is expressed in numerous human cancers including cancers of the small intestine, stomach, kidney, bladder, uterus, ovary, testes, lung, colon, prostate, bronchial tube, chronic lymphocytic leukemia, other B cell-based malignancies, and breast cancer such as infiltrating ductal carcinomas. Therefore, Brachyury protein, polypeptides and encoding nucleic acids can be used to induce Brachyury-specific CD4+ and CD8+ T cells useful for treatment or prevention of cancer.
Non-pox non-yeast vectors encoding Brachyury proteins are disclosed, including alphavirus, lentivirus, adenovirus, measles virus, and poliovirus vectors, as well as host cells transformed with these vectors, such as Salmonella or Listeria host cells. Methods include contacting dendritic cells with Brachyury protein or polypeptide and administering these antigen presenting cells to subjects to induce an immune response and inhibit cancer cell growth.
Claims Coverage
The patent contains one independent claim focusing on a method for inducing a Brachyury specific CD4+ T cell response using an adenoviral vector encoding specific Brachyury polypeptides.
Use of adenoviral vectors encoding specific Brachyury peptides to induce CD4+ T cell response
Administering to a subject an effective amount of an adenoviral vector encoding either a polypeptide comprising SEQ ID NO: 5 or consisting of SEQ ID NO: 6 to induce a Brachyury specific CD4+ T cell response and measuring this response.
Inclusion of costimulatory and immunostimulatory molecules in adenoviral vectors
The adenoviral vector can encode costimulatory molecules such as B7-1, B7-2, LFA-3, or ICAM-1, or immunostimulatory molecules including IL-2, ICAM-1, LFA-3, CD72, GM-CSF, TNF-α, IFN-γ, IL-12, and IL-6 to enhance the immune response.
Combination with adjuvants and additional therapeutic agents
The method can include administering adjuvants such as chitosan and therapeutically effective agents including chemotherapeutic drugs, radiation, small molecule targeted therapeutics, and monoclonal antibodies, particularly EGFR inhibitors, TGF-β inhibitors, or tyrosine kinase inhibitors.
Application to cancer treatment including chemotherapy or radiation resistant cancers
The method is applicable to subjects with cancer, including breast, small intestine, stomach, kidney, bladder, uterus, ovarian, testes, lung, colon, prostate cancers, chronic lymphocytic leukemia, B cell lymphomas, Burkitt's lymphoma, Hodgkin's lymphoma, with an emphasis on chemotherapy-resistant or radiation-resistant cancers.
The independent claim covers a method for inducing a Brachyury specific CD4+ T cell immune response by administering adenoviral vectors encoding particular Brachyury peptides, optionally encoding costimulatory or immunostimulatory molecules, optionally combined with adjuvants or additional anticancer agents, and directed to treatment or prevention of various cancers including resistant types.
Stated Advantages
Brachyury protein and polypeptides can induce both CD4+ and CD8+ T cell immune responses specific to Brachyury.
Use of non-pox non-yeast vectors allows for efficient delivery and expression of Brachyury protein or polypeptides.
Methods can be combined with other therapies such as chemotherapy, radiation, or immunostimulatory agents for enhanced cancer treatment.
Documented Applications
Induction of Brachyury-specific CD4+ and CD8+ T cells in vivo and ex vivo for cancer immunotherapy.
Treatment or prevention of cancers including breast cancer, small intestine cancer, stomach cancer, kidney cancer, bladder cancer, uterus cancer, ovarian cancer, testes cancer, lung cancer, colon cancer, prostate cancer, chronic lymphocytic leukemia, other B cell-based malignancies, and lymphomas.
Using dendritic cells pulsed with Brachyury protein or polypeptides to generate antigen presenting cells for immune activation against cancer.
Combining Brachyury immunotherapy with chemotherapeutic agents, radiation, targeted therapies, and monoclonal antibodies.
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