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 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 126 Issue 10 Pg. 3814-3826 (10 03 2016) ISSN: 1558-8238 [Electronic] United States
• PMID: 27571406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, CD19
• Antineoplastic Agents
• CD19 molecule, human
• CTL019 chimeric antigen receptor
• IL3RA protein, human
• Interleukin-3 Receptor alpha Subunit
• Receptors, Antigen, T-Cell

Topics

• Animals
• Antigens, CD19 (metabolism)
• Antineoplastic Agents (administration & dosage)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Humans
• Immunotherapy (methods)
• Interleukin-3 Receptor alpha Subunit (administration & dosage, metabolism)
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Recurrence, Local (prevention & control)
• Neoplastic Stem Cells (metabolism)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)
• Receptors, Antigen, T-Cell (administration & dosage)
• T-Lymphocytes (immunology, transplantation)
• Xenograft Model Antitumor Assays