scholarly journals Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia

Cell ◽  
2018 ◽  
Vol 173 (6) ◽  
pp. 1439-1453.e19 ◽  
Author(s):  
Miriam Y. Kim ◽  
Kyung-Rok Yu ◽  
Saad S. Kenderian ◽  
Marco Ruella ◽  
Shirley Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Genetic Inactivation ◽  
Cell Immunotherapy ◽  
Car T ◽  
T Cell Immunotherapy ◽  
Acute Myeloid

scholarly journals 716. Durable Acute Myeloid Leukemia Remission Without Myeloablation in an Innovative Xenotolerant Mouse Model of CD44v6 CAR-T Cell Immunotherapy

2015 ◽  
Vol 23 ◽  
pp. S286
Author(s):  
Margherita Norelli ◽  
Monica Casucci ◽  
Barbara Camisa ◽  
Laura Falcone ◽  
Aurore Saudemont ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T ◽  
T Cell Immunotherapy ◽  
Acute Myeloid

scholarly journals Chimeric antigen receptor T cell therapies for acute myeloid leukemia

2020 ◽  
Vol 14 (6) ◽  
pp. 701-710
Author(s):  
Bin Gu ◽  
Jianhong Chu ◽  
Depei Wu
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Antigen Receptor ◽  
Target Antigen ◽  
Hematopoietic Stem ◽  
Car T ◽  
Acute Myeloid

AbstractChimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

scholarly journals An anti–PR1/HLA-A2 T-cell receptor–like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells

Blood ◽  
2011 ◽  
Vol 117 (16) ◽  
pp. 4262-4272 ◽  
Author(s):  
Anna Sergeeva ◽  
Gheath Alatrash ◽  
Hong He ◽  
Kathryn Ruisaard ◽  
Sijie Lu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
T Cell Receptor ◽  
Myeloid Leukemia ◽  
Specific Binding ◽  
Cell Receptor ◽  
Specific Lysis ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract PR1 (VLQELNVTV) is a human leukocyte antigen-A2 (HLA-A2)–restricted leukemia-associated peptide from proteinase 3 (P3) and neutrophil elastase (NE) that is recognized by PR1-specific cytotoxic T lymphocytes that contribute to cytogenetic remission of acute myeloid leukemia (AML). We report a novel T-cell receptor (TCR)–like immunoglobulin G2a (IgG2a) antibody (8F4) with high specific binding affinity (dissociation constant [KD] = 9.9nM) for a combined epitope of the PR1/HLA-A2 complex. Flow cytometry and confocal microscopy of 8F4-labeled cells showed significantly higher PR1/HLA-A2 expression on AML blasts compared with normal leukocytes (P = .046). 8F4 mediated complement-dependent cytolysis of AML blasts and Lin−CD34+CD38− leukemia stem cells (LSCs) but not normal leukocytes (P < .005). Although PR1 expression was similar on LSCs and hematopoietic stem cells, 8F4 inhibited AML progenitor cell growth, but not normal colony-forming units from healthy donors (P < .05). This study shows that 8F4, a novel TCR-like antibody, binds to a conformational epitope of the PR1/HLA-A2 complex on the cell surface and mediates specific lysis of AML, including LSCs. Therefore, this antibody warrants further study as a novel approach to targeting leukemia-initiating cells in patients with AML.

scholarly journals Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment

Blood ◽  
2013 ◽  
Vol 122 (5) ◽  
pp. 749-758 ◽  
Author(s):  
Francis Mussai ◽  
Carmela De Santo ◽  
Issa Abu-Dayyeh ◽  
Sarah Booth ◽  
Lynn Quek ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
T Cell Proliferation ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Immunosuppressive Microenvironment ◽  
Acute Myeloid

Key Points AML blasts have an arginase-dependent ability to inhibit T-cell proliferation and hematopoietic stem cells. AML blasts have an arginase-dependent ability to modulate the polarization of monocytes.

