Multi-indication mRNA cancer immunotherapy
Inventors
Lawman, Michael J. P. • Lawman, Patricia D. • GENTILINI, MEGHAN • RAMIYA, VIJAY • BASTAWROUS, MARINA VICTOR ABDELMASEEH • Shamblott, Michael J.
Assignees
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Publication Number
US-10682401-B2
Publication Date
2020-06-16
Expiration Date
Abstract
Synthetic bacterial messenger RNA can be used to prepare autologous, allogenic or direct nucleic acid cancer vaccines. Cancer cells are transfected either in vitro or in vivo with mRNA obtained from DNA that encodes an immunogenic bacterial protein. An immune response to the cancer is generated from direct administration of the mRNA in vivo or administration of vaccines prepared from cancer cells in vitro.
Core Innovation
The disclosure relates to ribonucleic acid (mRNA) cancer immunotherapy in which a synthetic bacterial mRNA encodes an immunogenic bacterial protein and expresses the immunogenic polypeptide in tumor cells. The bacterial protein is exemplified by emmL / Emm55 / M-like protein. The ribonucleic acid is used to induce an immune response by enabling tumor cells to express the immunogenic polypeptide after introduction of the ribonucleic acid into tumor cells.
The disclosed approach is implemented as vaccine compositions. A nucleic acid vaccine composition includes the ribonucleic acid sequence corresponding to SEQ ID NO: 1 in a pharmaceutically acceptable excipient, intended to produce an immunogenic response when administered to a cancer patient. In addition, a cancer cell vaccine composition uses tumor cells transformed or transfected with the ribonucleic acid (SEQ ID NO: 1) so that the tumor cells express the immunogenic polypeptide and function as the vaccine component.
The disclosure emphasizes mRNA-specific safety and kinetics, describing mRNA as non-integrating and enabling transient expression with cytosolic translation and reduced need for nuclear entry compared with DNA approaches. It further describes mRNA stability and translation efficiency using features such as a 5′ cap and a 3′ poly(A) tail, optionally including modified nucleotides and cap analogs. Delivery formulations are described using delivery vehicles such as lipids, protamine, liposomes, nanoparticles, or polymers, and the disclosure also describes combining the mRNA immunotherapy with additional immunotherapy components such as checkpoint inhibitors and adjuvants.
The disclosed immunological effect is described in terms of immune system activation, including antibody and cytotoxic T lymphocyte (CTL) responses, and an impact on tumor size in evaluated settings. The disclosure also describes immune mechanisms consistent with tumor antigen presentation through antigen presenting cells and immune checkpoint modulation involving molecules such as PD-1, PD-L1, CTLA-4, and TIGIT. Multi-tumor and epitope-spreading effects are described as triggered by the immunogenic bacterial protein.
Claims Coverage
The provided independent claims cover four main areas: (1) a ribonucleic acid defined by SEQ ID NO: 1 that expresses an immunogenic polypeptide in transfected tumor cells, (2) a nucleic-acid vaccine composition comprising that ribonucleic acid for producing an immunogenic response in a cancer patient, (3) a cancer cell vaccine composition including tumor cells transformed with the ribonucleic acid of SEQ ID NO: 1, and (4) an in vitro transfected tumor-cell vaccine composition using a synthetic ribonucleic acid of SEQ ID NO: 1 in a pharmaceutically acceptable carrier.
Ribonucleic acid expressing immunogenic polypeptide in tumor cells
A ribonucleic acid comprising the sequence of SEQ ID NO: 1, wherein said ribonucleic acid expresses an immunogenic polypeptide in tumor cells transfected with said ribonucleic acid.
Nucleic acid vaccine composition producing immunogenic response
A vaccine composition comprising a nucleic acid having SEQ ID NO: 1, wherein an immunogenic response is produced when the vaccine composition is administered to a cancer patient.
Cancer cell vaccine with tumor cells transformed by SEQ ID NO: 1
A cancer cell vaccine composition comprising tumor cells transformed with a ribonucleic acid having the sequence of SEQ ID NO: 1.
In vitro transfected tumor-cell vaccine with synthetic SEQ ID NO: 1
A vaccine composition comprising tumor cells transfected in vitro with a synthetic ribonucleic acid having the sequence of SEQ ID NO: 1 comprised in a pharmaceutically acceptable carrier.
Across the independent claims, coverage centers on a defined ribonucleic acid sequence (SEQ ID NO: 1) enabling expression of an immunogenic polypeptide in tumor cells and supporting both nucleic-acid vaccine formulations and tumor-cell vaccine formulations, including in vitro transfected tumor cells in a pharmaceutically acceptable carrier.
Stated Advantages
mRNA is non-integrating and enables transient expression with cytosolic translation and reduced need for nuclear entry compared with DNA approaches.
mRNA stability and translation efficiency are described using a 5′ cap and a 3′ poly(A) tail, optionally including modified nucleotides and cap analogs.
Immune system activation includes antibody and cytotoxic T lymphocyte (CTL) responses.
Multi-tumor and epitope-spreading effects are described as triggered by the immunogenic bacterial protein.
Documented Applications
Nucleic acid vaccine composition administered to a cancer patient to produce an immunogenic response.
Cancer cell vaccine composition using tumor cells transformed or transfected with the ribonucleic acid.
Combination with additional immunotherapy components such as checkpoint inhibitors and adjuvants.
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