Swiss researchers have revealed that mutations of the TP53 gene harm the prognosis for patients with acute myeloid leukaemia (AML) treated with chimeric antigen receptor (CAR)-T cell therapies.
However, in a proof-of-concept study, the Zurich-based researchers say they have shown that drugs or genetic changes to CAR-T cells could counteract this effect and restore the efficacy of CAR-T therapy.
The TP53 gene codes for the p53 protein, a key tumour suppressor. Patients whose AML carries a mutation in TP53 often face an extremely poor prognosis.
Reporting their findings in EMBO Molecular Medicine, the researchers say that TP53-mutant AML cells are “significantly more” resistant to CAR-T treatment than cells without mutations in this gene.
Study co-leader Professor Steffen Boettcher, from University Hospital Zurich, said: “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.”
The team identified weak points in the TP53 mutant AML cells, showing that the mevalonate pathway is increased in these cells. Inhibiting this pathway with the drug simvastatin (a medication to treat high cholesterol) restored the ability of CAR-T cells to attack TP53-mutant cells in vitro.
They also found that the Wnt signalling pathway was reduced in CAR-T cells attacking TP53-mutant cells. CAR-T therapy effectiveness could be increased by restoring Wnt signalling, either with drugs or by further genetic manipulation of the CAR-T cells.
Collectively, these additional treatments they have identified “drastically” improve the effectiveness of CAR-T therapy in laboratory studies – to the extent there might not be any therapeutic differences.
Study co-leader Professor Markus Manz said: “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.”
Source:
Mueller J, Schimmer RR, Koch C, Schneiter F, Fullin J, Lysenko V, Pellegrino C, Klemm N, Russkamp N, Myburgh R, Volta L, Theocharides AP, Kurppa KJ, Ebert BL, Schroeder T, Manz MG, Boettcher S. (2024) “Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.” EMBO Molecular Medicine, doi: 10.1038/s44321-024-00024-2
Link: https://www.embopress.org/doi/full/10.1038/s44321-024-00024-2
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