1. Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
- Author
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Sworder, Brian J., Kurtz, David M., Alig, Stefan K., Frank, Matthew J., Shukla, Navika, Garofalo, Andrea, Macaulay, Charles W., Shahrokh Esfahani, Mohammad, Olsen, Mari N., Hamilton, James, Hosoya, Hitomi, Hamilton, Mark, Spiegel, Jay Y., Baird, John H., Sugio, Takeshi, Carleton, Mia, Craig, Alexander F.M., Younes, Sheren F., Sahaf, Bita, and Sheybani, Natasha D.
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T cells , *B cells , *CIRCULATING tumor DNA , *B cell lymphoma , *T cell receptors , *CELL-free DNA , *CD19 antigen - Abstract
Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches. [Display omitted] • Tumors and CAR T cell effectors can be simultaneously profiled using cell-free DNA • Alterations in multiple classes of genes influence outcomes after CAR19 therapy • Tumor genotype and phenotype influence CAR19 T cell expansion, and vice versa • A multivariable model incorporating tumor and effector features predicts outcomes Sworder et al. develop and apply a tool to simultaneously profile tumor and effector-mediated determinants of resistance to anti-CD19 CAR T cells using cell-free DNA. The authors profile two independent cohorts of patients with relapsed/refractory large B cell lymphoma and identify genomic alterations, molecular thresholds, and microenvironmental changes associated with resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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