Thérapie génique ciblant CD33 dans les cellules souches hématopoïétiques, une approche innovatrice pour le traitement de la leucémie myéloïde aiguë
With very few new treatments introduced in the past decades, acute myeloid leukemia (AML) remains a cancer with poor prognosis. Recently, a revolutionary immunotherapy for B-cell malignancies has been approved, named CAR-T cells. It is based on adoptive T-cell therapy but the cells are genetically engineered to express a “chimeric antigen receptor” (CAR), a surface protein used to redirect T cell’s natural cytotoxic activity against tumors. CD33 is one of the few clinically validated targets for AML immunotherapy. However, myelotoxicity is a major concern because this antigen is also present on normal hematopoietic stem cells (HSC). Interestingly, CD33 was dispensable in humans and in several animal models without any apparent consequences. We hypothesized that a HSC graft, engineered with a knock-out/knock-in of CD33/CAR-CD33, would be a safe and effective therapy for AML patients. This strategy would benefit from the clinical potential of CD33 without the associated myelotoxicity. Because of the continuous renewal of effector cells, CAR-HSC would have several advantages over the CAR-T cells such as long-term in vivo persistence and reduced cellular exhaustion. Cytokine release syndrome could also be diminished in CAR-HSC settings by the slow generation of CAR-T. In this study, we showed that the anti-CD33 CAR is effective and specific against AML cell lines even when its expression is mediated by a T-specific promotor. This promotor allows restriction of transgene expression to the T lineage progeny. We have designed efficient gRNA to target CD33 gene. The strategy will now be tested in HSC and in mice models.
CRISPR/Cas9 CD33 CAR acute myeloid leukemia gene editing hematopoietic stem cells cancer immunotherapy chimeric antigen receptor T cells specific promotor