CAR-T cell therapy in T-cell malignancies: Is success a low-hanging fruit?

Kozani, Pouya Safarzadeh; Kozani, Pooria Safarzadeh; Rahbarizadeh, Fatemeh

doi:10.1186/s13287-021-02595-0

Cited by 59 publications

(47 citation statements)

References 137 publications

(300 reference statements)

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“…Use of allogeneic donor cells would also eliminate the risk of contamination of the CAR product with tumor cells. In addition, NK cells are short-lived, so they would not persist in the host and would not cause long-term T-cell aplasia when targeting T-cell lineage molecules [15].…”

Section: Discussionmentioning

confidence: 99%

Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias

Voynova

Hawk

Flomerfelt

et al. 2022

Cancers

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NK effector cells expressing a CAR construct may be used to target T-lineage markers. In this work, we compared the activity of a NK-specific CAR-NK and a CAR-T framework when expressed on NK effector cells to target CD3 and CD5 in T-cell malignancies. Our results show that CD3-CAR-T is more active than CD5-CAR-T to eliminate malignant T cells in vitro, however, CD3-CAR-T were less efficient to eliminate tumor cells in vivo, while CD5-CAR-T had antitumor activity in a diffuse xenograft model. Lack of in vivo efficacy correlated with downregulation of CD3 levels in target T cells after coculture with CD3-CAR effector cells. The CAR-NK framework greatly improved the efficacy of CARs leading to increased degranulation, cytokine secretion and elimination of the tumor xenograft by CD5-CAR-NK effector cells. Finally, all CAR constructs were similarly effective to eliminate malignant T cells in vitro. Our results show that the NK-CAR framework improves the activity of CARs in NK cells and that CD5 would be a better target than CD3 for T-cell malignancies, as dynamic downregulation of target expression may affect in vivo efficacy.

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Section: Discussionmentioning

confidence: 99%

Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias

Voynova

Hawk

Flomerfelt

et al. 2022

Cancers

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“…Among the transforming growth factor-b is a predominantly immunosuppressive soluble factor identified in the TME. T-cell differentiation into Tregs is triggered by this powerful cytokine as well as the immunosuppressive polarisation of macrophages phenotype M2 [48]. The development of a chimeric antigen receptor that responds to transforming growth factor-b showed that chimeric antigen receptors usage to identify a soluble feature and T-cells are rearranged to transform inhibitory signals into antitumor activity signals [49].…”

Section: Switching From An Inhibited To a Stimulatory Mode Of Receptorsmentioning

confidence: 99%

Therapeutic Applications of Engineered Chimeric Antigen Receptors-T cell for Cancer Therapy

Hussain¹

2021

Preprint

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Findings of new targeted treatments with adequate safety evaluations is essential for better cancer cures and mortality rates. Immunotherapy holds promise for patients with relapsed disease, with the ability to elicit long-term remissions. Emerging promising clinical results in B-cell malignancy using gene-altered T-lymphocytes uttering chimeric antigen receptors have sparked a lot of interest. This treatment could open the path for a major difference in the way we treat tumors that are resistant or recurring. Genetically altered T cells used to produce tumor-specific chimeric antigen receptors are resurrected field of adoptive cell therapy by demonstrating remarkable success in the treatment of malignant tumors. Because of the molecular complexity of chimeric antigen receptors -T cells, a variety of engineering approaches to improve safety and effectiveness are necessary to realize larger therapeutic uses. In this study, we investigate at new strategies for enhancing chimeric antigen receptors-T cell therapy by altering chimeric antigen receptors proteins, T lymphocytes, and their relations with other solid tumor microenvironment (TME) aspects.

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“…Cancer immunotherapy first started as an idea to employ the patients' immune system and its components as fighting tools against various types of neoplasms (10,11). Today, monoclonal antibody (mAb)-based therapies, cancer vaccines, adoptive cell therapy (ACT), and oncolytic viruses are among famous types of cancer immunotherapy that have gained preclinical and clinical success (10).…”

Section: Introductionmentioning

confidence: 99%

“…The theory of utilizing T cells as fighting tools for a selective fight against cancer, which started in the early 1990s, has now become a treatment option for certain patients with B-cell-based malignancies (12)(13)(14)(15)(16)(17)(18)(19)(20). Over the past few years, the field of CAR-T therapy has progressed remarkably (11,21). In particular, various CAR generations have been developed and many innovative strategies have been proposed, aimed at improving the safety and efficacy of CAR-T therapy (11,(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Optimizing the Clinical Impact of CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia: Looking Back While Moving Forward

Kozani

Rahbarizadeh

2021

Front. Immunol.

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Chimeric antigen receptor T-cell (CAR-T) therapy has been successful in creating extraordinary clinical outcomes in the treatment of hematologic malignancies including relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). With several FDA approvals, CAR-T therapy is recognized as an alternative treatment option for particular patients with certain conditions of B-ALL, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, or multiple myeloma. However, CAR-T therapy for B-ALL can be surrounded by challenges such as various adverse events including the life-threatening cytokine release syndrome (CRS) and neurotoxicity, B-cell aplasia-associated hypogammaglobulinemia and agammaglobulinemia, and the alloreactivity of allogeneic CAR-Ts. Furthermore, recent advances such as improvements in media design, the reduction of ex vivo culturing duration, and other phenotype-determining factors can still create room for a more effective CAR-T therapy in R/R B-ALL. Herein, we review preclinical and clinical strategies with a focus on novel studies aiming to address the mentioned hurdles and stepping further towards a milestone in CAR-T therapy of B-ALL.

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CAR-T cell therapy in T-cell malignancies: Is success a low-hanging fruit?

Cited by 59 publications

References 137 publications

Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias

Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias

Therapeutic Applications of Engineered Chimeric Antigen Receptors-T cell for Cancer Therapy

Optimizing the Clinical Impact of CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia: Looking Back While Moving Forward

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