Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies
| Autor: | Vania Aikawa, Christopher A. Hunter, Miroslaw Kozlowski, Jennifer J.D. Morrissette, Michael Klichinsky, David L. Porter, Farzana Nazimuddin, David M. Barrett, John Scholler, David A. Christian, J. Joseph Melenhorst, Michael Kalos, Saar Gill, Stephan A. Grupp, Saad S. Kenderian, Carl H. June, Marco Ruella, Olga Shestova, Simon F. Lacey, Jessica Perazzelli, Ted J. Hofmann |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
T-Lymphocytes medicine.medical_treatment T cell Antigens CD19 Interleukin-3 Receptor alpha Subunit Receptors Antigen T-Cell Antineoplastic Agents Mice SCID CD19 03 medical and health sciences 0302 clinical medicine Antigen Mice Inbred NOD immune system diseases Cell Line Tumor Precursor B-Cell Lymphoblastic Leukemia-Lymphoma hemic and lymphatic diseases Animals Humans Medicine biology business.industry General Medicine Immunotherapy medicine.disease Xenograft Model Antitumor Assays Chimeric antigen receptor 3. Good health Leukemia 030104 developmental biology medicine.anatomical_structure Drug Resistance Neoplasm 030220 oncology & carcinogenesis Neoplastic Stem Cells biology.protein Cancer research Blinatumomab Interleukin-3 receptor Neoplasm Recurrence Local business Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 126:3814-3826 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci87366 |
| Popis: | Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies. |
| Databáze: | OpenAIRE |
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