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

Abstract

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.

Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia

“…We previously demonstrated significant depletion of normal hematopoietic cells in preclinical AML models treated with permanently modified CD33-or CD123-redirected CAR T cells. 20,24 Two recent reports of adults with relapsed AML treated with CD33 or CD123 CAR T cells describe transient antileukemia efficacy and consequent pancytopenia, 26,27 further suggesting need for CAR T-cell depletion and/or HSCT rescue.…”

“…Preclinical studies have demonstrated the potent antileukemia activity of CAR T cells targeting AML surface proteins, including Lewis-Y, CD33, CD44v6, and CD123 antigens. [18][19][20][21][22][23][24] Some of these approaches are under early clinical investigation in patients with relapsed/refractory AML [25][26][27] (www. clinicaltrials.gov NCT01864902, NCT02159495, NCT02623582, and NCT02799680).…”

Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia

“…Subsequently, one group generated a novel anti-CD123-CD28-CD137-CD27-CD3ζ-iCasp9 CAR (4SCAR123) that exhibited potent cytotoxicity against AML in vitro and then infused 4SCAR123 into a 47-year-old male patient with AML-M2. The patient exhibited a rapid response consistent with a controllable CRS and achieved partial remission within 20 days without any off-target cytotoxicities [ 80 ]. One significant concern is that CD123-directed CAR T cells could irreversibly increase the myeloablative impact on normal hematopoiesis.…”

Finding new lanes: Chimeric antigen receptor (CAR) T‐cells for myeloid leukemia

“…It was one of the first antigens that were found to be preferentially expressed in myeloid leukemia cells . Multiple centers have created and tested distinct CD123 targeting CAR T‐cells and antibodies with initial results suggesting this to be a promising approach for AML patients . T‐cells expressing CD123‐specific CAR and truncated EGFR (antiCD123‐CD28‐CD3ζ‐EGFRt+ T cells) are being tested in AML patients following lymphodepletion .…”