An NK-like CAR T cell transition in CAR T cell dysfunction

Good, Charly R.; Aznar, M. Ángela; Kuramitsu, Shunichiro; Samareh, Parisa; Agarwal, Sangya; Donahue, Greg; Ishiyama, Kenichi; Wellhausen, Nils; Rennels, Austin K.; Ma, Yujie; Tian, Lifeng; Guedan, Sonia; Alexander, Katherine; Zhang, Zhen; Rommel, Philipp C.; Singh, Nathan; Glastad, Karl M.; Richardson, Mike; Watanabe, Keisuke; Tanyi, János L.; O’Hara, Mark H.; Ruella, Marco; Lacey, Simon F.; Moon, Edmund K.; Schuster, Stephen J.; Albelda, Steven Μ.; Lanier, Lewis L.; Young, Regina M.; Berger, Shelley L.; June, Carl H.

doi:10.1016/j.cell.2021.11.016

Cited by 239 publications

(193 citation statements)

References 78 publications

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“…In addition, SOX4 and ID3 are key regulators of CAR-T cell exhaustion. CRISPR-mediated ID3 and SOX4 knockout can delay CAR-T cell dysfunction, laying a theoretical basis for enhancing the killing effect of CAR-T cells on solid tumors [ 199 ]. In addition to CAR-T cell dysfunction, a series of adverse reactions including allergic reactions, cytokine release syndrome and nervous system toxicity also are problems that need to be overcome in CAR-T cell therapy [ 200 ].…”

Section: Clinical Application Of Crispr Cancer Treatmentmentioning

confidence: 99%

Current applications and future perspective of CRISPR/Cas9 gene editing in cancer

et al. 2022

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Clustered regularly interspaced short palindromic repeats (CRISPR) system provides adaptive immunity against plasmids and phages in prokaryotes. This system inspires the development of a powerful genome engineering tool, the CRISPR/CRISPR-associated nuclease 9 (CRISPR/Cas9) genome editing system. Due to its high efficiency and precision, the CRISPR/Cas9 technique has been employed to explore the functions of cancer-related genes, establish tumor-bearing animal models and probe drug targets, vastly increasing our understanding of cancer genomics. Here, we review current status of CRISPR/Cas9 gene editing technology in oncological research. We first explain the basic principles of CRISPR/Cas9 gene editing and introduce several new CRISPR-based gene editing modes. We next detail the rapid progress of CRISPR screening in revealing tumorigenesis, metastasis, and drug resistance mechanisms. In addition, we introduce CRISPR/Cas9 system delivery vectors and finally demonstrate the potential of CRISPR/Cas9 engineering to enhance the effect of adoptive T cell therapy (ACT) and reduce adverse reactions.

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Section: Clinical Application Of Crispr Cancer Treatmentmentioning

confidence: 99%

Current applications and future perspective of CRISPR/Cas9 gene editing in cancer

et al. 2022

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“…Overall, it appears that the CAR-T cell approach is less suitable for solid tumors and still needs optimization. Indeed, using mesothelin-redirected CAR-T cells in pancreatic cancer and a continuous antigen exposure model, Carl June’s team has recapitulated hallmark features of T cell exhaustion and described a T-to-NK-like T cell transition for both CD8 and CD4 CAR-T cells resulting in a dysfunctional phenotype [ 213 ]. Otherwise, it has been reported that CAR-T cell therapy induces the release of excessive amounts of cytokines such as IFNγ and TNF following T cell activation resulting in cytokine release syndrome thus multi-organ dysfunction [ 214 ].…”

Section: Cd4 + T Cell Help For Cancer Immunotherapiesmentioning

confidence: 99%

Harnessing Antitumor CD4+ T Cells for Cancer Immunotherapy

Khelil

Godet

Abdeljaoued

et al. 2022

Cancers

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Over the past decades, CD4+ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4+ T cells during antitumor immunity. CD4+ T cells can either suppress or promote the antitumor cytotoxic CD8+ T cell responses, either in secondary lymphoid organs or in the tumor. In this review, we provide an overview of the multifaceted role of different CD4+ T cell subsets in cancer immune response and their contribution during cancer therapies. Specifically, we focus on the latest progress regarding the impact of CD4+ T cell modulation on immunotherapies and other cancer therapies and discuss the prospect for harnessing CD4+ T cells to control tumor progression and prevent recurrence in patients.

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“…While these in vitro models are indeed artificial mixtures of CAR T cells and their targets, they can still be modified to approximate the high tumor burden seen in actual clinical applications. Through sequential plating (when using precoated TAAs) [ 41 ], lowering effector:target (E:T) ratios and applying rechallenge (when using TAA-expressing cells) [ 43 , 67 , 68 , 69 ], researchers are able to recreate the condition where CAR T cells are repetitively exposed to TAAs, a process known to mediate T cell loss of function [ 70 ]. These more challenging in vitro models can support CAR T cell designs that resist exhaustion.…”

Section: In Vitro Models For Car T Cell Functional Evaluationmentioning

confidence: 99%

Preclinical Evaluation of CAR T Cell Function: In Vitro and In Vivo Models

Xiao

Brown

et al. 2022

IJMS

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Immunotherapy using chimeric antigen receptor (CAR) T cells is a rapidly emerging modality that engineers T cells to redirect tumor-specific cytotoxicity. CAR T cells have been well characterized for their efficacy against B cell malignancies, and rigorously studied in other types of tumors. Preclinical evaluation of CAR T cell function, including direct tumor killing, cytokine production, and memory responses, is crucial to the development and optimization of CAR T cell therapies. Such comprehensive examinations are usually performed in different types of models. Model establishment should focus on key challenges in the clinical setting and the capability to generate reliable data to indicate CAR T cell therapeutic potency in the clinic. Further, modeling the interaction between CAR T cells and tumor microenvironment provides additional insight for the future endeavors to enhance efficacy, especially against solid tumors. This review will summarize both in vitro and in vivo models for CAR T cell functional evaluation, including how they have evolved with the needs of CAR T cell research, the information they can provide for preclinical assessment of CAR T cell products, and recent technology advances to test CAR T cells in more clinically relevant models.

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An NK-like CAR T cell transition in CAR T cell dysfunction

Cited by 239 publications

References 78 publications

Current applications and future perspective of CRISPR/Cas9 gene editing in cancer

Current applications and future perspective of CRISPR/Cas9 gene editing in cancer

Harnessing Antitumor CD4+ T Cells for Cancer Immunotherapy

Preclinical Evaluation of CAR T Cell Function: In Vitro and In Vivo Models

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