Inactivation of CD33 in HSPCs permits CD33-directed CAR T-cell treatment of AML.

  • Major finding: Inactivation of CD33 in HSPCs permits CD33-directed CAR T-cell treatment of AML.

  • Concept: CD33-ablated HSPCs exhibited normal myeloid function and differentiation in vivo.

  • Impact: Gene editing of normal cells is a potential therapeutic approach to generate cancer-specific antigens.


The efficacy of target-directed immunotherapies such as CAR T cells depends upon either the cancer-specific expression of surface antigens or a tolerable level of normal tissue–associated toxicity. The CD33 antigen is highly expressed in acute myeloid leukemia (AML) blasts; however, its potential as an immunotherapeutic target for AML is curtailed by the expression of CD33 on normal myeloid progenitors. Currently, efforts have focused on designing transient CAR T cells to limit myeloablation and decrease CAR T cell–mediated normal toxicity, but this strategy would prevent the establishment of long-term immunosurveillence. To alleviate CAR T cell–mediated normal myeloid toxicity, Kim, Yu, and colleagues generated CD33−/− human hematopoietic stem and progenitor cells (HSPC). CD33−/− human HSPCs exhibited similar levels of engraftment, growth, differentiation, and myeloid function as control HSPCs and maintained CD33 loss in immunocompromised mice. Consistent with these findings, CD33−/− nonhuman rhesus macaque HSPCs exhibited similar levels of long-term engraftment, growth, multilineage differentiation, and myeloid trafficking and function as control HSPCs in vivo. Further, anti-CD33 CAR T cells eliminated CD33+ human AML but not HSPCs in mice engrafted with CD33−/− human HSPCs; in contrast, anti-CD33 CAR T cells eliminated both CD33+ human AML and HSPCs in mice engrafted with control human HSPCs. Taken together, these results identify a strategy to generate a leukemia-specific antigen from a shared antigen and show that shared antigens can be selectively eliminated from normal hematopoietic cells to eliminate normal toxicity without significantly affecting normal hematopoietic function.

Kim MY, Yu KR, Kenderian SS, Ruella M, Chen S, Shin T-H, et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell 2018;173:1439–53.

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