Treatment of transplanted and established multiple myeloma using oncolytic myxoma

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DESCRIPTION (provided by applicant): My interests as a scientist involve the study on virus-host interactions. Currently, I am interested in the study of a rabbit specific poxvirus called myxoma virus (MYXV) and how it interacts with normal and cancerous cells. Previously, our lab has demonstrated that myxoma specifically discriminates between normal and cancerous hematopoietic cells. We have proposed that this discrimination can be used to specifically eliminate cancerous multiple myeloma cells contaminating autologous stem cell samples prior to transplant into patients. This therapy has the potential to improve both the survival and quality o life of multiple myeloma patients by providing a safe and effective cure. Before MYXV can be used as a purging agent in a clinical setting, however, the basis of MYXV's ability to induce apoptosis in myeloma cells while not affecting engraftment of normal stem cells must be elucidated. Additionally, the potential impact of a functional recipient immune system on both ex vivo purging as well as treatment of established MM disease must be determined. This proposal is designed to advance the rationale for using MYXV as an ex vivo virotherapeutic as well as test its potential to treat established malignancy through several potential mechanisms. In the short term, my goal is to carry out the experiments proposed in this K22 grant and advance the scientific rationale for developing oncolytic virotherapy against cancers such as MM. I feel that the work proposed in this K22 grant corresponds to around 2 years of research and therefore represents work that can be accomplished during the course of this grant. I feel that I have the potential to become a strong independent investigator. I have the expertise, leadership and motivation necessary to successfully carry out the proposed work. My previous publications have received multiple awards and commendations proving that it is of high quality as well as interest to the academic community. I have also been successful in obtaining my own funding from multiple sources. I have mentored several graduate and undergraduate researchers and initiated collaborations with other researchers which are likely to result in multiple peer-reviewe publications and successful grant applications. As a result of these experiences, I feel that I am fully capable of: developing and executing a research plan, leading others through this plan, and obtaining the additional funding needed to continue my research. We have previously demonstrated that acute myeloid leukemia cells contaminating autologous stem cell transplant samples can be purged by ex vivo treatment with a rabbit specific poxvirus called myxoma virus. We now demonstrate that this treatment is also effective at purging contaminating multiple myeloma cells by inducing rapid cellular apoptosis. This proposal is designed to elucidate the mechanism(s) of how myxoma treatment results in myeloma cell apoptosis and whether the virus can also be used to reduce established myeloma.