My research goal is to demonstrate the value of oncolytic virotherapy as a new modality for the treatment of cancer.
Long-Term Research Aims
To develop genetically engineered oncolytic viruses that are selectively destructive to a variety of disseminated cancers, to elucidate the molecular targeting mechanisms that govern their cancer specificity, and to advance them to clinical testing.
Mid-Term Research Aims
- Generate, study and translate novel oncolytic rhabdoviruses (VSV) and picornaviruses (EMCV).
- Advance imaging strategies to noninvasively monitor in vivo spread of oncolytic viruses.
- Develop clinically viable approaches for transient suppression or evasion of antiviral immunity to oncolytic viruses.
- Develop strategies to enhance extravasation of oncolytic viruses in tumors.
- Identify and exploit synergistic interactions between anticancer drugs and oncolytic viruses.
- Continue to advance the clinical development of oncolytic measles viruses (MV-NIS).
Viruses from several families are engineered in our laboratory. We currently have oncolytic projects focusing on Measles, Vesicular Stomatitis Virus, Coxsackievirus A21, and Mengovirus. Nonreplicative AAV, lentivirus and adenovirus vectors are also used extensively.
Virus tropisms are engineered by the display of single chain antibodies and other targeting proteins on viral surface glycoproteins (measles, lentiviruses), or by incorporating microRNA target sequences at strategic sites in the viral genome (CVA21, VSV, Mengovirus). These targeting approaches were developed in our laboratory (Nat. Biotec. 2004, 22: 331-6; Nat. Biotec. 2005, 23: 209-14; Nat. Med. 2008, 14: 1278-83; J. Virol. 2010, 84: 1550-62)
In vivo, virus propagation is noninvasively monitored by engineering the oncolytic virus genomes to encode secretable marker peptides, like carcinoembryonic antigen, or the thyroidal sodium iodide symporter (NIS) which concentrates radioactive iodine into virus infected tissues. These oncolytic monitoring approaches were also developed in our laboratory (Nat. Med. 2002, 8: 527-531, Blood 2004,103: 1641-6) and the technology has been advanced to clinical testing in phase I clinical trials here at Mayo Clinic.
Immune elimination of intravenously administered oncolytic viruses is being addressed in several ways. For example, virus-infected cells are being used as vehicles to carry viruses via the bloodstream to sites of tumor growth, thereby avoiding antibody neutralization (Am J Hematol. 2009, 84: 401-7; Mol Ther. 2010, 18: 1155-64). Also, immunosuppressive drugs are being used in conjunction with oncolytic virotherapy to suppress the adaptive antiviral immune response, thereby facilitating repeat virus administration (Clin. Pharmacol. Ther. 2007, 82: 700-10).
Clinical translation is our goal (Cancer Res. 2010, 70: 875-82) and we are fortunate at Mayo Clinic to have a GMP manufacturing facility for pilot-scale production of clinical-grade oncolytic viruses to support phase I clinical trials. We also have a group of scientists at Mayo Clinic who are dedicated the performance of FDA-mandated pharmacology and toxicology testing in support of our translational efforts.
My research lab comprises approximately 10 scientists (3 technologists, 4 or 5 postdoctoral scientists and 1 or 2 graduate students). Additional students participate in lab. activities during the summer months. While the overarching goals of the projects undertaken in the laboratory are highly connected, individual lab members typically work relatively independently of each other, and are expected to play a major role in the development of their own project directions.