399. Evaluation of CD123 Targeting CART Cells in Non-Human Primates
| Autor: | Michael C. Milone, Elizabeth Skuba, Daher Ibrahim Aibo, LeeAnne Talbot, Regina M. Young, Lori Martin, Vijay Bhoj, Steve Busch, Saar Gill, Jennifer Marlowe, Timothy K. MacLachlan, Linda Dong, Olga Shestova, Celeste Richardson, Xiaorui Yao |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pharmacology Cell Myeloid leukemia Biology In vitro 03 medical and health sciences Haematopoiesis 030104 developmental biology medicine.anatomical_structure Antigen In vivo Drug Discovery Immunology Genetics medicine Molecular Medicine Interleukin-3 receptor Stem cell Molecular Biology |
| Zdroj: | Molecular Therapy. 24:S158 |
| ISSN: | 1525-0016 |
| Popis: | The CAR-T platform has provided an exceptionally potent means to treat cancers that have proven resistant to standard treatments. This potency, however, can work against normal tissue as well. Some clinical trials have identified adverse consequences as a result of CAR-T cell targeting of critical normal tissue. To enable as many targets as possible using the CAR-T cell approach, it is important to understand the potential liabilities of those targets in normal tissues prior to initiating clinical trials. CD123, the IL-3 receptor alpha subunit, is a viable target for treatment of acute myeloid leukemia, as it is expressed highly on primary AML blasts. We have previously shown that, in mice transplanted with human hematopoietic stem cells, CD123 targeting CAR T-cells eradicated these precursors and, in turn, normal hematopoiesis (Gill et al 2014xPreclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Gill, Saar, Tasian, Sarah K., Ruella, Marco, Shestova, Olga, Li, Yong, Porter, David L., Carroll, Martin, Danet-Desnoyers, Gwenn, Scholler, John, Grupp, Stephan A., June, Carl H., and Kalos, Michael. Blood. 2014; 123: 2343–2354Crossref | PubMed | Scopus (120)See all ReferencesGill et al 2014). Here, we describe an animal model developed to address the potential effects of targeting CD123 on non-hematopoietic tissue, namely endothelial cells that are found to express significant levels of CD123. An scFv that bound cynomolgus monkey CD123 was identified and a chimeric lentivirus that efficiently transduced monkey PBMCs was developed. Cells were demonstrated to be active in vitro and dosed into monkeys, after which cellular expansion was observed. In vivo safety assessments and histopathology results will be discussed. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|