Antibody Neutralization of Therapeutic Viruses

Multiple myeloma is an incurable, disseminated malignancy of terminally differentiated plasma cells that will be responsible for the deaths of more than 11,000 Americans in 2006. Attenuated measles viruses are selectively destructive to human myeloma plasma cells which express abundant CD46 (the viral receptor) and are therapeutically potent in murine myeloma xenograft models. We are therefore testing a recombinant measles virus by intravenous administration in patients with advanced, treatment-refractory multiple myeloma. Neutralizing antimeasles antibodies are expected to limit the therapeutic efficacy of the systemically administered measles viruses, particularly in those 70% of myeloma patients with higher antibody titers. The goal of this proposal is to develop optimal strategies to combat measles virus neutralization in the bloodstream by suppressing the production of antimeasles antibodies, or by delivering the virus inside autologous monocytes or dendritic cells, infected outside the body. The findings of these studies will be used to guide the design of future clinical trials of measles virotherapy in myeloma patients. Specific aims are as follows: Aim 1. Develop a clinically viable strategy using cyclophosphamide in combination with measles booster vaccination to reduce the plasma concentration of neutralizing anti-measles antibodies. Aim 2. Evaluate the performance of measles-infected monocytes, or monocyte-derived dendritic cells (immature or mature) as antibody-resistant virus delivery vehicles. Aim 3. Determine whether suppression of CCR7 chemokine receptor expression can favorably impact the biodistribution of measles-infected dendritic cells in CD46 transgenic SCID mice. Antibodies are the most important barrier to the successful deployment of viruses as anticancer agents. This grant seeks to develop clinical viable solutions to this problem.