TY - JOUR
T1 - Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas
AU - Deng, Qing
AU - Han, Guangchun
AU - Puebla-Osorio, Nahum
AU - Ma, Man Chun John
AU - Strati, Paolo
AU - Chasen, Beth
AU - Dai, Enyu
AU - Dang, Minghao
AU - Jain, Neeraj
AU - Yang, Haopeng
AU - Wang, Yuanxin
AU - Zhang, Shaojun
AU - Wang, Ruiping
AU - Chen, Runzhe
AU - Showell, Jordan
AU - Ghosh, Sreejoyee
AU - Patchva, Sridevi
AU - Zhang, Qi
AU - Sun, Ryan
AU - Hagemeister, Frederick
AU - Fayad, Luis
AU - Samaniego, Felipe
AU - Lee, Hans C.
AU - Nastoupil, Loretta J.
AU - Fowler, Nathan
AU - Eric Davis, R.
AU - Westin, Jason
AU - Neelapu, Sattva S.
AU - Wang, Linghua
AU - Green, Michael R.
N1 - Funding Information:
This work was supported by the Schweitzer Family Fund (J.R.W., R.E.D. and M.R.G.), The University of Texas MD Anderson Cancer Center B-Cell Lymphoma Moonshot (S.S.N. and M.R.G.), a National Cancer Institute Cancer Center Support Grant to The University of Texas MD Anderson Cancer Center (P30 CA016672) and Institutional Research Grant start-up research funds provided to L.W. and M.R.G. by The University of Texas MD Anderson Cancer Center. H.Y. is supported by a Fellow Award from the Leukemia and Lymphoma Society. M.R.G. is supported by a Scholar Award from the Leukemia and Lymphoma Society.
Funding Information:
B.C. reports advisory board membership for Advanced Accelerator Application and Clovis Oncology. N.F. reports advisory board membership for Roche, BMS, Gilead and Novartis; research funding from Roche, BMS, Novartis and BostonGene; and employment from BostonGene. H.C.L. reports consulting fees from Adaptive Biotechnologies, Amgen, Celgene, GlaxoSmithKline, Janssen, Sanofi and Takeda Pharmaceuticals and research funding from Amgen, Celgene, Daiichi Sankyo, GlaxoSmithKline, Janssen, Regeneron and Takeda Pharmaceuticals. L.J.N. reports personal fees and research fees from Celgene, Genentech, Juno, Merck and TG Therapeutics and personal fees from Bayer, Novartis and Spectrum Pharmaceuticals. J.W. reports advisory board membership for Kite/Gilead, Juno/Celgene/BMS, Novartis, Genentech, Janssen, Amgen, AstraZeneca, Curis and Morphosys and research funding from Kite/Gilead, June/Celgene/BMS, Novartis, Genentech, Janssen, AstraZeneca, 47, Unum Therapeutics, Curis and Morphosys. S.S.N. has received research support from Kite/Gilead, Cellectis, Poseida, Merck, Acerta, Karus, BMS, Unum Therapeutics, Allogene and Precision Biosciences; has served as consultant and advisory board member for Kite/Gilead, Celgene, Novartis, Unum Therapeutics, Pfizer, Merck, Precision Biosciences, Cell Medica, Incyte, Allogene, Calibr and Legend Biotech; has received royalty income from Takeda Pharmaceuticals; and has patents related to cell therapy. M.R.G. reports consulting for VeraStem Oncology and stock ownership interest in KDAc Therapeutics.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/12
Y1 - 2020/12
N2 - Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10−149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.
AB - Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10−149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.
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U2 - 10.1038/s41591-020-1061-7
DO - 10.1038/s41591-020-1061-7
M3 - Article
C2 - 33020644
AN - SCOPUS:85092083293
SN - 1078-8956
VL - 26
SP - 1878
EP - 1887
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -