In a new study, researchers identified genomic features that appear to be related to failures of anti-CD19 chimeric antigen receptor (CAR-19) T-cell therapy in patients with large B-cell lymphoma. The study results were reported in the journal Blood.
“Although 52% to 82% of patients respond immediately after CAR-19 infusion, only ~40% achieve complete tumor eradication and prolonged remission, and underlying mechanisms of treatment failures remain largely unknown,” the researchers wrote in their report. They had a study aim of identifying roles of genomic drivers involved in limiting the efficacy of CAR-19 treatment.
In this analysis, the researchers evaluated genomic characteristics of patients with large B-cell lymphoma who received CAR-19 therapy. The researchers performed whole genome sequencing, RNA sequencing, and flow cytometry analyses on tumor samples obtained before or after initiation of CAR-19 treatment. They examined clinical characteristics and patterns of mutations or gene expression in the context of treatment outcomes.
Samples were examined from 49 patients, 81.6% of whom had diffuse large B-cell lymphoma, while 16.3% had transformed follicular lymphoma and 2.0% had transformed chronic lymphocytic leukemia. Most patients (91.8%) had received axicabtagene ciloleucel as their CAR-19 therapy, while tisagenlecleucel and lisocabtagene maraleucel were used with 4.1% of patients each. Patients had a median age of 65 years (range, 44-79) and a median of 2 prior therapies (range, 1-6), with 81.6% having had platinum-containing treatment exposure.
The median progression-free survival in the overall population was 11.6 months, and the median overall survival was 8 months. Just fewer than half (46.9%) of patients experienced relapse, or response with progression, as a CAR-19 treatment outcome. Another 16.3% of patients had refractory disease, and 36.7% of patients had response without progression.
The researchers identified patterns in pretreatment samples that may predict resistance to CAR-19 treatment. These included complex structural variants, APOBEC mutational signatures, and genomic damage associated with reactive oxygen species. An additional feature that was found to be highly enriched in patients with CAR-19 failure was a recurrent deletion of chromosomal sequence at the 3p21.31 locus that contains the RHOA tumor suppressor gene.
However, reduced expression of CD19 did not appear related to CAR-19 failure in this study population. The researchers noted that other studies have shown a loss of CD19 to be associated with CAR-19 resistance.
The researchers considered the study results to indicate that resistance to chimeric antigen receptor T-cell therapy in patients with large B-cell lymphoma involves a complex interaction between cancer cells and the immune microenvironment.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Jain MD, Ziccheddu B, Coughlin CA, et al. Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma. Blood. 2022;140(5):491-503. doi:10.1182/blood.2021015008