PhD Student - "CRISPR-based optimization of CAR NK cell therapy for pediatric AML"

Pediatric acute myeloid leukemia (AML) comprises a group of genetically and morphologically heterogenous malignancies originating from early hematopoietic progenitor cells. Where eure rates of pediatric cancers exceed 80% for most tumor entities, AML still has a comparably poor prognosis in particular for those children with high-risk genetics. lmmunotherapy is an emerging field with intriguing potential in cancer therapy that is expected to improve treatment outcome of pediatric AML. Cellular immunotherapy with chimeric antigen receptor {CAR) T-cells has already shown amazing results in B-cell malignancies, and applications for solid tumor entities are rapidly evolving. Combining immunotherapy with genome editing, another transformative technology in biomedical research and medicine, has been key for the advances made in the field. However, with a major focus of immunotherapy being placed on CAR T-cells, alternative promising cell sources -like natural killer (NK) cells- are lacking behind. In particular the safety profile of NK cells, their ability of non-specific tumor killing and low rejection potential are highly beneficial for cancer treatments targeting essential cell types of the body. While recent applications of NK cell therapies for hematopoietic malignancies and solid tumors have shown highly promising results, further optimization will accelerate this breakthrough cancer therapy. Due to the inherent resistance to viral transduction, efforts to genetically optimize NK cells for therapeutic applications have so far been limited. Yet, recent advances in synthetic lentiviral envelope pseudotyping, transient genome-editing tool delivery, and new genome-editing technologies are now opening new windows for cellular genetic modifications of NK cells. This project aims to leverage these technical advances and a unique resource of pediatric patient samples and patient-derived xenograft models to adopt and optimize CAR NK cell­based immunotherapy for pediatric AML. The project will thereby overcome current hur­dles to tackle myeloid malignancies and will contribute to the development of personalized cancer therapies.