Research

The Gene and Virus Therapy Program collaborates with numerous Mayo Clinic faculty researchers on four defined research focus areas, with a goal of improving treatment options and outcomes for patients with cancer.

Research focus areas include:

  • Developing novel gene and virus platforms for use in cancer therapy
  • Developing cancer immunotherapies by exploring the immunomodulatory potential of gene-based and virus-based therapeutics
  • Assessing preclinical, clinical, pharmacologic and immunologic properties of vectors used in cancer therapy and optimizing their clinical application
  • Evaluating the role of cells as carriers in gene-based and virus-based therapeutic approaches to cancer therapy

Developing novel gene and virus platforms for use in cancer therapy

Recent advances in this research area include:

  • Identifying nectin-4 as the epithelial receptor of the measles virus
  • Demonstrating that combining oncolytic measles virus strains with inhibitors of Aurora-A kinase led to an increase in the measles virus oncolytic effect by causing mitotic arrest
  • Demonstrating that inhibition of Rho-associated coiled-coil kinases by ROCK inhibitors can significantly increase the efficacy of measles virotherapy by rendering the cell cytoskeleton more amenable to cell-to-cell fusion
  • Demonstrating significant anti-tumor activity of the measles virus against osteosarcoma and malignant peripheral nerve sheath tumor models
  • Demonstrating that the replication and polypeptide display characteristics of the avian leukosis virus offer a robust, eukaryotic version of bacteriophage display systems
  • Investigating the oncolytic properties of different adenoviral serotype platforms
  • Demonstrating that the low seroprevalence adenovirus serotype 6 (Ad6) may have better efficacy and safety than does the benchmark oncolytic virus Ad5 for systemic therapy of prostate cancer
  • Demonstrating that IFN signaling results in increased vesicular stomatitis virus efficiency
  • Demonstrating that substituting the G gene of vesicular stomatitis virus with the corresponding Maraba virus gene can protect the virus from neutralization and that these strains should be further investigated as candidates for human systemic oncolytic virotherapy and gene therapy applications
  • Demonstrating that functional tumor-targeting ligands can be displayed on replication-competent vesicular stomatitis viruses without perturbing viral growth and oncolytic efficacy
  • Demonstrating that microRNA targeting can be used to further increase the safety of mengovirus

Developing cancer immunotherapies by exploring the immunomodulatory potential of gene-based and virus-based therapeutics

Recent advances in this research area include:

  • Showing that the profile of tumor antigens that can be targeted by immunotherapy depends on the tumor's anatomical site
  • Demonstrating that mutated BRAF may be a major effector of melanoma recurrence and could serve as a target for chemotherapy or immunotherapy
  • Showing that the type and potency of anti-tumor immune responses against self-tumor-associated proteins can be manipulated in vivo
  • Showing that preconditioning with immune modulators can enhance virus-mediated anti-tumor activity
  • Demonstrating that oncolytic infection of tumor cells initiates anti-tumor immune responses through production of pathogen-associated chemokines and cytokines and release of damage-associated molecular pattern molecules and tumor-associated antigens
  • Showing that oncolytic virotherapy combined with immune checkpoint blockade is a promising approach to acute myeloid leukemia therapy
  • Showing that it is possible to generate fully systemic, highly effective anti-tumor immunovirotherapy by combining oncolytic viruses, along with immune checkpoint blockade, to induce complementary mechanisms of anti-tumor immune responses
  • Demonstrating that immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances anti-tumor activity in glioblastoma treatment
  • Demonstrating that intraperitoneal administration of measles virus-sodium iodide symporter in patients with recurrent ovarian cancer was associated with compelling survival outcomes, in part by generating an anti-tumor immune response
  • Demonstrating that measles virus expressing a NAP chimeric protein is highly immunogenic, as compared with the unmodified virus

Assessing preclinical, clinical, pharmacologic and immunologic properties of vectors used in cancer therapy and optimizing their clinical application

Recent advances in this research area include:

  • Demonstrating the safety of central nervous system administration of a measles virus strain expressing the human carcinoembryonic antigen in patients with glioma
  • Documenting that the interferon response pathway represents a key mechanism of tumor resistance to oncolytic measles virus therapy and describing for the first time the development of a prediction algorithm to preselect for oncolytic treatment or combinatorial strategies
  • Demonstrating that image-guided radiovirotherapy using a recombinant measles virus expressing the thyroidal sodium iodide symporter is a promising approach to the treatment of multiple myeloma
  • Demonstrating remission of disseminated cancer after systemic oncolytic virotherapy with an engineered measles virus that is selectively destructive to myeloma tumor cells, and showing it can be monitored by noninvasive radioiodine imaging of NIS gene expression
  • Demonstrating that MV-NIS, an Edmonston-lineage measles virus strain that expresses the human sodium iodide symporter, offers a promising new modality for the targeted infection and destruction of multiple myeloma, ovarian cancer, mesothelioma, head and neck cancer, and non-small cell lung cancer
  • Finding that recombinant vesicular stomatitis virus designed to exploit defects in mechanisms of host defense can provide the basis for new generations of effective, specific and safer viral vectors for the treatment of malignancies
  • Demonstrating that robust oncolytic virotherapy induces tumor lysis syndrome and associated toxicities in the MPC-11 plasmacytoma model
  • Demonstrating that a strain of vesicular stomatitis virus encoding IFNβ and NIS produces a significant anti-tumor effect against hematologic malignancies, including multiple myeloma and acute myeloid leukemia
  • Showing that different oncolytic platforms, including measles virus, vesicular stomatitis virus and vaccinia, have significant activity in vivo and in vitro against endometrial cancer

Evaluating the role of cells as carriers in gene-based and virus-based therapeutic approaches to cancer therapy

Recent advances in this research area include:

  • Generating data to support the potential therapeutic benefit of chaperoning vectors to sites of tumor growth inside cells capable of resisting antiviral antibodies, extravasating from tumor blood vessels, migrating in the tumor parenchyma and possibly responding to cues in the tumor microenvironment
  • Demonstrating that adipose tissue-derived mesenchymal stem cells can transfer measles virus infection to ovarian cancer target cells in a peritoneal ovarian cancer model via cell-to-cell heterofusion
  • Launching the first-in-human, proof-of-principle clinical trial to test the added value of cell-carrier delivery in oncolytic virotherapy in patients with recurrent ovarian cancer