Chimeric-antigen receptor engineered human T lymphocytes from induced pluripotent stem cells for cancer therapy. (VAC11P.1003)

• Published in: The Journal of immunology (1950) 2014-05, Vol.192 (1_Supplement), p.205-205.4
• Main Authors: Themeli, Maria, Sadelain, Michel
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.192.Supp.205.4

We hypothesized that genetic engineering of induced pluripotent stem cells (iPSC) with Chimeric Antigen Receptors (CARs) would be an efficient strategy to generate readily available functionally enhanced T cells targeted to a tumor antigen of interest. Since combined CD28 and 4-1BB signaling promote T cell proliferation and survival, we genetically engineered iPSCs from peripheral blood lymphocytes (T-iPSC) to express 1928z, a second-generation CAR specific to the B-cell lineage antigen CD19, and 4-1BBL. Stably transduced 1928z/4-1BBL-T-iPS lines were then directed to differentiate in vitro into CD3+TCRαβ+ T cells that expressed the 1928z CAR and 4-1BBL on the surface (1928zBBL-TiPSC-T). Upon exposure to cells expressing CD19, 1928zBBL-TiPS-T cells rapidly responded by forming clusters, increased the expression of activation markers and secreted type 1 cytokines. We were able to expand 1928zBBL-TiPSC-T cells and expanded 1928zBBL-T-iPSC-T cells displayed high antigen-specific cytotoxic activity in vitro. Treatment of CD19+ tumor-bearing mice with 1928zBBL-TiPSC-T cells delayed tumor progression and resulted in a significant survival advantage. In summary, the combination of iPSC and CAR technologies we describe here offers a tantalizing new source of “off the shelf” T cells of predetermined antigen specificity and enhanced properties.