التفاصيل البيبلوغرافية
| العنوان: |
Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates |
| المؤلفون: |
Daniel J. Hunt, Bruce R. Blazar, Hannah Brakke, Luis F. Gonzalez-Cuyar, Rebecca Gardner, Olivia Finney, Scott N. Furlan, H. Denny Liggitt, Rafael Ponce, Agne Taraseviciute, Stanley R. Riddell, Audrey Baldessari, Alison Yu, Carolina Berger, David Myerson, Virginia Hoglund, Jessica M. Snyder, Hengqi Zheng, Michael C. Jensen, Chris English, Leslie S. Kean, Victor Tkachev, Cameron J. Turtle |
| المصدر: |
Cancer discovery. 8(6) |
| سنة النشر: |
2017 |
| مصطلحات موضوعية: |
0301 basic medicine, Adoptive cell transfer, medicine.medical_treatment, T cell, Receptors, Antigen, T-Cell, Immunotherapy, Adoptive, Transplantation, Autologous, Article, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Cyclophosphamide, CD20, biology, business.industry, Neurotoxicity, Immunotherapy, medicine.disease, Antigens, CD20, Macaca mulatta, Chimeric antigen receptor, Cytokine release syndrome, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Immunology, biology.protein, Neurotoxicity Syndromes, business, K562 Cells |
| الوصف: |
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 |
| تدمد: |
2159-8290 |
| الوصول الحر: |
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::79421f30aebd52a4619435b1a17addb2Test
https://pubmed.ncbi.nlm.nih.gov/29563103Test |
| حقوق: |
OPEN |
| رقم الانضمام: |
edsair.doi.dedup.....79421f30aebd52a4619435b1a17addb2 |
| قاعدة البيانات: |
OpenAIRE |
