Support is requested for an integrated laboratory and clinical research program on """"""""CD16 Gene Therapy for Multiple Myeloma (MM)"""""""". Even though true complete remissions can now be achieved in up to 50% of patients with MM through intensive therapy requiring hemopoietic stem cell support, adjunctive post-transplant maneuvers are required to effect long term disease control and cure in MM, for which incidence and mortality rates both are increasing especially among black Americans. IgG is the most common MM phenotype, accompanied by an expansion of CD8+ CD16+ cells, which exert growth control and inhibition of IgG secretion through a soluble membrane constituent (sCD16). This biologic function of sCD16 involves down-regulation of c-myc for growth arrest and suppression of transcription for IgG inhibition. To test the hypothesis whether greater biologic activity and hence growth control can be effected, we propose to transduce peripheral blood CD8+ (and, in the future, possibly bone marrow cells) with the CD16 gene using a non-pathogenic parvoviral construct (AAV) that has high infectivity (> 70%) and also integrates well into non-cycling cells. Toward this goal, 3 basic research projects are designed: I. To evaluate AAV as an appropriate vector for CD16 gene transduction. 2. To examine, in a murine MM model, efficiency of sCD16 production be AAV-CD16-transduced T cells and to evaluate effects on tumor growth, immunologic response and hemopoiesis. 3. To investigate in vitro sCD16 and CD8+ CD16+ cells from patients with MM on human MM cell lines and fresh tumor samples along with biologic effects on the immune system and on hemopoiesis. The clinical Project 4 will determine toxicity and efficacy associated with AAV-CD16 transduction into circulating CD8+ cells and later into bone marrow cells. This work requires access to 2 Core Laboratories A: Tissue Core; B. Data Management and Program Administration. Thus, for the expedient development of gene therapy for MM, this program takes advantage of autologous T cell response to MM requiring further augmentation for clinical benefit to be derived.
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