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Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates

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Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. / Taraseviciute, Agne; Tkachev, Victor; Ponce, Rafael; Turtle, Cameron J; Snyder, Jessica M; Liggitt, H Denny; Myerson, David; Gonzalez-Cuyar, Luis; Baldessari, Audrey; English, Chris; Yu, Alison; Zheng, Hengqi; Furlan, Scott N; Hunt, Daniel J; Hoglund, Virginia; Finney, Olivia; Brakke, Hannah; Blazar, Bruce R; Berger, Carolina; Riddell, Stanley R; Gardner, Rebecca; Kean, Leslie S; Jensen, Michael C.

in: CANCER DISCOV, Jahrgang 8, Nr. 6, 06.2018, S. 750-763.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Taraseviciute, A, Tkachev, V, Ponce, R, Turtle, CJ, Snyder, JM, Liggitt, HD, Myerson, D, Gonzalez-Cuyar, L, Baldessari, A, English, C, Yu, A, Zheng, H, Furlan, SN, Hunt, DJ, Hoglund, V, Finney, O, Brakke, H, Blazar, BR, Berger, C, Riddell, SR, Gardner, R, Kean, LS & Jensen, MC 2018, 'Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates', CANCER DISCOV, Jg. 8, Nr. 6, S. 750-763. https://doi.org/10.1158/2159-8290.CD-17-1368

APA

Taraseviciute, A., Tkachev, V., Ponce, R., Turtle, C. J., Snyder, J. M., Liggitt, H. D., Myerson, D., Gonzalez-Cuyar, L., Baldessari, A., English, C., Yu, A., Zheng, H., Furlan, S. N., Hunt, D. J., Hoglund, V., Finney, O., Brakke, H., Blazar, B. R., Berger, C., ... Jensen, M. C. (2018). Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. CANCER DISCOV, 8(6), 750-763. https://doi.org/10.1158/2159-8290.CD-17-1368

Vancouver

Taraseviciute A, Tkachev V, Ponce R, Turtle CJ, Snyder JM, Liggitt HD et al. Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. CANCER DISCOV. 2018 Jun;8(6):750-763. https://doi.org/10.1158/2159-8290.CD-17-1368

Bibtex

@article{2f8f65bd1425498d87247fb5ac600032,
title = "Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates",
abstract = "Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell-mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell-mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan-T cell encephalitis.Significance: We provide the first immunologically relevant, nonhuman primate model of B cell-directed CAR T-cell therapy-mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750-63. {\textcopyright}2018 AACR.This article is highlighted in the In This Issue feature, p. 663.",
keywords = "Animals, Antigens, CD20/immunology, Cell Line, Tumor, Cyclophosphamide/administration & dosage, Disease Models, Animal, Humans, Immunotherapy, Adoptive/adverse effects, K562 Cells, Macaca mulatta, Neurotoxicity Syndromes/etiology, Receptors, Antigen, T-Cell/immunology, Transplantation, Autologous",
author = "Agne Taraseviciute and Victor Tkachev and Rafael Ponce and Turtle, {Cameron J} and Snyder, {Jessica M} and Liggitt, {H Denny} and David Myerson and Luis Gonzalez-Cuyar and Audrey Baldessari and Chris English and Alison Yu and Hengqi Zheng and Furlan, {Scott N} and Hunt, {Daniel J} and Virginia Hoglund and Olivia Finney and Hannah Brakke and Blazar, {Bruce R} and Carolina Berger and Riddell, {Stanley R} and Rebecca Gardner and Kean, {Leslie S} and Jensen, {Michael C}",
note = "{\textcopyright}2018 American Association for Cancer Research.",
year = "2018",
month = jun,
doi = "10.1158/2159-8290.CD-17-1368",
language = "English",
volume = "8",
pages = "750--763",
journal = "CANCER DISCOV",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

RIS

TY - JOUR

T1 - Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates

AU - Taraseviciute, Agne

AU - Tkachev, Victor

AU - Ponce, Rafael

AU - Turtle, Cameron J

AU - Snyder, Jessica M

AU - Liggitt, H Denny

AU - Myerson, David

AU - Gonzalez-Cuyar, Luis

AU - Baldessari, Audrey

AU - English, Chris

AU - Yu, Alison

AU - Zheng, Hengqi

AU - Furlan, Scott N

AU - Hunt, Daniel J

AU - Hoglund, Virginia

AU - Finney, Olivia

AU - Brakke, Hannah

AU - Blazar, Bruce R

AU - Berger, Carolina

AU - Riddell, Stanley R

AU - Gardner, Rebecca

AU - Kean, Leslie S

AU - Jensen, Michael C

N1 - ©2018 American Association for Cancer Research.

PY - 2018/6

Y1 - 2018/6

N2 - Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell-mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell-mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan-T cell encephalitis.Significance: We provide the first immunologically relevant, nonhuman primate model of B cell-directed CAR T-cell therapy-mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750-63. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.

AB - Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell-mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell-mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan-T cell encephalitis.Significance: We provide the first immunologically relevant, nonhuman primate model of B cell-directed CAR T-cell therapy-mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750-63. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.

KW - Animals

KW - Antigens, CD20/immunology

KW - Cell Line, Tumor

KW - Cyclophosphamide/administration & dosage

KW - Disease Models, Animal

KW - Humans

KW - Immunotherapy, Adoptive/adverse effects

KW - K562 Cells

KW - Macaca mulatta

KW - Neurotoxicity Syndromes/etiology

KW - Receptors, Antigen, T-Cell/immunology

KW - Transplantation, Autologous

U2 - 10.1158/2159-8290.CD-17-1368

DO - 10.1158/2159-8290.CD-17-1368

M3 - SCORING: Journal article

C2 - 29563103

VL - 8

SP - 750

EP - 763

JO - CANCER DISCOV

JF - CANCER DISCOV

SN - 2159-8274

IS - 6

ER -