CAR-T细胞,靶向CD123 z-bo 2020-10-07 651

　　Acute myeloid leukemia (AML) is a hematological malignant tumor, its incidence is increasing with age, and it has significant biological, phenotypic and genetic heterogeneity. The treatment of the disease is combined with chemotherapy followed by allogeneic hematopoietic stem/progenitor cell transplantation (allo-HSCT), depending on the patient’s condition, to enhance complete remission and prevent recurrence. However, with the exception of certain subtypes of AML called low-risk AML, it usually recurs after intensive treatment and transplantation. The toxicity, refractory and inability to eradicate the initiating cells of leukemia are the main reasons for the progression and recurrence of AML.

　　Unfortunately, in the past 40 years, improved AML treatments have hardly developed. Currently, the 5-year event-free survival rate of adult patients reaches 20%, while the 5-year event-free survival rate of children is less than 70%. This highlights the urgent need for safer and more effective treatments. AML patients have the same target antigen expression as healthy hematopoietic stem/progenitor cells (HSPC), which may lead to the lack of universal AML target antigens to guide CAR-T cells and life-threatening off-target cytotoxicity challenges. However, previous studies have shown that the use of CD33 and CD123 redirected CAR-T cells to treat AML has shown effective anti-leukemia activity and is in the pre-clinical and late stages of clinical development.

　　has caused controversy in the preclinical and clinical settings as to whether these CAR-T cells have myeloablative properties. This is because it may also target healthy HSPC. After all, HSPC is required for hematopoiesis or hematopoiesis. .. Since HSPCs also express these antigens to different degrees, it is speculated that these CAR-T cells may also attack them. Several independent short-term studies have been conducted in vitro and in vivo to confirm the safety of this CAR-T cell therapy on healthy HSPCs, but there is no substantial medium and long-term in vivo evidence. Matteo Baroni, a researcher in the Stem Cell Biology, Developmental Leukemia and Immunotherapy Research Group of the Josef-Carreras Leukemia Institute in Spain, and colleagues said that CAR-T cells may have a longer effect on healthy HSPC than leukemia cells. I guess it will take time. They believe that previous studies on the potential myeloid toxicity of CD123-targeted T cells underestimated the potential for off-target toxicity of these CAR-T cells.

　　In a six-week in vivo study, Baroni and his team found that the presence of CAR-T cells targeting CD123 strongly inhibited normal hematopoietic function and irreversibly damaged the formation of new blood cells. It provides a lot of evidence. The relevant research results were published online in the "Journal of Cancer Immunotherapy" on June 10, 2020. The title of the paper is "41BB-based and CD28-based CD123 redirected T cell ablation of human normal hemopoietin in vivo".

　　Baroni said: For AML patients who have relapsed from refractory disease and cannot benefit further from standard chemotherapy, CAR-T cells targeting CD123 should be used with caution before allogeneic transplantation. These patients have better options, and these results allow clinicians to consider the important long-term effects of CAR-T cell persistence for CD123, which is not the case in other cases. Help prevent it from being used for any purpose. "