Look what MD Anderson's up to. Nice of them to do research when a Company already holds the patent to the wild type and modified strain. Nice to see them join the list of researchers, U of Alabama, U of Minn & a few others now looking at the reovirus.
MD Anderson's technology commercialization description has some errors however. It incorrectly assumes that the wild type has not been used in animal models intravenously.
www2.mdanderson.org
Development of a Novel Reoviral Oncolytic Therapy for Hematologic Malignancy
Background
Mutations in the RAS oncogene appear to be the primary derangement driving malignant growth in approximately 30% of all cancers. Acute myelogenous leukemias have mutated RAS in 25 to 44% of cases. One major focus of current cancer research is targeting RAS positive cells for destruction. Recently it has been realized that viruses of the genus reovirus will actively replicate and spread within tumors that are RAS positive. In healthy individuals, infection of reovirus is usually asymptomatic. The high efficacy in tumor lysis coupled with the low apparent toxicity to normal hosts offers the potential for a new avenue in the treatment of cancer. The American Cancer Society estimates there will be over 1 million new cases of cancer in the United States in 2002, with 60,000 of them attributed to various leukemias.
Competitive Advantages
Previous publications have demonstrated the antitumor effect of reovirus when the virus is given by the intratumoral route. Although the intratumoral route is useful for demonstrating the potential of the system in animal models, it would not be applicable to leukemia and it would not be broadly applicable in the setting of solid tumors where the location and accessibility of metastatic lesions may limit this approach. An MD Anderson scientist has developed a modification of reovirus that can be administered intravenously rather than intratumorally. Preclinical studies have clearly demonstrated increased retention of the virus (versus the unmodified virus) in the circulation, low toxicity of the virus, and the ability of the virus to lyse RAS positive tumor cells in vitro and in vivo. Additional work in SCID mice is in progress. Advantages of the modification include preserved infectivity, blocked antibody interference, and prolonged clearance.
utm-notes-db2.mdacc.tmc.edu
Jeffrey J. Tarrand, MD
Research Interests:
Antifungal agents, aspergillosis, reoviridae, leukemia
Translational work is also being done to develop a clinically useful reovirus therapeutic agent. Reoviruses exit cells only through cell lysis, and they exhibit no latent state. They grow in ras-positive cells and thus may be able to inhibit a wide variety of tumors. Fortunately, all normal cells constitutively express a double-stranded RNA recognition protein that, through a kinase cascade, can rapidly shut down viral replication. Thus, the therapeutic index for this live viral therapy is potentially high. We are currently attempting to adapt the virus for testing in a leukemia model.
bloodjournal.org
Reovirus therapy of lymphoid malignancies
Tommy Alain, Kensuke Hirasawa, Kelly J Pon, Sandra G Nishikawa, Stefan J Urbanski, Yvonna Auer, Joanne Luider, Anita Martin, Randal N Johnston, Anna Janowska-Wieczorek, Patrick W K Lee, and Anna E Kossakowska*
Cancer Biology Research Group, University of Calgary, Calgary, AB, Canada; Department of Pathology, University of Calgary, Calgary, AB, Canada
Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, AB, Canada
Cancer Biology Research Group, University of Calgary, Calgary, AB, Canada; Calgary Laboratory Services, Calgary, AB, Canada; Department of Pathology, University of Calgary, Calgary, AB, Canada
Calgary Laboratory Services, Calgary, AB, Canada; Department of Pathology, University of Calgary, Calgary, AB, Canada
Calgary Laboratory Services, Calgary, AB, Canada
Cancer Biology Research Group, University of Calgary, Calgary, AB, Canada; Department of Medical Biochemistry, University of Calgary, Calgary, AB, Canada
Department of Medicine, University of Alberta, Edmonton, AB, Canada
Cancer Biology Research Group, University of Calgary, Calgary, AB, Canada; Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, AB, Canada
* Corresponding author; email: anna.kossakowska@cls.ab.ca.
Reoviruses infect cells that manifest an activated Ras-signaling pathway, and have been shown to effectively destroy many different types of neoplastic cells, including those derived from brain, breast, colon, ovaries, and prostate. In this study, we investigated reovirus as a potential therapeutic agent against lymphoid malignancies. A total of 9 lymphoid cell lines and 27 primary human lymphoid malignancies, as well as normal lymphocytes and hematopoietic stem/progenitor cells, were tested for susceptibility to reovirus infection. For in vitro studies, the cells were challenged with reovirus (serotype 3 Dearing), and viral infection was assessed by cytopathic effects, viability, viral protein synthesis and progeny virus production. We present evidence of efficient reovirus infection and cell lysis in the diffuse large B-cell lymphoma cell lines and Burkitt's lymphoma cell lines Raji and CA46 but not Daudi, Ramos and ST486. Moreover, when Raji and Daudi cell lines were grown subcutaneously in SCID/NOD mice and subsequently injected with reovirus intratumorally or intravenously, significant regression was observed in the Raji but not the Daudi induced tumors, which is consistent with the in vitro results. Susceptibility to reovirus infection was also detected in 21 of the 27 primary lymphoid neoplasias tested but not in the normal lymphocytes or hematopoietic stem/progenitor cells. Our results suggest that reovirus may be an effective agent against several types of human lymphoid malignancies. |
