Project 1

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and has been diagnosed worldwide in 150,000 people in 2020 only. Despite an initial curative approach, many patients do not respond or relapse after initial response. As a result, 100,000 people died from AML in the same period [1]. In the relapsed situation, allogenic stem cell transplantation is the only curative treatment, yet this applies to at most 25% of those treated, demonstrating the great medical need for innovative therapies [2]. So far, the development of new immunotherapies, such as chimeric antigen receptor (CAR)-modified T cells, has not been as successful as anticipated. This is due to their level of efficacy or their association with severe toxicity effects.

CAR (chimeric antigen receptors) are synthetic receptors consisting of the fusion of the variable part of an antibody with T cell activating and costimulatory domains [3]. These receptors can be introduced into immune cells, especially T cells, by gene transfer. This allows the target cell the ability to recognize and lyse antigen-positive cells [4]. This procedure has been successfully applied and approved for clinical use against CD19 as an antigen associated with lymphoma and B-cell leukaemia [5]. Our aim is to adapt this technology against AML blasts.

So far, attempts using CAR T cells directed against prominent targets (CD33 o CD123) in AML blasts have not been entirely successful. This is mainly because the presence of the targets on haematopoietic stem cells leads to the depletion of human haematopoiesis [6, 7].

The current literature suggests that leukemia is caused by mutations in different hematopoietic progenitor cells [8]. This implies that AML blasts and their stem cells share many phenotypic similarities with the cells healthy hematopoiesis. Consequently, this leads to a lack of discrimination of AML-targeted therapies and thus, among others, to severe haematological toxicities [9]. Therefore, the urge of finding better targets for AML. Such structures would have the potential to allow immunotherapies in AML and would have a great medical and economic potential.

In preliminary work, we could identify, for the first time antigens with predicted superior selectivity for AML blasts [10]. We developed CAR against these targets and demonstrated superior efficacy and discriminatory capacity in preclinical models. To now advance to clinical development, the parties will establish technologies and a manufacturing process involving GMP materials and media developed by Sirion/Revvity that comply with regulatory requirements, while preserving the previously described properties.