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Full NameDr Eva Szegezdi
Apoptosis Research Centre
National University of Ireland Galway
- genetics, genomics and molecular biology
My research focuses on understanding the pathophysiology of acute myeloid leukemia (AML). AML is an aggressive cancer, with a 5-year survival rate of less than 20% in the most affected, elderly population. With other research groups we showed that the bone marrow stroma drives AML drug resistance and consequent relapse (O’Reilly et al., Sci Rep, 2018; O’Reilly et al., Blood Reviews, 2021). To better understand the AML-tumour stroma/microenvironment interaction, with Prof. Michael O’Dwyer we have established Blood Cancer Network Ireland (BCNI), a national research consortium, which I lead since Dec 2019. In BCNI, we developed sophisticated AML culture models replicating key features of the leukaemic bone marrow microenvironment (AUC=0.94; Dhami et al., Br. J. Haematol., 2020, Dhami et al., Blood, 2018, O’Reilly et al., Frontiers in Cell Dev.Biol., 2021).
Using these organoid models and single cell level analysis (scRNAseq), current research in my laboratory aims to understand how AML changes the bone marrow microenvironment and how it drives drug resistance. By understanding these features, we can find vulnerabilities of AML cells, especially leukemic stem cells that can be used to develop new treatments. One such treatment we are developing is based on chimeric antigen receptor (CAR)-expressing natural killer cells.
Developing novel CAR-NK cell therapy against acute myeloid leukaemia
Chimeric antigen receptor-based immunotherapy holds great promise. CAR-T cells have shown promising preclinical activity and has recently entered the clinic. However, CAR-NK cells may have several advantages over a CAR-T cells, which include:
1) The shorter persistence of NK cells, reducing the risk of sustained neutropenia
2) Inherent (CAR-independent) anti-cancer activity of NK cells
3) Reduced likelihood of toxicity due to cytokine release syndrome
4) Off-the-shelf nature (no need to isolate, engineer and ex vivo expand each patients’ cells for therapy), reducing time to treatment.
AML is a very challenging disease in which to achieve sustained, long term disease control. This is due to the plasticity of AML stem cells and the tendency for resistant clones to emerge under selective pressure. Relapse of AML is largely driven by leukaemic stem cells. These cells are often quiescent and resistant to drugs. Consequently, they persist during chemotherapy and once the treatment finished they can repopulate the disease. CAR-NK cell-based therapy offers the option to selectively target AML LSCs and eradicate them.
The aim of this project is to identify AML LSC-specific markers/antigens and develop a CAR-NK therapy against these markers. As targeting a single antigen alone may prove insufficient, the project will evaluate different dual/multi-targeted approaches that can achieve synergistic LSC killing. These include the co-expression of CARs targeting more than one antigen (e.g. CD96, TIM3, CD38) as well as exploring combination of CAR expression with ectopic expression of the death ligand, TRAIL. NK cells use TRAIL to kill tumour cells, however, TRAIL expression declines over time after NK cell activation and expansion. Thus, maintained, ectopic expression of TRAIL can overcome this limitation.
Within this project we aim to validate which of these combinations makes most sense to bring forward into clinical development.