Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia
| العنوان: | Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia |
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| المؤلفون: | Michael C. Boyle, Rocio Hernandez, Brendon Frank, Qinghong Yan, Chi-Ming Li, Herve Lebrec, Tara Arvedson, Oliver Homann, Xiaoting Wang, Rebecca Goldstein, K.H. Kim, Benjamin Brooks, Christine M. Karbowski, Gregor Adams, Kelly Hensley |
| المصدر: | Toxicological Sciences |
| بيانات النشر: | Oxford University Press (OUP), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | safety, Adult, 0301 basic medicine, AcademicSubjects/SCI01040, Cell- and Tissue-Based Therapy, CD34, acute myeloid leukemia, Toxicology, chimeric antigen receptor T cells, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, hemic and lymphatic diseases, medicine, Clinical and Translational Toxicology, Animals, Humans, Progenitor cell, Receptors, Chimeric Antigen, AcademicSubjects/MED00305, business.industry, Myeloid leukemia, medicine.disease, Chimeric antigen receptor, Featured, Leukemia, Myeloid, Acute, Macaca fascicularis, Leukemia, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cats, Cancer research, Chimeric Antigen Receptor T-Cell Therapy, Bone marrow, business |
| الوصف: | Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia (AML). AMG 553 is an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of AML. FLT3 expression analysis and in vitro and in vivo studies were leveraged to evaluate the nonclinical safety of AMG 553. Cynomolgus monkeys administered autologous anti-FLT3 CAR T cells demonstrated no evidence of CAR T-cell-mediated toxicity, expansion, or persistence, likely due to restricted cell surface FLT3 protein expression in healthy animals. This highlights the limited value of such in vivo studies for safety assessment of the CAR T-cell modality when directed against a target with restricted expression. To complement these studies and directly evaluate the potential toxicities of eliciting T-cell-mediated cytotoxicity against cells with surface expression of FLT3 protein in vivo, data from cynomolgus monkey toxicology studies with 2 bispecific T-cell engager molecules targeting FLT3 were leveraged; findings were consistent with the targeted killing of bone marrow cells expressing cell surface FLT3. Potential AMG 553-induced cytotoxicity was assessed against a wide range of normal human primary cells and cell lines; cytotoxicity was observed against FLT3-positive AML cell lines and a percentage of primary bone marrow CD34+ cells. In conclusion, the nonclinical safety data suggest that AMG 553 can target FLT3 protein on AML cells, whereas only affecting a percentage of normal hematopoietic stem and progenitor cells, supporting clinical development. |
| تدمد: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfaa098 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bccf5d203ae6e3cb166793e27eeb086e https://doi.org/10.1093/toxsci/kfaa098 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....bccf5d203ae6e3cb166793e27eeb086e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10960929 10966080 |
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| DOI: | 10.1093/toxsci/kfaa098 |