The research interests of Stephen J. Russell, M.D., Ph.D., center on demonstrating the value of oncolytic virotherapy as a new modality for the treatment of cancer. Viruses from several families are engineered in Dr. Russell's laboratory. His team currently has oncolytic projects focusing on measles, vesicular stomatitis virus (VSV), coxsackievirus A21 (CVA21) and Mengo virus. Nonreplicative adeno-associated viruses, lentivirus and adenovirus vectors also are used extensively.
Virus tropisms are engineered by the display of single-chain antibodies and other targeting proteins on viral surface glycoproteins such as measles or lentiviruses, or by incorporating microRNA target sequences at strategic sites in the viral genome, using CVA21, VSV or Mengo virus. These targeting approaches were developed in Dr. Russell's laboratory.
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, which concentrates radioactive iodine into virus-infected tissues. These oncolytic monitoring approaches were also developed in Dr. Russell's laboratory, and the technology has been advanced to clinical testing in phase I clinical trials 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. Also, immunosuppressive drugs are being used in conjunction with oncolytic virotherapy to suppress the adaptive antiviral immune response, thereby facilitating repeat virus administration.
Clinical translation is the overall goal of Dr. Russell's research team, and team members they utilize Mayo Clinic's licensed facility for pilot-scale production of clinical-grade oncolytic viruses to support phase I clinical trials. The team also works with scientists at Mayo Clinic who are dedicated to the performance of Food and Drug Administration-mandated pharmacology and toxicology testing in support of their translational efforts.
- Generating, studying and translating novel oncolytic rhabdoviruses and picornaviruses
- Advancing imaging strategies to noninvasively monitor in vivo spread of oncolytic viruses
- Development of clinically viable approaches for transient suppression or evasion of antiviral immunity to oncolytic viruses
- Developing strategies to enhance extravasation of oncolytic viruses in tumors
- Identification and exploitation of synergistic interactions between anti-cancer drugs and oncolytic viruses
- Further advancement of the clinical development of oncolytic measles viruses
Significance to patient care
Dr. Russell's long-term research goals are 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.