18 May 2022

Scientists have discovered some of the ways in which genetic drivers can predict poor responses to CAR-T therapy in large B cell lymphomas.

Dr Jonathan Schatz and his team at the University of Miami, USA, used whole genome sequencing to identify mutations that appear to make B-cell lymphomas resistant to CAR-T immunotherapies.

Findings were published in the journal Blood recently. The team focused on CAR (chimeric antigen receptor) T cells – immune cells taken from the patient and engineered to target the CD19 receptor on lymphoma cells.

Although these treatments are highly successful, some patients develop resistance to the treatment.

The work looked beyond previously discovered mechanisms of CAR-T resistance, such as mutations in the CD19 gene and the inflammatory tumour microenvironment.

The team sequenced the genomes of 51 tumour samples from 49 patients. They identified a series of complex genomic variations which “laid the groundwork” for cancers to resist CAR-T.

These included patterns of mutations caused by either the APOBEC family of enzymes or reactive oxygen species; a recurrent deletion of the RHOA gene; and complex changes to chromosomes. Collectively, patients whose tumours had any of these genomic drivers were four times more likely to see their lymphoma progress after CAR-T cell therapy.

“So much of the work in the field has focused on the tumour microenvironment and the overall inflammatory mechanisms that drive resistance,” said Dr Schatz.

“However, by looking at these genetic drivers together, we see how strongly they predict poor responses to CAR-T and possibly other therapies.”

He added: “It really gets to this whole idea that there’s a complex interplay between tumours, immune environment and CAR-T cells. The same changes that made the tumour so aggressive in the first place are often keeping it from responding to immunotherapy.”

Source: Jain MD, Ziccheddu B, Coughlin CA, Faramand RG, Griswold AJ, Reid KM, Menges M, Zhang Y, Cen L, Wang X, Hussaini MO, Landgren O, Davila ML, Schatz JH, Locke FL, Maura F. (2022) “Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma.” Blood, doi: 10.1182/blood.2021015008

Link: https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2021015008/485092/Whole-genome-sequencing-reveals-complex-genomic

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