Immunotherapeutic approaches against hematopoietic stem cell malignancies

Research focus

Together with our collaboration partners in the CRPP, we will advance the development of novel immunotherapeutic agents for the treatment of hematopoietic stem cell (HSC) malignancies. Malignantly transformed myeloid leukemia-initiating cells (LIC) derive from healthy hematopoietic stem and progenitor cells (HSPCs) and share high cell surface protein similarity with their cell of origin (COO) compartment. We therefore propose to immunologically eliminate the entire HSC and LIC compartment, and subsequently replace hematopoiesis by allogeneic stem cell transplantation. We postulate that HSC/LIC specific chimeric antigen receptor (CAR) immune-cells and/or engineered antibodies could provide increased anti-leukemic efficacy while simultaneously making toxic conditioning chemotherapy obsolete/dispensable.

We address the following challenges:

• Evaluation of efficacy and specificity by targeting different HSC/LIC expressed antigens (antigen A vs n B vs C)
• Comparison of different immunotherapeutical modalities (CAR T/NK-cell vs engineered antibody constructs) against the same target antigen
• Development of multi-specific CAR T-cells for increased specificity against hematopoietic cells and reduced on-target-off-tumor toxicity (antigen A plus B not C)
• Optimization of methods for termination of CAR T-cell activity for increased safety and to enable subsequent allogeneic stem cell transplantation

Members:

• Markus G. Manz
• Jonathan Kiefer
• Chiara Magnani
• Jan Müller
• Renier Myburgh
• Surema Pfister
• Norman Russkamp