Successful Anti-CLL1 CAR T-Cell Therapy in Secondary Acute Myeloid Leukemia

Zhang, Hui; Gan, Wenting; Hao, Wen-Ge; Wang, Pengfei; Li, Zhuo-Yan; Chang, Lung‐Ji

doi:10.3389/fonc.2020.00685

Cited by 41 publications

(33 citation statements)

References 25 publications

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“…Therefore, targeting the CLEC12A antigen will target AML blasts and leukemic stem cells while sparing normal hematopoiesis. Several groups have advanced CLEC12A-targeting CAR T cells into clinical trials (30,31). Our results demonstrate that targeting CLEC12A eliminates AML cells in vitro and significantly reduces tumor burden in vivo.…”

Section: Discussionmentioning

confidence: 61%

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Rennert¹,

Dufort²,

Su³

et al. 2021

Molecular Cancer Therapeutics

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Refractory Acute Myeloid Leukemia (AML) remains an incurable malignancy despite the clinical use of novel targeted therapies, new antibody-based therapies and cellular therapeutics.Here we describe the preclinical development of a novel cell therapy that targets the antigen CLEC12A with a biparatopic bridging protein. Bridging proteins are designed as "CAR-T cell engagers", with a CAR-targeted protein fused to antigen binding domains derived from antibodies. Here, we created a CD19-anti-CLEC12A bridging protein that binds to CAR19 T cells and to the antigen CLEC12A. Biparatopic targeting increases the potency of bridging protein-mediated cytotoxicity by CAR19 T cells. Using CAR19 T cells that secrete the bridging protein we demonstrate potent activity against aggressive leukemic cell lines in vivo. This CARengager platform is facile and modular, as illustrated by activity of a dual-antigen bridging protein targeting CLEC12A and CD33, designed to counter tumor heterogeneity and antigen escape, and created without the need for extensive CAR T cell genetic engineering. CAR19 T cells provide an optimal cell therapy platform with well understood inherent persistence and fitness characteristics.

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Section: Discussionmentioning

confidence: 61%

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Rennert¹,

Dufort²,

Su³

et al. 2021

Molecular Cancer Therapeutics

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“…CLL-1 is another potential molecular target for CAR-T cell therapy as CLL-1 is expressed on AML including leukemia stem cells [ 85 ]. A case study by Zhang et al reported that secondary AML patient treated with anti-CLL CAR-T therapy achieved minimal residual disease (MRD) negative CR that lasted for 10 months [ 83 ]. In another study, two patients treated with CLL-1 and CD33 dual targeting CAR-Ts achieved MRD-negative CR within three weeks [ 84 , 85 ].…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

State-of-Art of Cellular Therapy for Acute Leukemia

Lee

Vasic

Kang

et al. 2021

IJMS

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With recent clinical breakthroughs, immunotherapy has become the fourth pillar of cancer treatment. Particularly, immune cell-based therapies have been envisioned as a promising treatment option with curative potential for leukemia patients. Hence, an increasing number of preclinical and clinical studies focus on various approaches of immune cell-based therapy for treatment of acute leukemia (AL). However, the use of different immune cell lineages and subsets against different types of leukemia and patient disease statuses challenge the interpretation of the clinical applicability and outcome of immune cell-based therapies. This review aims to provide an overview on recent approaches using various immune cell-based therapies against acute B-, T-, and myeloid leukemias. Further, the apparent limitations observed and potential approaches to overcome these limitations are discussed.

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“…Another promising target for AML lies with the investigation of C-type lectin-like molecule-1 (CLL1) as a target highly expressed on AML stem cells and blasts but not on healthy HSCs. The first human use of anti-CLL1 CAR T-cells in a pediatric patient with relapsed AML was reported in 2020 [ 135 ]. The patient received an infusion of anti-CLL1 CAR T-cells after lymphodepleting chemotherapy, with adverse effects including transient hypotension and grade I-II cytokine release syndrome.…”

Section: Cellular and Vaccine Therapies For Mds And Amlmentioning

confidence: 99%

“…The patient received an infusion of anti-CLL1 CAR T-cells after lymphodepleting chemotherapy, with adverse effects including transient hypotension and grade I-II cytokine release syndrome. The patient achieved complete remission, which was maintained nine months post-therapy, at the time of the paper submission [ 135 ].…”

Section: Cellular and Vaccine Therapies For Mds And Amlmentioning

confidence: 99%

Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia

Kapoor

Champion

Basu

et al. 2021

Cancers

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Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most suitable for this treatment remains unclear. Over the past decade, there has been remarkable progress in identifying genomic features of MDS and AML, which has led to an improved discernment of the molecular pathogenesis of these diseases. An improved understanding of immune and inflammatory molecular mechanisms of MDS and AML have also recently revealed novel therapeutic targets. Emerging treatments for MDS and AML include monoclonal antibodies such as immune checkpoint inhibitors, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and NK cells. In this review, we provide an overview of the current understanding of immune dysregulation in MDS and AML and an update on novel immune therapies for these bone marrow malignancies.

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Successful Anti-CLL1 CAR T-Cell Therapy in Secondary Acute Myeloid Leukemia

Cited by 41 publications

References 25 publications

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

State-of-Art of Cellular Therapy for Acute Leukemia

Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia

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