An Antibody‐CRISPR/Cas Conjugate Platform for Target‐Specific Delivery and Gene Editing in Cancer

Yang, Seungju; Im, San Hae; Chung, Ju Yeon; Lee, Juhee; Lee, Kyung‐Hun; Kang, Yoo Kyung; Chung, Hyun Jung

doi:10.1002/advs.202308763

Cited by 1 publication

(1 citation statement)

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“…In vivo technologies look especially promising, as their application can be envisioned beyond the mere deployment of the CAR components. Both viral and non-viral vectors are being actively tested for in vivo CRISPR delivery and editing ( 210 – 212 ), for oncological as well as for gene therapy applications. Even more interestingly, in vivo targeting can be envisioned for the modification of other components of TME ( 213 ), such as macrophages, regulatory cells and the cancer cells themselves, thus manipulating the cytokine, immune checkpoints and metabolite milieu.…”

Section: Perspective: Engineering a New Generation Of Safer And More ...mentioning

confidence: 99%

Engineering strategies to safely drive CAR T-cells into the future

Rossi,

Breman

2024

Front. Immunol.

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Chimeric antigen receptor (CAR) T-cell therapy has proven a breakthrough in cancer treatment in the last decade, giving unprecedented results against hematological malignancies. All approved CAR T-cell products, as well as many being assessed in clinical trials, are generated using viral vectors to deploy the exogenous genetic material into T-cells. Viral vectors have a long-standing clinical history in gene delivery, and thus underwent iterations of optimization to improve their efficiency and safety. Nonetheless, their capacity to integrate semi-randomly into the host genome makes them potentially oncogenic via insertional mutagenesis and dysregulation of key cellular genes. Secondary cancers following CAR T-cell administration appear to be a rare adverse event. However several cases documented in the last few years put the spotlight on this issue, which might have been underestimated so far, given the relatively recent deployment of CAR T-cell therapies. Furthermore, the initial successes obtained in hematological malignancies have not yet been replicated in solid tumors. It is now clear that further enhancements are needed to allow CAR T-cells to increase long-term persistence, overcome exhaustion and cope with the immunosuppressive tumor microenvironment. To this aim, a variety of genomic engineering strategies are under evaluation, most relying on CRISPR/Cas9 or other gene editing technologies. These approaches are liable to introduce unintended, irreversible genomic alterations in the product cells. In the first part of this review, we will discuss the viral and non-viral approaches used for the generation of CAR T-cells, whereas in the second part we will focus on gene editing and non-gene editing T-cell engineering, with particular regard to advantages, limitations, and safety. Finally, we will critically analyze the different gene deployment and genomic engineering combinations, delineating strategies with a superior safety profile for the production of next-generation CAR T-cell.

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Section: Perspective: Engineering a New Generation Of Safer And More ...mentioning

confidence: 99%