(OT) Preclinical data (to be presented at the ASCGT meeting) from another company (private) working on iPSC (CAR)NK and (CAR/TCR)T-cell therapies
Abstract: ''Induced-pluripotent stem cells (iPSCs) offer a unique opportunity to create novel cell therapies for cancer with advantages over conventional cell therapies that are derived from leukapheresis products. These advantages include: 1) ability to perform multiple genetic editing steps at the renewable iPSC stage, 2) ability to select and fully characterize single cell clones for genetic integrity and functionality before selecting final product candidate, and 3) ability to generate a clonal master cell bank that is used to produce highly uniform drug products at low cost. Here we describe a highly-engineered iPSC derived natural killer cell (iNK) with six precise genetic modifications intended for the treatment of cancer. These modifications include the use of stealth edits to reduce alloreactivity, a safety switch for product elimination if necessary, the expression of a homeostatic cytokine for improved functionality and persistence, and a chimeric antigen receptor (CAR) targeting CD19 to mediate tumor cell engagement and killing.
For resistance to CD8 T cell-mediated allogenic immune rejection, the beta-2-microbulin (ß2M) gene is disrupted with simultaneous insertion of a transgene encoding the HLA-E protein with tethered ß2M and a peptide. HLA-E was introduced to prevent NK cell cytotoxicity against the engineered cells, which lack HLA-I. For resistance to CD4 T cell-mediated allogenic immune rejection, the class II major histocompatibility complex transactivator (CIITA) gene is disrupted with simultaneous insertion of a transgene encoding both the extracellular and transmembrane domains of EGFR, and the NK cell growth factor IL-15. EGFR provides an elimination tag that can be engaged by clinically approved anti-EGFR antibodies, such as Cetuximab. Finally, a CAR targeting the CD19 antigen is encoded by a transgene delivered into a safe harbor locus.
From the engineered, clonal iPSC bank, iNK cells are differentiated using a 30-day long feeder cell-free process. These iNK cells resemble peripheral blood derived CD3- CD56+ NK cell lymphocytes based on cell surface phenotype. They eliminate HLA-I negative tumor cells comparable to peripheral blood NK cells and when exposed to CD19+ target cells, CAR-iNK cells, they demonstrate potent antigen specific killing that is comparable to conventional CART cells. The multi-engineered iNK cell platform provides a new paradigm for cancer cell therapies through an off-the-shelf product that can be delivered in repeated doses with reduced risk of allo-rejection.''
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