Project 2

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with limited therapeutic options and poor prognosis in the relapsed or refractory situation [1]. So far, specific, safe and effective use of immunotherapy in AML has not been achieved. For other hematologic neoplasms, the use of Chimeric antigen receptor (CAR) modified T cells has been well established; unfortunately, with AML, initial results from clinical trials suggest a highly unfavorable risk profile [2, 3]. This is mainly due to the lack of suitable targets that allow discrimination between blasts from healthy hematopoiesis.

A major challenge for immunotherapies lies in the fact that such therapies are highly personalized; therefore, many patients do not qualify for them. These are because CAR-modified T cells are either unable to be generated or cannot be generated fast enough [4]. Taken together, there is a huge medical need for innovative AML therapies, in particular for the development of off-the-shelf approaches, which could enable a faster deployment at a lower cost [5, 6].

The present project aims to use a CAR that can discriminate between healthy and malignant bone marrow cells. This could be possible, for the first time, thanks to our preliminary work, which was able to identify antigens with a predicted superior selectivity for AML blasts [7]. The CAR will be optimized for expression and function on NK cells. The optimized CAR will be incorporated into induced pluripotent stem cells (iPSCs) from which CAR-expressing NK cells (CAR-iNK cells) will be differentiated. The in vitro function of CAR-iNK cells will be analyzed to assess their potential as a cell therapy product. NK cells derived from iPSCs offer the opportunity to manufacture allogeneic cell products with consistently high quality and scalable quantities. This would allow the use of such CAR-modified cells in a patient-independent, so-called off-the-shelf manner.