DNA vector and transformed tumor cell vaccines
Inventors
Lawman, Michael J. P. • Lawman, Patricia D. • RAMIYA, VIJAY
Assignees
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Publication Number
US-9839680-B2
Publication Date
2017-12-12
Expiration Date
Abstract
Customized whole cell cancer vaccines can be produced from autologous (ex vivo or in situ) or allogeneic human or veterinary patient cell lines. Cells are transformed with S. pyogenes DNA that expresses an Emm protein on the cell surface and cytosol. Treatment of cancer patients with an Emm vector vaccine induces an immunologic response to the cancer by enhancing immunogenicity of a tumor. Emm vaccines can be used in patients where the cancer is not identified due to lower tumor burden or used to treat a specific cancer and subsequently treat for a second type that may have arisen through metastasis.
Core Innovation
The patent describes therapeutic cancer vaccines using S. pyogenes emm DNA vectors that encode an Emm M-type surface/cytosolic immunogenic polypeptide. A plasmid DNA vector comprising a nucleic acid sequence set forth as SEQ ID NO: 1 is operatively linked to a promoter to express an immunogenic polypeptide on the cell surface. In embodiments, the vaccine positions Emm expression in tumor cells as an in situ/on-tumor “danger” signal intended to enhance anti-tumor immunity.
The described approach addresses a problem in which tumors develop self-tolerance that limits effective immune activation. By using Emm-derived microbial signals, the patent states that this can overcome tumor self-tolerance and help activate antigen presenting cells and dendritic cells. The patent further states that this supports cross-priming and tumor-draining lymph node responses, leading to anti-tumor immune activity.
The patent also describes embodiments enabling both direct intratumoral plasmid DNA vaccination and whole-cell vaccination using tumor cells transformed with the emm vector. For solid and liquid tumors, embodiments include using multiple M/Emm types and preparing autologous or allogeneic whole-cell vaccines from tumor cells transformed with the emm vector. The document further discusses potential combination with checkpoint inhibitors, costimulatory antibodies, cytokines, TLR agonists, and includes embodiments with standardized allogeneic cell lines.
Claims Coverage
The independent claims are directed to two inventive features: a plasmid DNA vaccine that expresses a specified immunogenic polypeptide on the cell surface from a defined SEQ ID NO: 1 sequence, and a vaccine comprising tumor cells transformed in vitro with the same SEQ ID NO: 1 plasmid DNA vector, where the transformed cells express an immunogenic polypeptide on the cell surface.
Plasmid DNA vector with SEQ ID NO: 1 for surface immunogenic polypeptide expression
A plasmid DNA vaccine comprising a plasmid DNA vector comprising a nucleic acid sequence set forth as SEQ ID NO: 1 operatively linked to a promoter expressing an immunogenic polypeptide on the cell surface.
In vitro transformed tumor cells expressing surface immunogenic polypeptide from SEQ ID NO: 1
A vaccine comprising tumor cells transformed in vitro with a plasmid DNA vector comprising a nucleic acid sequence set forth as SEQ ID NO: 1 operatively linked to a promoter, said transformed cells expressing an immunogenic polypeptide on the cell surface.
Both independent claims rely on the same core plasmid design defined by SEQ ID NO: 1 operatively linked to a promoter to drive expression of an immunogenic polypeptide on a cell surface, with the second claim shifting the format to vaccines comprising tumor cells transformed in vitro with that plasmid DNA vector.
Stated Advantages
Enhances innate and adaptive anti-tumor immunity by positioning Emm expression in tumor cells as an in situ/on-tumor “danger” signal.
Overcomes tumor self-tolerance.
Helps activate antigen presenting cells and dendritic cells and supports tumor-draining lymph node responses and cross-priming.
Increases anti-tumor IgG responses as supported by ELISA.
Increases immune cell infiltration including CD45+ immune cell infiltration and T and B cells.
Provides tumor regression or tumor stabilization and improved survival/QOL in described canine and equine subjects.
Documented Applications
Therapeutic cancer vaccination in cancer patients using plasmid DNA vaccination and tumor-cell based vaccination, including direct intratumoral plasmid DNA vaccination and whole-cell vaccines prepared from tumor cells transformed with the emm vector.
Use in solid and liquid tumors, with embodiments covering tumor types including carcinoma, sarcoma, myeloma, lymphoma, leukemia, and mixed tumor types.
Combination with other cancer therapies including checkpoint inhibitors, and additionally with radiation and/or chemotherapy as described for certain embodiments.
Veterinary settings in described canine and equine subjects, where increased anti-tumor IgG responses and improved survival/QOL are reported.
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