Research

Poxviruses infect a broad spectrum of vertebrate hosts but the basis for the host range specificity exhibited by individual virus isolates is poorly understood. MYXV is a poxvirus that causes lethal infection only in rabbits in nature, but the mechanism underlying the strict MYXV species tropism is poorly understood. Like all poxviruses, MYXV expresses a wide array of immunomodulatory proteins, but relatively few of these are actually rabbit-specific when tested in vitro. In fact, at least one such species-nonspecific immunomodulatory protein derived from MYXV, called SERP-1, has been shown to be a potent anti-inflammatory drug in human clinical trials conducted by Viron Therapeutics, a biotech company co-founded by Dr. McFadden and Dr. Alexandra Lucas, currently a cardiologist at Dignity Health and a scientist in the Biodesign Center for Personalized Diagnostics. Another anti-inflammatory protein derived from MYXV, called M013, has been combined with gene therapy vectors to treat chronic inflammatory eye diseases.

The study of host tropism by poxviruses not only offers the potential for development of novel platforms for replication-restricted vaccine vectors and oncolytic viruses, but it also produces novel insights into how and why poxviruses can occasionally leap from a long-term evolutionary host species to cause zoonotic infections in humans. In fact, there is a real need to better understand the dynamics of how “emerging” viruses in general can occasionally leap into non-evolutionary hosts to cause novel disease. Also, there is a need to better understand why specific viruses attack not only specific hosts, but also why many of them infect and damage only specific host tissues. In fact, the field of oncolytic virotherapy exploits this biological property of certain viruses, when the virus-permissive “organ” is cancer tissue. It is a contention of this lab that virotherapy will combine successfully with the other major new innovations for cancer therapies, particularly immunotherapy and modified cell-based therapies.

Oncolytic viruses are defined by their ability to selectively target and kill cancerous cells while sparing normal cells and tissues. Like immunotherapy, the field of oncolytic virotherapy is growing rapidly, and many specific viruses are being developed for the treatment of specific cancers. The McFadden lab studies on MYXV tropism have shown that this virus is also fully permissive not only for rabbit cells, its normal host in nature, but also for a wide spectrum of human cancer cells in vitro and in vivo. They are currently developing MYXV as an oncolytic virotherapeutic to treat a spectrum of human cancers that exhibit defective cell anti-viral signaling responses. For example, MYXV can selectively infect and kill primary human cancer cells that contaminate bone marrow samples from patients with acute myeloid leukemia (AML) or multiple myeloma (MM). However, this virus cannot infect the normal CD34+ hematopoetic stem and progenitor cells within the sample needed to reconstitute the immune system following autologous bone marrow transplantation. In addition, the MYXV ex vivo treatment of allogeneic (ie “non-self”) bone marrow transplant samples from normal cancer-free donors was found to also suppress the development of graft-vs-host-disease (GVHD) in recipient immunodeficient mice. Our recent studies indicate that ex vivo MYXV virotherapy of bone marrow transplants can also eliminate pre-existing residual cancer in recipients, thus opening up the possibility of exploiting normal cells within a bone marrow transplant sample as “carrier cells” to deliver the virus to sites of disseminated disease within the patient receiving the transplant, and thereby eliminate this residual cancer. Thus, the fundamental study of a rabbit-specific poxvirus.