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3778 First-in-Man CD123-Specific Chimeric Antigen Receptor-Modified T Cells for the Treatment of Refractory Acute Myeloid Leukemia

Acute Myeloid Leukemia: Commercially available Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemia: Commercially available Therapy, excluding Transplantation: Poster III
Monday, December 7, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Yi Luo1*, Lung-Ji Chang, PhD2,3*, Yongxian Hu, MD1*, Lujia Dong4*, Guoqing Wei1* and He Huang, MD, PhD5

1Bone Marrow Transplantation Center, the First Affiliated Hospital of Zhejiang University, Hangzhou, China
2Shenzhen Genoimmune Medical Institute (GIMI),, Shenzhen, China
3Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL
4America Yuva Biomed, Bejing, China
5Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, School of Medicine., Hangzhou, China

Introduction:Adoptive immunotherapy using T-cells endowed with chimeric antigen receptors (CARs) has emerged as a promising new approach to treating CD19+ acute lymphoblastic leukemia (ALL). However,treatments for relapse/refractory acute myeloid leukemia (AML) have remained largely unchanged for nearly 50 years, and some AML patients have very poor prognosis. The interleukin-3 receptor alpha chain (CD123) has been identified as a potential immunotherapeutic target due to its overexpression in AML cells compared with normal hematopoietic stem cells. Antibodies targeting CD123 for the treatment of AML have demonstrated promising anti-leukemic activity in murine models but showed limited efficacy in clinical trials, suggesting that alternative and more potent therapies targeting CD123 are required.

Methods: We have generated a 4th generation, apoptosis-inducible lentiviral CAR targeting CD123: CD123-scFv/CD28/CD137/CD27/CD3ζ-iCasp9 (4SCAR123), and demonstrated its high AML killing and AP1903-inducible apoptosis functions in ex vivo analyses. In a pilot trial of 4SCAR123, we enrolled a 47-year-old male patient with AML-M2 (FLT3/ITD+). The patient underwent allogeneic hematopoietic stem cell transplantation and relapsed. After 3 chemotherapies combined with sorafenib, his AML cells kept at 59% in bone marrow. He received CTX 250mg/kg/day for 3 days as conditioning regimen followed by 1.8x106/kg 4SCAR123 T cell infusion. Serum cytokine levels were measured by flow cytometric bead assay.

Results: At day 1 after 4SCAR123 T infusion, the patient experienced rigorous chills and fevers, low blood pressure and hypoxemia. We detected elevated serum cytokine levels including interleukin-6 (2,500pg/ml) and tumor necrosis factor-α (33.8 pg/ml) at day 8, and the patient suffered from severe cytokine release syndrome (CRS) on day 4, which was controlled by one dose of Tocilizumab. BM examination detected a decrease of blasts from 59% to 45% 20 days after CAR-T therapy.

Conclusion: Here we report a first-in-man pilot safety study of CD123 CAR-T therapy for AML patients. The 4SCAR123 exhibited potent cytotoxicity against AML in vitro, and in this pilot trial, the patient developed a rapid response consistent with CRS and achieved partial remission within 20 days. Importantly, although CD123 is universally expressed in myeloid and endothelial cells, we did not observe overt off-target cytotoxicity from the 4SCAR123 T cells, except for a controllable CRS. Our pilot study warrants further exploration of CD123 CAR for the management of refractory AML.

Disclosures: Dong: America Yuva Biomed: Consultancy .

*signifies non-member of ASH