Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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, Sheybani Natasha D, Schroers-Martin Joseph G, Liu Chih Long, Oak Jean S, Jin Michael C, Beygi Sara, Hüttmann Andreas, Hanoun Christine, Dührsen Ulrich, Westin Jason R, Khodadoust Michael S, Natkunam Yasodha, Majzner Robbie G, Mackall Crystal L, Diehn Maximilian, Miklos David B, Alizadeh Ash A
Аннотация
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.