CAR T cells targeting CD99 as an approach to eradicate T-cell acute lymphoblastic leukemia without normal blood cells toxicity

Shi, Jiangzhou; Zhang, Zijian; Cen, Hong; Wu, Han; Zhang, Shangkun; Liu, Jiaxing; Leng, Yingqi; Ren, Anqi; Liu, Xiyu; Zhang, Zhijie; Tong, Xiqin; Liang, Jinjue; Li, Zhe; Zhou, Fuling; Huang, Liang; Qin, You; Yang, Kunyu; Zhang, Tongcun; Zhu, Haichuan

doi:10.1186/s13045-021-01178-z

Cited by 38 publications

(35 citation statements)

References 9 publications

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“…In particular, solid tumor types such as lung cancer (80), breast cancer (84) and gastric cancer (85) associated with vascular, mesenchymal and inflammatory architecture can be better recapitulated in vivo with PDX-based xenograft models. These preclinical models reflecting tumor heterogeneity are key for obtaining an understanding of how this heterogeneity affects responses to CAR-T cell immunotherapy and how it may change during treatment both at the genomic and at the phenotypic levels (86)(87)(88)(89)(90).…”

Section: Preclinical Models For Testing Car-t Cells and Off-the-shelf...mentioning

confidence: 99%

Review: Sustainable Clinical Development of CAR-T Cells – Switching From Viral Transduction Towards CRISPR-Cas Gene Editing

et al. 2022

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T cells modified for expression of Chimeric Antigen Receptors (CARs) were the first gene-modified cell products approved for use in cancer immunotherapy. CAR-T cells engineered with gammaretroviral or lentiviral vectors (RVs/LVs) targeting B-cell lymphomas and leukemias have shown excellent clinical efficacy and no malignant transformation due to insertional mutagenesis to date. Large-scale production of RVs/LVs under good-manufacturing practices for CAR-T cell manufacturing has soared in recent years. However, manufacturing of RVs/LVs remains complex and costly, representing a logistical bottleneck for CAR-T cell production. Emerging gene-editing technologies are fostering a new paradigm in synthetic biology for the engineering and production of CAR-T cells. Firstly, the generation of the modular reagents utilized for gene editing with the CRISPR-Cas systems can be scaled-up with high precision under good manufacturing practices, are interchangeable and can be more sustainable in the long-run through the lower material costs. Secondly, gene editing exploits the precise insertion of CARs into defined genomic loci and allows combinatorial gene knock-ins and knock-outs with exciting and dynamic perspectives for T cell engineering to improve their therapeutic efficacy. Thirdly, allogeneic edited CAR-effector cells could eventually become available as “off-the-shelf” products. This review addresses important points to consider regarding the status quo, pending needs and perspectives for the forthright evolution from the viral towards gene editing developments for CAR-T cells.

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Section: Preclinical Models For Testing Car-t Cells and Off-the-shelf...mentioning

confidence: 99%

Review: Sustainable Clinical Development of CAR-T Cells – Switching From Viral Transduction Towards CRISPR-Cas Gene Editing

et al. 2022

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“…Importantly, it could retain a majority of normal T cells in vivo (35). CD99 is highly expressed in newly diagnosed T-ALL patients, and it represents a novel target for T-ALL (36). Furthermore, chemokine receptor CCR9 is expressed in over 70% of T-ALL patients, and only on less than 5% of normal T cells.…”

Section: Targets For Car-t Cell Therapy In T Cell Lymphoblastic Leuke...mentioning

confidence: 99%

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

et al. 2022

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Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.

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“…Identifying tumor-specific antigens that restrict T-cell expression is another strategy to avert fratricide and overcome CAR T therapy for T-ALL ( Figure 3 B). Currently, TRBC1/2, CDR3, CD1a, CD4, CCR7, CCR9, CD33, CD30, and CD99 are now being identified and evaluated as targets for CAR T therapy to treat T-cell malignancies ( Figure 3 B, Table 1 ) [ 46 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. These biomarkers have limited expression on normal T cells and antigen-derived CAR T cells continue to proliferate normally.…”

Section: Fratricide and Promising Strategiesmentioning

confidence: 99%

“…Furthermore, our group also tried to identify tumor-specific antigens for T-ALL CAR T therapy and demonstrated that CD30 and CD99 are potential options for R/R T-ALL cases [ 59 , 72 ]. In detail, CD99 is expressed at very high levels in newly diagnosed T-ALL patients and at low levels in normal hematopoietic cells.…”

Section: Fratricide and Promising Strategiesmentioning

confidence: 99%

CAR T-Cell Immunotherapy Treating T-ALL: Challenges and Opportunities

Ren

Tong

et al. 2023

Vaccines

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T-cell acute lymphoblastic leukemia (T-ALL), a form of T-cell malignancy, is a typically aggressive hematological malignancy with high rates of disease relapse and a poor prognosis. Current guidelines do not recommend any specific treatments for these patients, and only allogeneic stem cell transplant, which is associated with potential risks and toxicities, is a curative therapy. Recent clinical trials showed that immunotherapies, including monoclonal antibodies, checkpoint inhibitors, and CAR T therapies, are successful in treating hematologic malignancies. CAR T cells, which specifically target the B-cell surface antigen CD19, have demonstrated remarkable efficacy in the treatment of B-cell acute leukemia, and some progress has been made in the treatment of other hematologic malignancies. However, the development of CAR T-cell immunotherapy targeting T-cell malignancies appears more challenging due to the potential risks of fratricide, T-cell aplasia, immunosuppression, and product contamination. In this review, we discuss the current status of and challenges related to CAR T-cell immunotherapy for T-ALL and review potential strategies to overcome these limitations.

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CAR T cells targeting CD99 as an approach to eradicate T-cell acute lymphoblastic leukemia without normal blood cells toxicity

Cited by 38 publications

References 9 publications

Review: Sustainable Clinical Development of CAR-T Cells – Switching From Viral Transduction Towards CRISPR-Cas Gene Editing

Review: Sustainable Clinical Development of CAR-T Cells – Switching From Viral Transduction Towards CRISPR-Cas Gene Editing

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

CAR T-Cell Immunotherapy Treating T-ALL: Challenges and Opportunities

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