Abstract
Most CAR-T cell therapies for treatment of multiple myeloma (MM) are directed towards BCMA, a target antigen that is highly expressed on malignant plasma cells. It has become evident that the extracellular BCMA-binding domain of a CAR, derived from a monoclonal antibody (mAb), is an important determinant of clinical efficacy of anti-BCMA CAR-T cell therapies. In this project, we want to further investigate and compare anti-BCMA mAbs from different animal species for their competence for incorporation in CAR-T cell therapies against MM. In addition, most CAR-T cells get their genetic material delivered via viral transduction or transposons. A major disadvantage of viral loading methods are the need for highly specialized infrastructure and the long time needed for production. The speed up the production process, make it safer and to counteract virus-mediated insertion of DNA in the genome, we want to use episomal vectors. These vectors exist extrachromosomal, yet are duplicated and thus passed along to daughter cells. Next, we want to turn on/off specific CARs by (de)methylating the genes, thereby regulating transcription. It also enables speeding up and optimization of the production process by incorporating different CARs in a single T-cell, whereby only the CAR of choice is switched on. This could be incorporated into allogenic cell therapy in which different CARs are present in an off-the-shelf allogenic T-cell/NK-cell.
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