Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

被引：80

作者：

Sworder, Brian J. ^{[1
]}

Kurtz, David M. ^{[1
,2
]}

Alig, Stefan K. ^{[1
]}

Frank, Matthew J. ^{[3
,4
]}

Shukla, Navika ^{[1
]}

Garofalo, Andrea ^{[1
]}

Macaulay, Charles W. ^{[1
]}

Esfahani, Mohammad Shahrokh ^{[1
]}

Olsen, Mari N. ^{[1
]}

Hamilton, James ^{[1
]}

Hosoya, Hitomi ^{[5
]}

Hamilton, Mark ^{[3
]}

Spiegel, Jay Y. ^{[3
,4
]}

Baird, John H. ^{[3
,4
]}

Sugio, Takeshi

Carleton, Mia

Craig, Alexander F. M.

Younes, Sheren F. ^{[6
]}

Sahaf, Bita ^{[3
,4
]}

Sheybani, Natasha D. ^{[1
]}

Schroers-Martin, Joseph G. ^{[1
,5
]}

Liu, Chih Long ^{[1
]}

Oak, Jean S. ^{[6
]}

Jin, Michael C. ^{[1
]}

Beygi, Sara ^{[1
]}

Huttmann, Andreas ^{[7
]}

Hanoun, Christine ^{[7
]}

Duhrsen, Ulrich ^{[7
]}

Westin, Jason R. ^{[8
]}

Khodadoust, Michael S. ^{[1
,2
]}

Natkunam, Yasodha

Majzner, Robbie G. ^{[4
,6
,9
]}

Mackall, Crystal L. ^{[9
,10
]}

Diehn, Maximilian ^{[2
,11
,12
]}

Miklos, David B. ^{[3
,4
]}

Alizadeh, Ash A. ^{[1
,2
,5
,12
]}

机构：

[1] Stanford Univ, Dept Med, Div Oncol, 265 Campus Dr, Stanford, CA 94305 USA

[2] Stanford Univ, Stanford Canc Inst, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Div Blood & Marrow Transplantat & Cellular Therap, Stanford, CA 94305 USA

[4] Stanford Canc Inst, Ctr Canc Cell Therapy, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Med, Div Hematol, Stanford, CA 94305 USA

[6] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[7] Univ Hosp Essen, Dept Hematol, Essen, Germany

[8] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA

[9] Stanford Univ, Sch Med, Dept Pediat, Div Hematol Oncol, Stanford, CA 94305 USA

[10] Stanford Univ, Parker Inst Canc Immunotherapy, Sch Med, Stanford, CA 94305 USA

[11] Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA

[12] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

来源：

CANCER CELL | 2023年 / 41卷 / 01期

关键词：

CLONAL HEMATOPOIESIS; COMMITMENT; DNA; REMISSIONS; MUTATIONS; DISCOVERY; GENES;

D O I：

10.1016/j.ccell.2022.12.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 longitudi-nal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabta-gene 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 microenvi-ronment (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.

引用

页码：210 / +

页数：22

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