scholarly journals CD38-Directed CAR-T Cell Therapy: A Novel Immunotherapy Strategy for Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34 ◽  
Author(s):  
Xiaowen Tang ◽  
Depei Wu ◽  
Qingya Cui ◽  
Chongsheng Qian ◽  
Nan Xu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Car T Cell ◽  
Car T ◽  
Relapsed Acute Myeloid Leukemia ◽  
Grade Iii ◽  
Acute Myeloid

There are few effective therapies for relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which has a poor prognosis. Although CD19-targeted chimeric antigen receptor T cell (CAR-T-19) therapy has achieved remarkable success for B-cell malignancies, few successful CAR-T cell therapies in AML have been reported. In this prospective study, we explored the therapeutic effect and clinical safety of the application of CAR-T-38 in 6 AML patients with relapsed post allo-HSCT and CD38 expression. The decitabine (DAC) + HAAG regimen was used to reduce tumor burden, followed by the fludarabine and cyclophosphamide (FC) regimen for lymphodepletion chemotherapy before CAR-T cell infusion. In total, 8.05 (6.1-10) x 106/kg CAR-T-38 were infused by dose escalation over a 3- to 4-day period. At 1, 2 and 4 weeks after CAR-T infusion, two (33.3%), four (66.7%) and four (66.7%) of six patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), respectively. Five of six (83.3%) patients experienced mild (grade I-II) cytokine release syndrome (CRS), and only one patient presented grade III hepatotoxicity. No neurological toxicities were observed, but all six patients had grade III/IV hematological toxicities. The 6-month overall survival (OS) and leukemia-free survival (LFS) rates were 50% and 50%, respectively, and the median OS and LFS were 12.3 and 10.3 months, respectively. The cumulative relapse rates at 3 and 6 months were 25% and 50%, respectively. Multiparameter flow cytometry (FCM) showed that the percentage of CD38-positive blasts remarkably decreased at day 7 and remained at low levels on day 28 after CAR-T cell infusion, but CD38-positive monocytes and lymphocytes were not depleted. This study is the first to indicate that CAR-T-38 therapy is a promising effective and safe approach for patients with relapsed AML after allo-HSCT. (NCT04351022) Disclosures No relevant conflicts of interest to declare.

CD70-specific CAR T-cells have potent activity against Acute Myeloid Leukemia (AML) without HSC toxicity

Blood ◽  
2021 ◽  
Author(s):  
Tim Sauer ◽  
Kathan Parikh ◽  
Sandhya Sharma ◽  
Bilal Omer ◽  
David Nikolov Sedloev ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Target Antigen ◽  
Single Chain ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T ◽  
Acute Myeloid

The prognosis of patients with acute myeloid leukemia (AML) remains dismal highlighting the need for novel innovative treatment strategies. The application of chimeric antigen receptor (CAR) T-cell therapy to AML patients has been limited in particular by the lack of a tumor-specific target antigen. CD70 is a promising antigen to target AML as it is expressed on the majority of leukemic blasts, whereas little or no expression is detectable in normal bone marrow samples. To target CD70 on AML cells, we generated a panel of CD70-CARs that contained a common single chain variable fragment (scFv) for antigen detection but differed in size and flexibility of the extracellular spacer, and in the transmembrane and the co-stimulatory domains. These CD70scFv CARs were compared with a CAR construct that contained the human CD27, the ligand of CD70 fused to the CD3z chain (CD27z). The structural composition of the CAR strongly influenced expression levels, viability, expansion and cytotoxic capacities of CD70scFv CAR T-cells, but the CD27z-CAR T-cells demonstrated superior proliferation and anti-tumor activity in vitro and in vivo, compared to all CD70scFv-CARs. While CD70-CAR T-cells recognized activated virus-specific T-cells (VSTs) that expressed CD70, they did not prevent colony formation by normal hematopoietic stem cells (HSCs). Thus, CD70-targeted immunotherapy is a promising new treatment strategy for patients with CD70-positive AML that does not affect normal hematopoiesis but will require monitoring of virus-specific T-cell responses.

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