Journal Article

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

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

2016

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Acute lymphocytic leukemia / Animals / Antigen-antibody reactions / Antigens / Antigens, CD19 - metabolism / Antineoplastic Agents - administration & dosage / Biomedical research / Cancer / Cancer therapies / Care and treatment / Cell Line, Tumor / Cellular proteins / Clinical trials / Colleges & universities / Development and progression / Drug Resistance, Neoplasm / Experiments / Flow cytometry / Genetic aspects / Genotype & phenotype / Health aspects / Humans / Immunoglobulins / Immunotherapy / Immunotherapy - methods / Institutional repositories / Interleukin-3 Receptor alpha Subunit - administration & dosage / Interleukin-3 Receptor alpha Subunit - metabolism / Laboratory animals / Leukemia / Lymphocytes / Medical prognosis / Medical research / Methods / Mice, Inbred NOD / Mice, SCID / Neoplasm Recurrence, Local - prevention & control / Neoplastic Stem Cells - metabolism / Patient outcomes / Patients / Pediatrics / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism / Properties / Receptors, Antigen, T-Cell - administration & dosage / Response rates / Stem cells / T cell receptors / T-Lymphocytes - immunology / T-Lymphocytes - transplantation / Tumors / Xenograft Model Antitumor Assays