@article{46992f1cdcec414685433d2c555f7d0d,
title = "Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies",
abstract = "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 CARexpressing 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.",
author = "Marco Ruella and Barrett, {David M.} and Kenderian, {Saad S.} and Olga Shestova and Hofmann, {Ted J.} and Jessica Perazzelli and Michael Klichinsky and Vania Aikawa and Farzana Nazimuddin and Miroslaw Kozlowski and John Scholler and Lacey, {Simon F.} and Melenhorst, {Jan J.} and Morrissette, {Jennifer J.D.} and Christian, {David A.} and Hunter, {Christopher A.} and Michael Kalos and Porter, {David L.} and June, {Carl H.} and Grupp, {Stephan A.} and Saar Gill",
note = "Funding Information: The authors would like to thank Fang Chen and Natalka Kengle for the support with the Luminex cytokine assays. The authors would like to thank Charles {"}Hank{"} Pletcher and Paul Hallberg (Flow Cytometry Core, University of Pennsylvania) for help with the flow cytometry sorting of leukemia CD19-negative subsets. The chimeric antigen receptor used in this study was obtained under a materials transfer agreement from Dario Campana, Chihaya Imai, and the St. Jude Children's Research Hospital and was subsequently modified by cloning into a lentiviral vector and expressed with a eukaryotic promoter (62). This work was supported by grants from the University of Pennsylvania-Novartis Alliance (PI: CHJ and SG), NIH grant 5R01CA120409 (PI: CHJ), the EMD-Serono Cancer Immunotherapy Clinical Fellowship by the Society for Immunotherapy of Cancer (SITC) (PI: MR), the Bristol-Myers Squibb Oncology Fellowship in Clinical Cancer Research by the American Association for Cancer Research (AACR) (PI: MR), the Gabrielle's Angel Foundation (PI: MR), the SIES-AIL fellowship by the Italian Society for Experimental Hematology and the Italian Leukemia Association (PI: MR), and the St. Baldrick's Foundation Scholar Award and SU2C (PI: DMB and SAG). Imaging was performed at the University of Pennsyl-vania Small Animal Imaging Facility (SAIF) Optical/Bioluminescence Core, supported by NIH grant CA016520.",
year = "2016",
month = oct,
day = "3",
doi = "10.1172/JCI87366",
language = "English (US)",
volume = "126",
pages = "3814--3826",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",
}