Persistence and Efficacy of Second Generation CAR T Cell Against the LeY Antigen in Acute Myeloid Leukemia

Chemotherapy resistance and relapse remain significant sources of mortality for children and adults with acute myeloid leukemia (AML). Further intensification of conventional cytotoxic chemotherapy is likely not feasible due to the severity of acute and long-term side effects upon normal tissues commonly induced by these drugs. Successful development and implementation of new precision medicine treatment approaches for patients with AML, which may improve leukemia remission and diminish toxicity, is thus a major priority. Tumor antigen-redirected chimeric antigen receptor (CAR) T-cell immunotherapies have induced remarkable responses in patients with relapsed or chemorefractory B-lymphoblastic leukemia, and similar strategies are now under early clinical study in adults with relapsed/refractory AML. However, potential on target/off tumor toxicity of AML CAR T-cell immunotherapies, notably aplasia of normal myeloid cells, may limit broader implementation of such approaches. Careful selection of optimal target antigens, consideration of toxicity mitigation strategies, and development of methodologies to circumvent potential CAR T-cell resistance are essential for successful implementation of cellular immunotherapies for patients with high-risk AML.

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

Molecular Therapy ◽

10.1016/s1525-0016(16)34325-8 ◽

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

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CARving the Path to Allogeneic CAR T Cell Therapy in Acute Myeloid Leukemia

Frontiers in Oncology ◽

10.3389/fonc.2021.800110 ◽

2022 ◽

Vol 11 ◽

Author(s):

Oren Pasvolsky ◽

May Daher ◽

Gheath Alatrash ◽

David Marin ◽

Naval Daver ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

T Cell ◽

Cell Therapy ◽

Myeloid Leukemia ◽

Disease Free Survival ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Acute Myeloid

Despite advances in the understanding of the genetic landscape of acute myeloid leukemia (AML) and the addition of targeted biological and epigenetic therapies to the available armamentarium, achieving long-term disease-free survival remains an unmet need. Building on growing knowledge of the interactions between leukemic cells and their bone marrow microenvironment, strategies to battle AML by immunotherapy are under investigation. In the current review we describe the advances in immunotherapy for AML, with a focus on chimeric antigen receptor (CAR) T cell therapy. CARs constitute powerful immunologic modalities, with proven clinical success in B-Cell malignancies. We discuss the challenges and possible solutions for CAR T cell therapy development in AML, and examine the path currently being paved by preclinical and clinical efforts, from autologous to allogeneic products.

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Cytotoxic effect of CLL‑1 CAR‑T cell immunotherapy with PD‑1 silencing on relapsed/refractory acute myeloid leukemia

Molecular Medicine Reports ◽

10.3892/mmr.2021.11847 ◽

2021 ◽

Vol 23 (3) ◽

Author(s):

Guoqiang Lin ◽

Yanming Zhang ◽

Lei Yu ◽

Depei Wu

Keyword(s):

Acute Myeloid Leukemia ◽

T Cell ◽

Myeloid Leukemia ◽

Cytotoxic Effect ◽

Car T Cell ◽

Cell Immunotherapy ◽

Car T ◽

Refractory Acute Myeloid Leukemia ◽

T Cell Immunotherapy ◽

Acute Myeloid

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Chimeric Antigen Receptor (CAR) T Cell Therapy in Acute Myeloid Leukemia (AML)

Journal of Clinical Medicine ◽

10.3390/jcm8020200 ◽

2019 ◽

Vol 8 (2) ◽

pp. 200 ◽

Cited By ~ 23

Author(s):

Susanne Hofmann ◽

Maria-Luisa Schubert ◽

Lei Wang ◽

Bailin He ◽

Brigitte Neuber ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

T Cell ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Myeloid Leukemia ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Acute Myeloid

Despite high response rates after initial chemotherapy in patients with acute myeloid leukemia (AML), relapses occur frequently, resulting in a five-year-survival by <30% of the patients. Hitherto, allogeneic hemotopoietic stem cell transplantation (allo-HSCT) is the best curative treatment option in intermediate and high risk AML. It is the proof-of-concept for T cell-based immunotherapies in AML based on the graft-versus-leukemia (GvL)-effect, but it also bears the risk of graft-versus-host disease. CD19-targeting therapies employing chimeric antigen receptor (CAR) T cells are a breakthrough in cancer therapy. A similar approach for myeloid malignancies is highly desirable. This article gives an overview on the state-of-the art of preclinical and clinical studies on suitable target antigens for CAR T cell therapy in AML patients.

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

Blood ◽

10.1182/blood-2020-141602 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34 ◽

Cited By ~ 1

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.

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