41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative. METHODS: We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs. RESULTS: Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs. CONCLUSIONS: This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.
|Keywords||cell engineering, immunotherapy, adoptive, T lymphocytes|
|Persistent URL||dx.doi.org/10.1136/jitc-2020-000845, hdl.handle.net/1765/127864|
|Journal||Journal for immunotherapy of cancer|
Baroni, M.L. (Matteo Libero), Sanchez Martinez, D. (Diego), Gutierrez Aguera, F. (Francisco), Roca Ho, H. (Heleia), Castella, M. (Maria), Zanetti, S. (Samanta), … Menéndez, P. (2020). 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. Journal for immunotherapy of cancer, 8(1). doi:10.1136/jitc-2020-000845