Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia

Publication date: 31 May 2018 Source:Cell, Volume 173, Issue 6 Author(s): Miriam Y. Kim, Kyung-Rok Yu, Saad S. Kenderian, Marco Ruella, Shirley Chen, Tae-Hoon Shin, Aisha A. Aljanahi, Daniel Schreeder, Michael Klichinsky, Olga Shestova, Miroslaw S. Kozlowski, Katherine D. Cummins, Xinhe Shan, Maksim Shestov, Adam Bagg, Jennifer J.D. Morrissette, Palak Sekhri, Cicera R. Lazzarotto, Katherine R. Calvo, Douglas B. Kuhns, Robert E. Donahue, Gregory K. Behbehani, Shengdar Q. Tsai, Cynthia E. Dunbar, Saar Gill The absence of cancer-restricted surface markers is a major impediment to antigen-specific immunotherapy using chimeric antigen receptor (CAR) T cells. For example, targeting the canonical myeloid marker CD33 in acute myeloid leukemia (AML) results in toxicity from destruction of normal myeloid cells. We hypothesized that a leukemia-specific antigen could be created by deleting CD33 from normal hematopoietic stem and progenitor cells (HSPCs), thereby generating a hematopoietic system resistant to CD33-targeted therapy and enabling specific targeting of AML with CAR T cells. We generated CD33-deficient human HSPCs and demonstrated normal engraftment and differentiation in immunodeficient mice. Autologous CD33 KO HSPC transplantation in rhesus macaques demonstrated long-term multilineage engraftment of gene-edited cells with normal myeloid function. CD33-deficient cells were impervious to CD33-targeting CAR T cells, allowing for efficient eliminati...
Source: Cell - Category: Cytology Source Type: research