The Black Hole: CAR T Cell Therapy in AML

Atilla, Erden; Benabdellah, Karim

doi:10.3390/cancers15102713

Cited by 23 publications

(8 citation statements)

References 148 publications

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“… 46 , 47 The results of existing clinical studies have shown that although CAR-T cells targeting CD33, CD123, and CLL-1 have certain curative effects, they face problems such as poor persistence, insufficient efficacy, and target escape. 48 , 49 Dual-targeted CAR-T cells have been found in studies to have more activity and affinity for tumor cells than single-targeted CART cells, and more importantly, dual-targeted CART cells control disease more consistently. 50–53 CD123 and NKG2DLs are good CAR targets as they are known to be elevated in AML cells.…”

Section: Discussionmentioning

confidence: 99%

CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells

Jin,

Xie,

Sun

et al. 2023

OncoImmunology

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Chimeric antigen receptor (CAR)-T cells have not made significant progress in the treatment of acute myeloid leukemia (AML) in earlyclinical studies. This lack of progress could be attributed in part to the immunosuppressive microenvironment of AML, such as monocyte-like myeloid-derived suppressor cells (M-MDSCs) and alternatively activated macrophages (M2 cells), which can inhibit the antitumor activity of CAR-T cells. Furthermore, AML cells are usually heterogeneous, and single-target CAR-T cells may not be able to eliminate all AML cells, leading to disease relapse. CD123 and NKG2D ligands (NKG2DLs) are commonly used targets for CAR-T therapy of AML, and M-MDSCs and M2 cells express both antigens. We developed dual-targeted CAR-T (123NL CAR-T) cells targeting CD123 and NKG2DL by various structural optimization screens. Our study reveals that 123NL CAR-T cells eradicate AML cells and selectively target immunosuppressive cells. A highly compact marker/suicide gene, RQR8, which binds targeting epitopes of CD34 and CD20 antigens, was also incorporated in front of the CAR structure. The binding of Rituximab to RQR8 leads to the elimination of 123NL CAR-T cells and cessation of their cytotoxicity. In conclusion, we successfully developed dual effects of 123NL CAR-T cells against tumor cells and immunosuppressive cells, which can avoid target escape and resist the effects of immunosuppressive microenvironment.

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Section: Discussionmentioning

confidence: 99%

CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells

Jin,

Xie,

Sun

et al. 2023

OncoImmunology

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“…Despite disappointing progress in the field of immunotherapeutic approaches in AML ( 197 ), the implementation of proteomics ( 198 ) and transcriptomics ( 199 ) in designing a more personalized CAR-T-cell therapies holds promises. Single-cell sequencing offers the possibility to investigate mutational changes across the DNA, epigenetic and protein level ( 200 ). A recent review by Shahzad et al.…”

Section: Discussionmentioning

confidence: 99%

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Karsten,

Matrisch,

Cichutek

et al. 2023

Front. Immunol.

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Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström’s macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

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“…Additionally, AML is a very heterogeneous disease and varies between patients depending on chromosomal abnormalities and mutations. It also creates a very immunosuppressive tumor microenvironment containing various cell types like regulatory T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells that suppress T-cell activity and decrease CAR T-cell responses [46]. Addressing this concern, a current approach under investigation involves the use of CRISPR/Cas9 technology to edit out the CAR target antigen from a donor allograft.…”

Section: Investigational Therapiesmentioning

confidence: 99%

New Approaches for the Treatment of AML beyond the 7+3 Regimen: Current Concepts and New Approaches

Roman Diaz,

Vazquez Martinez,

Khimani

2024

Cancers

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Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily on chemotherapy in combinations, doses, or schedules of the same drugs. Patients with advanced age, comorbidities, or relapsed or refractory disease were left with no effective options for treatment. New advances in the understanding of the biology and the molecular and genetic changes associated with leukemogenesis, as well as recent advances in drug development, have resulted in the introduction over the last few years of novel therapeutic agents and approaches to the treatment of AML as well as a new classification of the disease. In this article, we will discuss the new classification of AML; the mechanisms, actions, and indications of the new targeted therapies; the chemotherapy combinations; and the potential role of cellular therapies as new treatment options for this terrible disease.

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The Black Hole: CAR T Cell Therapy in AML

Cited by 23 publications

References 148 publications

CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells

CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells

Broadening the horizon: potential applications of CAR-T cells beyond current indications

New Approaches for the Treatment of AML beyond the 7+3 Regimen: Current Concepts and New Approaches

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