期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 10, 页码 3814-3826出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI87366
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资金
- University of Pennsylvania-Novartis Alliance
- NIH grant [5R01CA120409, CA016520]
- EMD-Serono Cancer Immunotherapy Clinical Fellowship by the Society for Immunotherapy of Cancer (SITC)
- Bristol-Myers Squibb Oncology Fellowship in Clinical Cancer Research by the American Association for Cancer Research (AACR)
- Gabrielle's Angel Foundation
- SIES-AIL fellowship by the Italian Society for Experimental Hematology
- Italian Leukemia Association
- St. Baldrick's Foundation Scholar Award
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 a 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
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