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- 저자 : Shestova, Olga (검색결과 1 건)
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Kim, Miriam Y.,Yu, Kyung-Rok,Kenderian, Saad S.,Ruella, Marco,Chen, Shirley,Shin, Tae-Hoon,Aljanahi, Aisha A.,Schreeder, Daniel,Klichinsky, Michael,Shestova, Olga,Kozlowski, Miroslaw S.,Cummins, Kathe Elsevier 2018 Cell Vol.173 No.6
<P><B>Summary</B></P> <P>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 elimination of leukemia without myelotoxicity. These studies illuminate a novel approach to antigen-specific immunotherapy by genetically engineering the host to avoid on-target, off-tumor toxicity.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CD33 is not required for human myeloid development and function </LI> <LI> CD33-deficient non-human primate myeloid cells are fully functional </LI> <LI> Anti-CD33 CAR T cells can eradicate AML while sparing CD33-deficient hematopoiesis </LI> <LI> This is a synthetic biology approach to generating a leukemia-specific antigen </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
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