Methods for treatment of cancer using chikungunya-VSV chimeric virus
Inventors
Assignees
Publication Number
US-12274724-B2
Publication Date
2025-04-15
Expiration Date
2039-07-17
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Chimeric viruses having a vesicular stomatitis virus (VSV) background where the VSV G protein is supplemented or replaced with an alphavirus glycoprotein(s), or a functional fragment(s) thereof, are provided. A preferred alphavirus is Chikungunya virus. In particular embodiments, the glycoprotein(s) is or includes E3, E2, K6, and E1 proteins of an alphavirus, preferably Chikungunya virus. Methods of using the chimeric viruses for treatment of cancers, particularly brain cancers and metastasis thereof are also provided. In some embodiments, the chimeric viruses retain superior oncolytic activity to infect and destroy cancer cells selectively, such as glioblastoma and intracranial melanoma metastases. In some embodiments, the chimeric viruses have reduced toxicity to e.g., heathy cells relative to a control such as the parent VSV with the VSV G protein.
Core Innovation
Chimeric viruses comprising a vesicular stomatitis virus (VSV) background where the VSV G protein is supplemented or replaced with one or more alphavirus glycoproteins, preferably from the Chikungunya virus, are provided. In particular embodiments, the glycoprotein(s) include E3, E2, 6K, and E1 proteins of Chikungunya virus. These chimeric viruses can be further modified to express therapeutic proteins, reporters, vaccine antigens, or targeting moieties, making them suitable for pharmaceutical compositions and cancer treatments.
The invention addresses the problem that native VSV glycoprotein is highly neurotropic, leading to significant neurological toxicity when used as an oncolytic agent, particularly in the brain. Existing alternatives have failed to universally reduce neurotropism or have enhanced it in some cases. There remains a need for improved VSV chimeric viruses that can selectively infect and kill tumor cells while exhibiting low toxicity toward normal, especially neural, cells.
The provided chimeric VSVs, with the VSV G protein replaced by Chikungunya virus glycoproteins, retain superior oncolytic activity against various cancers, notably brain tumors such as glioblastoma and melanoma metastases, both in vitro and in vivo. These viruses demonstrate selective targeting and destruction of cancer cells with negligible infection or toxicity to normal or healthy cells. The invention also discloses methods of administration for treating cancer, including direct injection, systemic delivery, and combination with other therapies, as well as strategies for immune priming and adaptive T cell therapy.
Claims Coverage
There is one independent inventive feature in the claims, centered on a method of treating cancer using a specific chimeric vesicular stomatitis virus (VSV) construct.
Method of treating cancer using a chimeric VSV with Chikungunya virus glycoproteins
A method of treating cancer in a subject by administering a pharmaceutical composition containing an effective amount of a chimeric vesicular stomatitis virus (VSV). This chimeric virus comprises: - A VSV background in which the VSV glycoprotein (G) is replaced by Chikungunya virus glycoproteins. - The chimeric VSV genome encodes VSV nucleocapsid (N), phosphoprotein (P), matrix (M), large (L) polymerase proteins and Chikungunya virus E3, E2, 6K, and E1 proteins. - The method specifically covers use where the virus selectively treats cancer by utilizing these glycoprotein substitutions, and further embraces pharmaceutical administration routes for effective cancer treatment. This inventive feature serves as the foundation for dependent claims that specify aspects such as particular Chikungunya strains, additional genetic modifications, types of cancers treated, administration routes, and combination therapies.
The inventive feature defines the use of a genetically engineered chimeric VSV, where the glycoprotein is replaced with Chikungunya virus glycoproteins (E3, E2, 6K, E1), for effective and selective treatment of cancer.
Stated Advantages
The chimeric VSV viruses demonstrate superior oncolytic activity, selectively infecting and destroying cancer cells with little or no infection of normal or healthy cells.
The chimeric VSVs have reduced neurotropism and dramatically decreased toxicity to normal and healthy neurons compared to VSV with its native glycoprotein.
Treatment with the chimeric viruses substantially extends survival in tumor-bearing subjects.
The chimeric viruses can be used in immunocompromised subjects and show safety even when administered directly to the brain.
The modified viruses exhibit a broad spectrum of anti-cancer activity against multiple tumor types, including brain cancers and metastases.
The platform allows for further genetic modifications to include therapeutic proteins, vaccine antigens, or targeting moieties.
Documented Applications
Treatment of cancer in a subject, including local or systemic administration of the chimeric VSV for tumor reduction or elimination.
Treatment of brain cancers such as glioblastoma, meningioma, pineal region tumors, medulloblastoma, astrocytoma, and melanoma metastases to the brain.
Treatment of other cancers outside the brain, including multiple myeloma, bone, bladder, breast, cervical, colo-rectal, esophageal, kidney, liver, lung, nasopharyngeal, pancreatic, prostate, skin, stomach, and uterine cancers.
Use in combination with surgery, such as injection into or adjacent to tumor sites, or into tumor resection cavities.
Use in combination with chemotherapy agents, immunosuppressants, or therapeutic proteins as part of a combination therapy regimen.
Priming the immune system and adaptive T cell therapy, including harvesting and expanding T cells after viral treatment for adoptive cell transfer.
Administration as part of a protocol to vaccinate against unrelated microbial antigens by incorporating additional vaccine antigens into the viral genome.
Interested in licensing this patent?