CAR‐T cells beyond CD19, UnCAR‐Ted territory

Leick, Mark B.; Maus, Marcela V.

doi:10.1002/ajh.25398

Cited by 7 publications

(3 citation statements)

References 79 publications

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“…99 CAR-T therapy is another type of ACT in which T cells carry a desired chimeric antigen receptor (CAR) that specifically recognizes an antigen expressed exclusively on tumor cells. 279,280 After the success of CAR-T-based therapy in the treatment of hematological malignancies, [281][282][283] multiple studies focused on this kind of therapy in solid tumors. In the case of HCC, the most promising targets for CAR-T-cell-based therapy consist of AFP and GPC3, which are both specific to liver cancer, as well as mucin-1 (MUC-1), CD147, EpCAM, and MET (expressed in a range of tumors).…”

Section: Adoptive Cell Therapy (Act)mentioning

confidence: 99%

The therapeutic landscape of hepatocellular carcinoma

Gallage

García‐Beccaria

Szydlowska

et al. 2021

Med

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The liver is endowed with an amazing regenerative capacity that allows it to withstand an enormous amount of damage. Nevertheless, it is precisely this highly regenerative capacity that renders it susceptible to dysplasia and liver cancer. Liver cancer is not only one of the most common cancers but also one of the deadliest. Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for up to 70%-90% of all cases, but treatment options for advanced stages remain scarce. Therefore, a great deal of effort has gone into identifying early diagnostic markers as well as novel therapies, both local and systemic, for the treatment of this deadly disease. In this review, we aim to shed light into the current therapeutic landscape of HCC with an emphasis on the available treatments, ranging from surgical and local-ablative therapy for early and intermediate stages of the disease to systemic therapies for advanced cancer treatments. We will also address the molecular mechanisms and limitations of currently available systemic therapies and the causes of treatment resistance and finally summarize the emerging future avenues and novel concepts that are promising.

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Section: Adoptive Cell Therapy (Act)mentioning

confidence: 99%

The therapeutic landscape of hepatocellular carcinoma

Gallage

García‐Beccaria

Szydlowska

et al. 2021

Med

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“…Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated efficacy in treating R/R-ALL by targeting CD19 [ 7 ], an ideal therapeutic target due to its high expression in ALL [ 8 ]. However, disease recurrence persists in a significant proportion (approximately 40 ~ 60%) of patients post CD19 CAR-T therapy [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

CD19/CD20 dual-targeted chimeric antigen receptor-engineered natural killer cells exhibit improved cytotoxicity against acute lymphoblastic leukemia

Yang,

Zhang,

Zhang

et al. 2024

J Transl Med

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Background Chimeric antigen receptor natural killer (CAR-NK) cells represent a promising advancement in CAR cell therapy, addressing limitations observed in CAR-T cell therapy. However, our prior study revealed challenges in CAR-NK cells targeting CD19 antigens, as they failed to eliminate CD19+ Raji cells in NSG tumor-bearing mice, noting down-regulation or loss of CD19 antigen expression in some Raji cells. In response, this study aims to enhance CD19 CAR-NK cell efficacy and mitigate the risk of tumor recurrence due to target antigen escape by developing CD19 and CD20 (CD19/CD20) dual-targeted CAR-NK cells. Methods Initially, mRNA encoding anti-CD19 CARs (FMC63 scFv-CD8α-4-1BB-CD3ζ) and anti-CD20 CARs (LEU16 scFv-CD8α-4-1BB-CD3ζ) was constructed via in vitro transcription. Subsequently, CD19/CD20 dual-targeted CAR-NK cells were generated through simultaneous electrotransfection of CD19/CD20 CAR mRNA into umbilical cord blood-derived NK cells (UCB-NK). Results Following co-electroporation, the percentage of dual-CAR expression on NK cells was 86.4% ± 1.83%, as determined by flow cytometry. CAR expression was detectable at 8 h post-electric transfer, peaked at 24 h, and remained detectable at 96 h. CD19/CD20 dual-targeted CAR-NK cells exhibited increased specific cytotoxicity against acute lymphoblastic leukemia (ALL) cell lines (BALL-1: CD19+CD20+, REH: CD19+CD20−, Jurkat: CD19−CD20−) compared to UCB-NK, CD19 CAR-NK, and CD20 CAR-NK cells. Moreover, CD19/CD20 dual-targeted CAR-NK cells released elevated levels of perforin, IFN-γ, and IL-15. Multiple activation markers such as CD69 and cytotoxic substances were highly expressed. Conclusions The creation of CD19/CD20 dual-targeted CAR-NK cells addressed the risk of tumor escape due to antigen heterogeneity in ALL, offering efficient and safe 'off-the-shelf' cell products. These cells demonstrate efficacy in targeting CD20 and/or CD19 antigens in ALL, laying an experimental foundation for their application in ALL treatment.

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“…To date, the most clinically investigated indications for CAR-T therapy are hematological malignancies [3, 4] (Fig. 1).…”

Section: Introduction To the Chimeric Antigen Receptor-t Cell (Car-t)mentioning

confidence: 99%

Chimeric Antigen Receptor-T Cells for Targeting Solid Tumors: Current Challenges and Existing Strategies

et al. 2019

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Chimeric antigen receptor-T cells (CAR-Ts) are an exciting new cancer treatment modality exemplified by the recent regulatory approval of two CD19-targeted CART therapies for certain B cell malignancies. However, this success in the hematological setting has yet to translate to a significant level of objective clinical responses in the solid tumor setting. The reason for this lack of translation undoubtedly lies in the substantial challenges raised by solid tumors to all therapies, including CART , that differ from B cell malignancies. For instance, intravenously infused CARTs are likely to make rapid contact with cancerous B cells since both tend to reside in the same vascular compartments within the body. By contrast, solid cancers tend to form discrete tumor masses with an immune-suppressive tumor microenvironment composed of tumor cells and non-tumor stromal cells served by abnormal vasculature that restricts lymphocyte infiltration and suppresses immune function, expansion, and persistence. Moreover, the paucity of uniquely and homogeneously expressed tumor antigens and inherent plasticity of cancer cells provide major challenges to the specificity, potency, and overall effectiveness of CART therapies. This review focuses on the major preclinical and clinical strategies currently being pursued to tackle these challenges in order to drive the success of CART therapy against solid tumors. Key Points Chimeric antigen receptor-T cell (CAR-T) therapy for the treatment of solid tumors is currently being evaluated in approximately one-third of all CART clinical trials. CART therapies targeting solid cancers have yet to demonstrate similar levels of clinical response as those being achieved in hematological indications. Developing methods and technologies to overcome the immune-suppressive tumor environment, tumor accessibility and infiltration, as well as optimization of CART function are the current focus of the CART field in order to improve therapy for solid tumors.

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CAR‐T cells beyond CD19, UnCAR‐Ted territory

Abstract: CAR‐T cells have made dramatic inroads in targeting CD19‐positive B‐cell malignancies. This review focuses on application of CAR‐T cells in hematologic malignancies beyond targeting CD19, with specific attention to Hodgkin's lymphoma and acute myeloid leukemia.

Cited by 7 publications

References 79 publications

The therapeutic landscape of hepatocellular carcinoma

The therapeutic landscape of hepatocellular carcinoma

CD19/CD20 dual-targeted chimeric antigen receptor-engineered natural killer cells exhibit improved cytotoxicity against acute lymphoblastic leukemia

Chimeric Antigen Receptor-T Cells for Targeting Solid Tumors: Current Challenges and Existing Strategies

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