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14 June 2018

CAR T-cell therapy could be used to treat acute myeloid leukaemia (AML)- with the aid of CRISPR gene editing, a US study has revealed.

Researchers at the University of Pennsylvania's Abramson Cancer Center used the therapy to target the protein CD33, which is expressed on healthy and cancerous cells, in animal models of AML.

They used genome editing to remove CD33 from healthy blood-forming stem cells. This left the cancerous cells as the only targets left for the CD33 hunter cells to attack.

The findings are published in the latest edition of Cell.

The innovation follows previous research by Penn scientists, who developed CAR T cell therapy to treat AML. The current approach involves targeting the myeloid marker CD33, however since non-myeloid cells also express this gene, this results in the destruction of healthy cells. 

In this step forward, the researchers genetically engineered normal stem cells so they no longer resembled the leukaemia cells by using CRISPR/Cas9 to remove the target gene CD33.

The healthy stem cells without CD33 functioned normally, and the CAR T cells were shown to selectively eliminate the leukaemia without toxicity.

Co-senior author Dr Cynthia Dunbar, a senior investigator at the US National Heart, Lung, and Blood Institute, said: “This study represents a significant advance toward effective and safe targeting of leukaemia cells using CAR T cells.

“A key to this advance is the use of next-generation gene-editing technology to achieve this type of antigen-specific immunotherapy, even when the target is also present on normal bone marrow cells.”

"None of the existing CAR T approaches target a cancer-specific antigen - other than EGFRvIII in brain cancer - but with this approach, we can create a cancer-specific antigen, which allows us to unleash CAR T cells to their maximal capacity," added co-senior author Dr Saar I. Gill, assistant professor of haematology-oncology added.

The team has shown the technique to be effective in mouse and primate models, and human cells in vitro. They now hope to move to human trials.


Source: Kim, M.Y., Yu, K.R., Kenderian, S.S., Ruella, M., Chen, S., Shin, T.H., Aljanahi, A.A., Schreeder, D., Klichinsky, M., Shestova, O. and Kozlowski, M.S., 2018. Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia. Cell173(6), pp.1439-1453. 

Link: https://www.cell.com/cell/fulltext/S0092-8674(18)30590-7