Zurich – Researchers at the University of Zurich and the University Hospital Zurich have discovered how mutated blood cancer cells respond to immunotherapy. Genetically enhanced immune cells and the combination with drugs can eliminate the resistance of blood cancer cells.
A research team led by Markus Manz and Steffen Böttcher from the University of Zurich and the Department of Medical Oncology and Hematology at the University Hospital Zurich has discovered that acute myeloid leukemia (AML) blood cancer cells develop resistance to the novel chimeric antigen receptor T-cell therapy when the tumor suppressor gene TP53 is mutated. For this CAR-T cell immunotherapy, immune cells are taken from the patients and genetically modified in the laboratory so that they have more receptors against the cancer cells.
"The reason for the poorer effect of CAR T cells with mutated TP53 is that these defense cells are exhausted more quickly and are therefore less active against cancer cells," Steffen Böttcher, lead physician in the research team, is quoted as saying in a press release. Conventional chemotherapies are no longer effective anyway if resistance develops.
In their study, the researchers deciphered both the mechanism of this resistance formation and how they can strengthen the endurance of CAR T cells and make a weak point of AML cells with a mutated TP53 gene therapeutically usable. With these genetically improved CAR T cells or an additional pharmacological concomitant therapy, the researchers were able to increase the efficacy of the CAR T cells against TP53-mutated AML cells to such an extent that they showed no therapeutic difference compared to non-mutated AML cells.
"This proof-of-principle study shows that concomitant pharmacological therapies and genetically engineered CAR T cells are promising strategies for developing more effective and better tolerated immunotherapies for patients with TP53-mutated AML," said clinic director Markus Manz in the press release. ce/js