Sten Eirik Jacobsen

Recurrence after apparently effective cancer treatment is a major challenge in many cancers, including blood cancers. We have, in chronic blood cancer, identified cancer stem cells that lie dormant and only occasionally divide to replenish malignant cells. Since most conventional treatments against cancer target rapidly dividing cells, the resting stem cells escape the treatment and thus often become a source of relapse. Elimination of cancer stem cells is therefore necessary and may even be sufficient to cure the disease. The purpose of this project is to target the immune system directly against the blood cancer stem cells. We want to modify immune cells so that they recognize blood cancer stem cell-specific proteins and thus specifically and effectively kill these while healthy tissues are not damaged. We will evaluate the effectiveness and specificity of this approach by growing blood cancer cells together with modified immune cells and by transplanting blood cancer cells into mice and then treating the mice with modified immune cells. By screening for cancer stem cells after therapy, we also want to identify the risk of relapse at an early stage, and identify new stem cell-specific proteins against which we can develop new immunotherapy. These studies aim to develop new and highly specific immunotherapy against blood cancer, which currently lacks effective and curative treatment. In addition, these studies should provide new insights into fundamental and clinically relevant questions about the importance of cancer stem cells in the progression and recurrence of blood cancers and whether their elimination is not only required but also sufficient to cure the cancer. Finally, an effective targeted immunotherapy of otherwise treatment-resistant and dormant cancer stem cells should reduce the number of relapses and lead to higher survival rates in blood cancer as well as in other cancers.

Although insults to the blood-forming system highlight the need for more rapid blood replenishment from hematopoietic stem cells (HSCs), existing models of hematopoiesis implicate only one, mandatory, differentiation pathway for each blood lineage. We have evidence for non-hierarchical relationships between mouse HSCs replenishing all blood lineages and exclusively platelets through distinct pathways. We will investigate the role of these 2 pathways and the replenished platelets at different stages of ontogeny and in response to different challenges, using single HSC transplantations, genetic fate mapping and single cell RNA sequencing, with the goal of providing a platform for combatting transplantation-and drug-induced thrombocytopenia. It remains unclear to what degree the extensive steady-state turn-over of blood cells can progress in absence of HSCs, a question with important implications also for the cancer stem cell hypothesis, implying that efficient therapeutic targeting of the malignant stem cells might be sufficient to eliminate the entire malignancy. No studies have addressed this following efficient and selective elimination of stem cells in vivo. Herein we aim to  engineer T cell receptors (TCRs) that efficiently and specifically target antigens selectively and highly expressed on normal and malignant HSCs to establish if elimination of the rare malignant stem cells is not only required, but potentially sufficient for a cure.