Zürich - Researchers from the University of Zurich and University Hospital Zurich have discovered how mutated blood cancer cells can be made to respond to an immunotherapy approach again. Genetically enhanced immune cells used in combination with drugs can eliminate resistance in blood cancer cells.

A research team led by Markus Manz and Steffen Böttcher from the University of Zurich and Department of Medical Oncology and Hematology at University Hospital Zurich has discovered that acute myeloid leukemia (AML) blood cancer cells develop a resistance against the novel chimeric antigen receptor T-cell therapy in cases where a mutation occurs in the TP53 tumor suppressor gene. For this CAR T-cell immunotherapy, immune cells are taken from patients and genetically modified in the laboratory in such a way that more receptors are formed to identify the cancer cells. 

“The reason for the poorer effect of CAR T-cells with mutated TP53 is that these immune cells are exhausted more quickly and are therefore less active against the cancer cells”, comments Steffen Böttcher, lead doctor in the research team, in a press release. Conventional chemotherapies are no longer effective in cases where resistance builds up.

In their study, the researchers decoded the mechanism of this resistance development in addition to working out how to increase the endurance of the CAR T-cells and how to therapeutically exploit a weak point in the AML cells with a mutated TP53 gene. With these genetically improved CAR T-cells or additional pharmacological concomitant therapy, the researchers were able to enhance the effectiveness of the CAR T-cells against TP53-mutated AML cells to such an extent that there was no therapeutic difference compared to that of non-mutated AML cells.

“This proof-of-principle study shows that concurrent pharmacological therapies and genetically engineered CAR T-cells are promising strategies to develop more effective and tolerable immunotherapies for patients with TP53-mutant AML”, explains head of clinic Markus Manz in the press release. ce/js

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