CD19-directed chimeric antigen receptor (CAR-19)-T cells are groundbreaking immunotherapies approved for use against large B-cell lymphomas. While host inflammatory and tumor microenvironmental markers associate with efficacy and resistance, the tumor-intrinsic alterations underlying these phenomena remain undefined. CD19 mutations associate with resistance but are uncommon, and most patients who relapse retain expression of the wild-type receptor, implicating other genomic mechanisms. We therefore leveraged the comprehensive resolution of whole-genome sequencing to assess 51 tumor samples from 49 CAR-19-treated large B-cell lymphoma patients. We find that pre-treatment presence of complex structural variants, APOBEC mutational signatures, and genomic damage from reactive oxygen species predict CAR-19 resistance. In addition, the recurrent 3p21.31 chromosomal deletion containing the RHOA tumor suppressor was strongly enriched in patients failed by CAR-T therapy. Pretreatment reduced expression or mono-allelic loss of CD19 did not affect responses, suggesting CAR-19 therapy success and resistance are due to multiple mechanisms. Our study shows tumor-intrinsic genomic alterations are key among the complex interplay of factors that underly CAR-19 efficacy and resistance for large B-cell lymphomas.
Pharmacology, Toxicology and Pharmaceutical Science
2
2%
Nursing and Health Professions
2
2%
Other
8
9%
Unknown
45
49%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 26. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 May 2023.
All research outputs
#1,857,068
of 34,306,620 outputs
Outputs from Blood
#2,016
of 46,788 outputs
Outputs of similar age
#32,449
of 459,486 outputs
Outputs of similar age from Blood
#30
of 204 outputs
Altmetric has tracked 34,306,620 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 94th percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 46,788 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.6. This one has done particularly well, scoring higher than 95% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 459,486 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 92% of its contemporaries.
We're also able to compare this research output to 204 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 85% of its contemporaries.
