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

Marco Ruella, David M. Barrett, Saad 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. GruppSaar Gill

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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 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.

Original languageEnglish (US)
Pages (from-to)3814-3826
Number of pages13
JournalJournal of Clinical Investigation
Volume126
Issue number10
DOIs
StatePublished - Oct 3 2016

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Immunotherapy
Antigens
Recurrence
T-Cell Antigen Receptor
Precursor Cell Lymphoblastic Leukemia-Lymphoma
B-Lymphocytes
Heterografts
Leukemia
CD19 Antigens
Interleukin-3 Receptors
Synapses
T-Lymphocytes
Survival
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ruella, M., Barrett, D. M., Kenderian, S., Shestova, O., Hofmann, T. J., Perazzelli, J., ... Gill, S. (2016). Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. Journal of Clinical Investigation, 126(10), 3814-3826. https://doi.org/10.1172/JCI87366

Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. / Ruella, Marco; Barrett, David M.; Kenderian, Saad; Shestova, Olga; Hofmann, Ted J.; Perazzelli, Jessica; Klichinsky, Michael; Aikawa, Vania; Nazimuddin, Farzana; Kozlowski, Miroslaw; Scholler, John; Lacey, Simon F.; Melenhorst, Jan J.; Morrissette, Jennifer J.D.; Christian, David A.; Hunter, Christopher A.; Kalos, Michael; Porter, David L.; June, Carl H.; Grupp, Stephan A.; Gill, Saar.

In: Journal of Clinical Investigation, Vol. 126, No. 10, 03.10.2016, p. 3814-3826.

Research output: Contribution to journalArticle

Ruella, M, Barrett, DM, Kenderian, S, Shestova, O, Hofmann, TJ, Perazzelli, J, Klichinsky, M, Aikawa, V, Nazimuddin, F, Kozlowski, M, Scholler, J, Lacey, SF, Melenhorst, JJ, Morrissette, JJD, Christian, DA, Hunter, CA, Kalos, M, Porter, DL, June, CH, Grupp, SA & Gill, S 2016, 'Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies', Journal of Clinical Investigation, vol. 126, no. 10, pp. 3814-3826. https://doi.org/10.1172/JCI87366
Ruella, Marco ; Barrett, David M. ; Kenderian, Saad ; Shestova, Olga ; Hofmann, Ted J. ; Perazzelli, Jessica ; Klichinsky, Michael ; Aikawa, Vania ; Nazimuddin, Farzana ; Kozlowski, Miroslaw ; Scholler, John ; Lacey, Simon F. ; Melenhorst, Jan J. ; Morrissette, Jennifer J.D. ; Christian, David A. ; Hunter, Christopher A. ; Kalos, Michael ; Porter, David L. ; June, Carl H. ; Grupp, Stephan A. ; Gill, Saar. / Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 10. pp. 3814-3826.
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AU - Hofmann, Ted J.

AU - Perazzelli, Jessica

AU - Klichinsky, Michael

AU - Aikawa, Vania

AU - Nazimuddin, Farzana

AU - Kozlowski, Miroslaw

AU - Scholler, John

AU - Lacey, Simon F.

AU - Melenhorst, Jan J.

AU - Morrissette, Jennifer J.D.

AU - Christian, David A.

AU - Hunter, Christopher A.

AU - Kalos, Michael

AU - Porter, David L.

AU - June, Carl H.

AU - Grupp, Stephan A.

AU - Gill, Saar

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