Method of targeting oncolytic viruses to tumors
Inventors
Mohapatra, Shyam S. • Mohapatra, Subhra
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-11607426-B2
Publication Date
2023-03-21
Expiration Date
2037-09-19
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Abstract
The present invention pertains to a strategy of selectively targeting oncolytic virotherapy, using either naturally occurring or genetically modified viruses by packaging them in mesenchymal stem cells (MSCs). The present invention concerns MSCs, compositions comprising the MSCs, and methods of using the MSCs for treatment of cancer and for lysing or inducing apoptosis of cancer cells in vitro or in vivo.
Core Innovation
The invention provides a method of selectively targeting oncolytic virotherapy to tumors by packaging either naturally occurring or genetically modified oncolytic viruses within mesenchymal stem cells (MSCs), particularly human MSCs (hMSCs). This approach leverages the tumor-homing capacity of MSCs, enabling the oncolytic virus to specifically infect tumor cells, lyse them, or induce apoptosis while sparing surrounding non-malignant cells. The resulting compositions comprise MSCs infected with the oncolytic virus, optionally IDO-deficient to reduce immunosuppressive effects, and pharmaceutically acceptable carriers or adjuvants for administration to subjects in need.
Current treatments for lung cancers, especially non-small cell lung cancer (NSCLC), face difficulties such as drug-induced toxicity, tumor heterogeneity leading to resistance against chemotherapy and radiotherapy, and tumor radio-resistance linked to genes like p53, EGFR, and TNNC1. Despite clinical progress, advanced or metastatic NSCLC remains difficult to treat, underscoring the need for novel therapeutic strategies. Oncolytic virotherapy has re-emerged as a potential approach but faces challenges including host immune clearance of viruses, non-specific uptake by non-target tissues, and lack of effective tumor targeting, particularly for lung tumors. The invention addresses these issues by using MSCs as vectors to deliver oncolytic viruses directly to tumor sites, improving specificity and efficacy.
The invention further addresses the problem that RSV-infected MSCs upregulate indoleamine 2,3-dioxygenase (IDO), an enzyme that inhibits anti-tumor immunity through immunosuppressive properties. By producing IDO-deficient MSCs using CRISPR/Cas9 gene editing, the invention enables the retention of MSCs’ tumor-homing and virus-infectibility functions while reducing immunosuppression. Infected IDO-deficient MSCs can be administered systemically or locally and can be used with or without additional IDO inhibitors or anti-cancer agents to treat cancer effectively. This strategies yield a platform to improve the delivery and therapeutic effects of oncolytic viruses including RSV against lung and other cancers.
Claims Coverage
The claims include one independent composition claim and two independent method claims involving the use of MSCs with specific genetic modifications and properties related to IDO deficiency and virus infection.
Indoleamine 2,3-dioxygenase (IDO)-deficient mesenchymal stem cell that over-expresses interferon-beta
An MSC that is IDO-deficient due to CRISPR-mediated knockout of IDO and also over-expresses interferon-beta, with the MSC optionally being human.
Method for treating cancer using IDO-deficient MSCs
Administering an effective amount of an IDO-deficient MSC (as described) to a human or non-human animal subject to treat cancer, including lung cancer and non-small cell lung cancer (NSCLC). This method may further include administering an IDO inhibitor composed of small molecules or biologics such as nucleic acids, proteins, peptides, antibodies, or antibody fragments, including specific examples like IDO peptide vaccines or NLG919.
Method for lysing or inducing apoptosis of cancer cells with IDO-deficient MSCs
Contacting or bringing into close proximity cancer cells in vitro or in vivo with an effective amount of IDO-deficient MSCs, with cancer cells optionally being lung cancer cells, specifically NSCLC, and optionally further including an IDO inhibitor in the treatment.
Pharmaceutical composition comprising IDO-deficient MSC
A composition comprising an IDO-deficient MSC as described and a pharmaceutically acceptable carrier or diluent, further optionally comprising an adjuvant.
The independent claims cover MSCs genetically modified to be IDO-deficient and over-express interferon-beta, methods of using these MSCs to treat cancer and induce tumor cell apoptosis, optionally combined with IDO inhibitors, and pharmaceutical compositions comprising these MSCs. The claims focus on targeting oncolytic virotherapy via these engineered MSCs to achieve selective tumor targeting and improved therapeutic effect.
Stated Advantages
Targeted delivery of oncolytic viruses to tumors through MSCs enhances selective infection and destruction of cancer cells while sparing normal cells.
IDO deficiency in MSCs prevents immunosuppression typically induced by IDO expression, thereby potentially improving anti-tumor immune responses.
MSC-mediated delivery can overcome challenges of systemic administration of oncolytic viruses, such as immune clearance and non-specific uptake, increasing the amount of virus reaching tumors.
Use of CRISPR/Cas9 gene editing to produce IDO-deficient MSCs offers a precise method to eliminate immunosuppressive function without affecting virus infectibility or tumor tropism.
Documented Applications
Treatment of cancers, including lung cancer and specifically non-small cell lung cancer (NSCLC), by administering MSCs infected with oncolytic viruses.
Lysing or inducing apoptosis of cancer cells in vitro or in vivo by contacting them with IDO-deficient MSCs infected with oncolytic viruses.
Production of oncolytic agents by infecting MSCs with oncolytic viruses for use as therapeutics.
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