Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

Lü, You; Xue, Jianxin; Deng, Tao; Zhou, Xiaojuan; Yu, Kun; Deng, Lei; Huang, Meijuan; Yi, Xin; Liang, Mingzhu; Wang, Yu; Shen, Haige; Tong, Ruizhan; Wang, Wenbo; Li, Li; Song, Jin Sook; Li, Jing; Su, Xiaoxing; Ding, Zhenyu; Gong, Youling; Zhu, Jiang; Wang, Yongsheng; Zou, Bingwen; Zhang, Yan; Li, Yanying; Zhou, Lin; Liu, Yongmei; Yu, Min; Wang, Yuqi; Zhang, Xuanwei; Yin, Lu; Xia, Xuefeng; Zeng, Yong; Zhou, Qiao; Ying, Binwu; Chen, Chong; Wei, Yuquan; Liu, Weimin; Mok, Tony

doi:10.1038/s41591-020-0840-5

Cited by 403 publications

(335 citation statements)

References 42 publications

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“…The same observations were seen in xenografted cells in mice (10). The aforementioned results raise doubts about the adequacy of CRISPR-Cas9-mediated-PD-1 disruption in T cells (1,7). The clinical consequences of Wang et al (10) are unknown at this moment, however it offers a new view that the tumor cell intrinsic PD-1/PD-L1 axis suppresses tumor growth and inhibits AKT and ERK1/2 signaling pathways and could prevent the interaction with PD-1 expressing cells.…”

Section: Discussionmentioning

confidence: 59%

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Commentary: Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

Rosell¹,

Filipska²,

Chaib³

et al. 2020

Front. Oncol.

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Section: Discussionmentioning

confidence: 59%

“…NGS targeted sequencing of the PD-1 gene indicated that the median editing efficiency of all 12 patients was 5.8%. A significant increase in the proportion of CD8 + IFN-gamma + cells was found in edited T cells (7).…”

Section: Introductionmentioning

confidence: 92%

Commentary: Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

Rosell¹,

Filipska²,

Chaib³

et al. 2020

Front. Oncol.

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“…Development of a gene therapeutic is an enormously complex endeavor, 5,9 weighing strategies incorporating unmet medical need, editing approach, needed repair percentages, availability of disease models that faithfully recapitulate human biology, and delivery considerations among a multitude of aspects that are crucial to creating a safe and efficacious medicine. Correspondingly, the path toward enabling a new therapy follows a multifaceted development cascade (Fig.…”

Section: Therapeutic Development Cascadementioning

confidence: 99%

Translating CRISPR-Cas Therapeutics: Approaches and Challenges

et al. 2020

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CRISPR-Cas clinical trials have begun, offering a first glimpse at how DNA and RNA targeting could enable therapies for many genetic and epigenetic human diseases. The speedy progress of CRISPR-Cas from discovery and adoption to clinical use is built on decades of traditional gene therapy research and belies the multiple challenges that could derail the successful translation of these new modalities. Here, we review how CRISPR-Cas therapeutics are translated from technological systems to therapeutic modalities, paying particular attention to the therapeutic cascade from cargo to delivery vector, manufacturing, administration, pipelines, safety, and therapeutic target profiles. We also explore potential solutions to some of the obstacles facing successful CRISPR-Cas translation. We hope to illuminate how CRISPR-Cas is brought from the academic bench toward use in the clinic.

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“…Off target (OT) editing is a key concern for production of a cellular therapy 26,27 . To evaluate OT editing, we utilized computational prediction followed by targeted next generation sequencing (NGS) 16 .…”

Section: Cish Knockout Enhances Neoantigen Reactivity In Tilmentioning

confidence: 99%

Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade

Palmer

Webber

Patel

et al. 2020

Preprint

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While neoantigen-specific tumor infiltrating lymphocytes (TIL) can be derived from in antigen-expressing tumors, their adoptive transfer fails to consistently elicit durable tumor regression. There has been much focus on the role of activation/exhaustion markers such as PD1, CD39 and TOX in TIL senescence. We found these markers were inversely expressed to Cytokine-Induced SH2 protein (CISH), a negative regulator of TCR signaling and tumor immunity in mice. To evaluate the physiological role of CISH in human TIL we developed a high-efficiency CRIPSR-based method to knock out CISH in fully mature TIL. CISH KO resulted in increased T cell receptor (TCR) avidity, tumor cytolysis and neoantigen recognition. CISH expression in the tumor resections correlated with TIL inactivity against p53 hotspot mutations and CISH KO in TIL unmasked reactivity against these universal neoantigens. While CISH KO resulted in T cell hyperactivation and expansion it did not alter maturation, perhaps by preferential PLCγ-1 and not AKT inhibition. Lastly, CISH KO in T cells increased PD1 expression and the adoptive transfer of Cish KO T cells synergistically combines with PD1 antibody blockade resulting in durable tumor regression and survival in a preclinical animal model. These data offer new insights into the regulation of neoantigen recognition, expression of activation/exhaustion markers, and functional/maturation signals in tumor-specific T cells.

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Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

Cited by 403 publications

References 42 publications

Commentary: Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

Commentary: Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

Translating CRISPR-Cas Therapeutics: Approaches and Challenges

Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade

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