[논문]Unleashing the Therapeutic Potential of CAR-T Cell Therapy Using Gene-Editing Technologies

Jung, In-Young; Lee, Jungmin

doi:10.14348/molcells.2018.0242

[국내논문] Unleashing the Therapeutic Potential of CAR-T Cell Therapy Using Gene-Editing Technologies 원문보기

Molecules and cells, v.41 no.8, 2018년, pp.717 - 723

Jung, In-Young (ToolGen, Inc.) , Lee, Jungmin (ToolGen, Inc.)

Abstract ▼ AI-Helper

Chimeric antigen receptor (CAR) T-cell therapy, an emerging immunotherapy, has demonstrated promising clinical results in hematological malignancies including B-cell malignancies. However, accessibility to this transformative medicine is highly limited due to the complex process of manufacturing, limited options for target antigens, and insufficient anti-tumor responses against solid tumors. Advances in gene-editing technologies, such as the development of Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9), have provided novel engineering strategies to address these limitations. Development of next-generation CAR-T cells using gene-editing technologies would enhance the therapeutic potential of CAR-T cell treatment for both hematologic and solid tumors. Here we summarize the unmet medical needs of current CAR-T cell therapies and gene-editing strategies to resolve these challenges as well as safety concerns of gene-edited CAR-T therapies.

주제어

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제안 방법

Because the CRISPR/Cas9 DNA binding site can be designed to target any sequence of interest by simply altering the guideRNA without the need for complex protein engineering, the CRISPR system is highly versatile and is emerging as an efficient alternative to conventional programmable nucleases (Sander and Joung, 2014); as such, it is already being tested in CAR-T cell clinical trials (Table 1). Here, we summarize the recent use of gene-editing technologies to resolve problems associated with CAR-T cell therapy and discuss the potential safety issues and limitations of gene-edited CAR-T cells.
The three guideRNAs, under the control of three different promoters (human U6, mouse U6, and H1) successfully produced triple KO CAR-T cells that showed reduced Activation Induced Cell Death (AICD) and superior expansion capability. These studies support the strong promise of CRISPR/Cas9 as a tool for multiplex genome editing as well as the beneficial role of FAS KO in enhancing T-cell survival.

성능/효과

There are several barriers to expanding the accessibility of current autologous CAR-T cell therapies. First, quality control for CAR-T cell production is very challenging. The considerable variability of each patient’s starting materials significantly impacts both the feasibility of manufacturing and the therapeutic potential of the product (Singh et al.
Although potential safety concerns of gene-editing technologies still need to be resolved, the promising outcomes of gene-edited CAR-T cell therapy may offset the risks. In conclusion, unequivocally, gene-editing technologies, especially CRISPR/Cas9 alongside further understanding of T-cell exhaustion, TME, and clinical outcomes, will ensure the development of more potent CAR-T cell therapies.

후속연구

, 2017a). Together, these studies have clearly demonstrated that gene editing has great promise for resolving problems associated with autologous CAR-T cells, although further clinical investigations are needed to validate these approaches.

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표제어: PCR

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