Multi-indication mRNA cancer immunotherapy
Inventors
Lawman, Michael J. P. • Lawman, Patricia D. • GENTILINI, MEGHAN • RAMIYA, VIJAY • BASTAWROUS, MARINA VICTOR ABDELMASEEH
Assignees
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Publication Number
US-9636388-B2
Publication Date
2017-05-02
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 invention relates to multi-indication cancer immunotherapy that uses synthetic bacterial mRNA having the sequence of SEQ ID NO: 1 encoding an immunogenic M-like protein, including Emm55/emmL or related M-like protein. The approach is directed to eliciting immune triggering through antigen presentation pathways mediated by major histocompatibility complex on antigen presenting cells, leading to multi-tumor antigen and/or epitope spreading.
The synthetic bacterial mRNA is administered directly into a tumor or a tumor draining lymph node of a cancer patient, or introduced into tumor cells in vitro to generate a vaccine. Upon expression, the bacterial immunogenic protein provides an immunogenic effect, which is described as translating into an immune response after in vivo administration.
The invention also includes engineered mRNA features and combination strategies, including the use of 5′-methylguanosine cap and a 3′ polyA tail, and the combination with checkpoint inhibitors such as anti-PD1 and anti-CTLA4. Reported immune readouts include antibody responses and cytotoxic T cell responses, together with tumor measurement outcomes, including tumor burden reduction in described tumor models.
Claims Coverage
The partial content includes two independent claims. Across the independent claims, the coverage is anchored on two inventive frameworks: direct SEQ ID NO: 1 nucleic acid delivery into tumor tissue or tumor draining lymph node, and in vitro transformed tumor-cell vaccine expressing an immunogenic polypeptide after administration.
Direct administration of SEQ ID NO: 1 into tumor or tumor draining lymph node
Administering a ribonucleic acid having the sequence of SEQ ID NO: 1 directly into a tumor or tumor draining lymph node of a cancer patient.
In vitro transformed tumor-cell vaccine expressing an immunogenic polypeptide from SEQ ID NO: 1
Administering a vaccine comprising tumor cells transformed in vitro with a ribonucleic acid having the sequence of SEQ ID NO: 1, wherein the transformed cells expressing an immunogenic polypeptide on the cell surface induces an immunogenic effect upon in vivo administration, and wherein the cancer patient has at least one type of cancer cell comprised by the vaccine.
Overall, the independent claims cover cancer treatment by either direct administration of SEQ ID NO: 1 ribonucleic acid into tumor or tumor draining lymph node, or by vaccinating with tumor cells transformed in vitro with SEQ ID NO: 1 so the cells express an immunogenic polypeptide on the cell surface to induce an in vivo immunogenic effect for a patient whose cancer cell types are included by the vaccine.
Stated Advantages
mRNA is described as having advantages over DNA, including no genomic integration, transient expression, faster translation, and safety.
Documented Applications
Multi-indication cancer immunotherapy including treatment contexts described across cancer settings, with examples discussed for melanoma, lymphoma, and other tumor models in the document, including mouse melanoma tumor model, canine lymphoma, and equine melanoma.
Vaccine administration derived from tumor cells transformed in vitro with SEQ ID NO: 1 to induce an immunogenic effect upon in vivo administration.
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