4.7 Article

Safe and effective off-the-shelf immunotherapy based on CAR.CD123-NK cells for the treatment of acute myeloid leukaemia

期刊

JOURNAL OF HEMATOLOGY & ONCOLOGY
卷 15, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s13045-022-01376-3

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资金

  1. Accelerator Award-Cancer Research UK/AIRC-INCAR project
  2. Associazione Italiana Ricerca per la Ricerca sul Cancro (AIRC)-Special Project 5 x 1000 [9962]
  3. AIRC [21724]
  4. Ministero dell'Universita e della Ricerca
  5. Italian Healthy Ministry [CAR T RCR-2019-23669115, GR-2016-02364546, RF-2021-12374120]
  6. Post-doctoral Fellowships 2021-Fondazione Umberto Veronesi
  7. NEMO Project -Fondazione Umberto Veronesi Grant
  8. T2-EVOLVE, IMI-2 [116026]
  9. Amy Strelzer Manasevit Research Program
  10. Italian PNRR CN3 National Center for Gene Therapy and Drugs based on RNA Technology
  11. MFAG [21979, 22889]

向作者/读者索取更多资源

The study demonstrates the potential of using off-the-shelf CAR.CD123-NK cells as a therapeutic strategy for paediatric AML patients, showing significant anti-leukaemia activity and improved safety compared to CAR.CD123-T cells.
Background Paediatric acute myeloid leukaemia (AML) is characterized by poor outcomes in patients with relapsed/refractory disease, despite the improvements in intensive standard therapy. The leukaemic cells of paediatric AML patients show high expression of the CD123 antigen, and this finding provides the biological basis to target CD123 with the chimeric antigen receptor (CAR). However, CAR.CD123 therapy in AML is hampered by on-target off-tumour toxicity and a long vein-to-vein time. Methods We developed an off-the-shelf product based on allogeneic natural killer (NK) cells derived from the peripheral blood of healthy donors and engineered them to express a second-generation CAR targeting CD123 (CAR.CD123). Results CAR.CD123-NK cells showed significant anti-leukaemia activity not only in vitro against CD123(+) AML cell lines and CD123(+) primary blasts but also in two animal models of human AML-bearing immune-deficient mice. Data on anti-leukaemia activity were also corroborated by the quantification of inflammatory cytokines, namely granzyme B (Granz B), interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha), both in vitro and in the plasma of mice treated with CAR.CD123-NK cells. To evaluate and compare the on-target off-tumour effects of CAR.CD123-T and NK cells, we engrafted human haematopoietic cells (hHCs) in an immune-deficient mouse model. All mice infused with CAR.CD123-T cells died by Day 5, developing toxicity against primary human bone marrow (BM) cells with a decreased number of total hCD45(+) cells and, in particular, of hCD34(+)CD38(-) stem cells. In contrast, treatment with CAR.CD123-NK cells was not associated with toxicity, and all mice were alive at the end of the experiments. Finally, in a mouse model engrafted with human endothelial tissues, we demonstrated that CAR.CD123-NK cells were characterized by negligible endothelial toxicity when compared to CAR.CD123-T cells. Conclusions Our data indicate the feasibility of an innovative off-the-shelf therapeutic strategy based on CAR.CD123-NK cells, characterized by remarkable efficacy and an improved safety profile compared to CAR.CD123-T cells. These findings open a novel intriguing scenario not only for the treatment of refractory/resistant AML patients but also to further investigate the use of CAR-NK cells in other cancers characterized by highly difficult targeting with the most conventional T effector cells.

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