Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma
| Autor: | Michael D. Jain, Bachisio Ziccheddu, Caroline A. Coughlin, Rawan Faramand, Anthony J. Griswold, Kayla M. Reid, Meghan Menges, Yonghong Zhang, Ling Cen, Xuefeng Wang, Mohammad Hussaini, Ola Landgren, Marco L. Davila, Jonathan H. Schatz, Frederick L. Locke, Francesco Maura |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Blood. 140:491-503 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | CD19-directed chimeric antigen receptor (CAR-19) T cells are groundbreaking immunotherapies approved for use against large B-cell lymphomas. Although 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 with relapsed disease 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 patients with CAR-19–treated large B-cell lymphoma. We found that the pretreatment 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 for whom CAR T-cell therapy failed. Pretreatment reduced expression or monoallelic loss of CD19 did not affect responses, suggesting CAR-19 therapy success and resistance are related to multiple mechanisms. Our study showed that tumor-intrinsic genomic alterations are key among the complex interplay of factors that underlie CAR-19 efficacy and resistance for large B-cell lymphomas. |
| Databáze: | OpenAIRE |
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