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Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies
Marco Ruella, … , Stephan A. Grupp, Saar Gill
Marco Ruella, … , Stephan A. Grupp, Saar Gill
Published August 29, 2016
Citation Information: J Clin Invest. 2016;126(10):3814-3826. https://doi.org/10.1172/JCI87366.
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Research Article Hematology Immunology

Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies

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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 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

Authors

Marco Ruella, David M. Barrett, Saad S. Kenderian, Olga Shestova, Ted J. Hofmann, Jessica Perazzelli, Michael Klichinsky, Vania Aikawa, Farzana Nazimuddin, Miroslaw Kozlowski, John Scholler, Simon F. Lacey, Jan J. Melenhorst, Jennifer J.D. Morrissette, David A. Christian, Christopher A. Hunter, Michael Kalos, David L. Porter, Carl H. June, Stephan A. Grupp, Saar Gill

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Figure 1

CD123 is highly expressed in B-ALL, including the LIC and the CD19-negative relapses occurring after CD19-targeted immunotherapies.

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CD123 is highly expressed in B-ALL, including the LIC and the CD19-negat...
(A) High expression of CD123 in 42 R/R B-ALL samples (gated on blasts: SSClo, single, live, CD45dim/neg). (B) CD123 and CD19 are typically coexpressed in B-ALL blasts, although minor CD19-negative and CD123-negative blasts can be detected at very low frequencies. (C) CD123 is expressed in the LIC compartment (red), defined as CD34+CD38– blasts (blue represents control CD45++ cells). RIght panel shows expression of CD123 in the ALL LIC of 23 B-ALL patients. (D) B-ALL blasts were sorted using a flow cytometry sorter, based on the expression of CD19 and CD123, obtaining 4 subsets: CD19+CD123–, CD19+CD123+, CD19–CD123–, and CD19–CD123+. These 4 subsets were highly pure and were analyzed by FISH for their specific genetic marker. Boxes indicate percentage of FISH-positive cells in each subset. Importantly, CD19–CD123+ blasts were positive in most cases. (E) The sorting experiment was repeated in a total of 6 B-ALL samples with different FISH abnormalities, and results were consistent. (F) Injection of sorted CD19-negative CD123-positive leukemic subpopulations into NSG mice led to reconstitution of the original B-ALL phenotype (BM, day 120), confirming this population’s LIC function (graph representative of 2 independent experiments each with 2 mice per group). (G) CD123 expression (MFI, mean fluorescence intensity) is maintained in CD19-negative B-ALL relapses occurring after CART19 (CTL019) treatment; representative case is shown. Gating is based on isotype control.
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