CD123-CAR T Cells Manufactured in the Presence of Dasatinib Induce High Grade CRS and/or IEC-HS without Improving Efficacy in Pediatric Patients with Recurrent/Refractory Leukemia

作者：Swati Naik, Madden Renee, Aimee C. Talleur, Rebecca Epperly, Timothy Lockey, Jennyfer Bran, Liqing Tian, Ying Li, Dinesh Keerthi, Alexandra Boyd, Amanda Lipsitt, Jeffrey E. Rubnitz, Jeffery M. Klco, Barry L. Shulkin, Sarah Schell, Polly Adams, Jeoungeun John Park, Janice M. Riberdy, Na Shang, Jaquelyn T. Zoine, Raghuvaran Shanmugam, Chris Nevitt, Unmesha Thanekar, Jennifer Wallace, Elaine Harstead, Scott Perry, Catherine Willis, Jean‐Yves Métais, Deanna Langfitt, Sheng Zhou, Salem Akel, Caitlin C. Zebley, Jeremy Chase Crawford, Ben Youngblood, Paul G. Thomas, Frank Fazio, Brandon M. Triplett, Stephen Gottschalk, Mireya Paulina Velasquez · 发表于：Blood · 年份：2024 · DOI：10.1182/blood-2024-208795 · 被引用次数：10 · 研究领域：CAR-T cell therapy research、Viral Infectious Diseases and Gene Expression in Insects、Biosimilars and Bioanalytical Methods

Background We are conducting a Phase 1 clinical study to evaluate the safety and efficacy of escalating doses of autologous CD123-CAR T cells for pediatric patients with r/r CD123-positive AML or ALL. We previously reported (Naik et al, Blood 2022, 140 (Supplement 1): 4584-5) that infusion of CD123-CAR T cells after lymphodepleting chemotherapy with fludarabine and cyclophosphamide was well tolerated, with transient fevers representing grade 1 cytokine release syndrome (CRS) and without dose limiting toxicities. We observed anti-AML activity as evidenced by responses in two out of six infused patients albeit with limited CAR T-cell expansion. Mechanistic studies revealed that CD123-CAR T cells were predominantly effector memory and expressed markers associated with T cell exhaustion (TIM3, PD1 or CD39). This phenotype was completely reversed by generating CD123-CAR T cells in the presence of dasatinib (CD123-CAR.dasa T cells), a multikinase inhibitor known to transiently inhibit CAR signaling. Based on these findings, we modified the CD123-CAR T cell production for our protocol and now report on an extended comparison of CD123-CAR and CD123-CAR.dasa T cells and on the clinical course of patients who were infused with CD123-CAR.dasa T cells. Methods and Results Single cell RNA seq analysis revealed that CD123-CAR.dasa T cells had upregulated IFNa signaling pathways in comparison to CD123-CAR T cells. In addition, they were in a less differentiated state as judged by a methylat...