Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells

Dong, Matthew B.; Wang, Guangchuan; Chow, Ryan D.; Ye, Lupeng; Zhu, Lv‐yun; Dai, Xiaoyun; Park, Jonathan J.; Kim, Hyunu R; Errami, Youssef; Guzman, Christopher D.; Zhou, Xiaoyu; Chen, Krista Y.; Renauer, Paul; Du, Yaying; Shen, Johanna; Lam, Stanley Z.; Zhou, Jingjia J.; Lannin, Donald R.; Herbst, Roy S.; Chen, Sidi

doi:10.1016/j.cell.2019.07.044

Cited by 216 publications

(207 citation statements)

References 115 publications

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“…Discussion CRISPR-based genetic screens are powerful tools to define vulnerabilities of cancer cells and to uncover the determinants of their response to therapies. Previously, CRISPR screens have been used to identify novel immunotherapy target antigens (34), better understand immune checkpoint regulation (1), understand resistance mechanisms to different immunotherapies (2,35) and regulators of immune function (36).…”

Section: Bcma Car-t Cell Co-culture Screen Reveals Myeloma Cell-intrimentioning

confidence: 99%

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Ramkumar

Abarientos

Tian

et al. 2019

Preprint

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Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell-surface expression of the multiple myeloma immunotherapy antigen - B cell maturation antigen, BCMA. We discovered that pharmacological inhibition of HDAC7 and the Sec61 complex increased cell-surface BCMA, including in primary patient cells. Importantly, pharmacological Sec61 inhibition enhanced the anti-myeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference CAR-T coculture screen enabled us to identify both antigen-dependent and -independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study demonstrates the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.Key PointsUsing CRISPR screens, we systematically identify mechanisms increasing expression of the immunotherapy target BCMA and ADC efficacy.We also identify antigen-independent mechanisms regulating response of cancer cells to BCMA-CAR-T cells.

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Section: Bcma Car-t Cell Co-culture Screen Reveals Myeloma Cell-intrimentioning

confidence: 99%

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Ramkumar

Abarientos

Tian

et al. 2019

Preprint

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“…The efficacy, stability and persistence of CAR-T cell in vivo were crucial for exerting its anti-tumor activities. These essential properties of CAR-T cell were acquired by using genome editing tools consisting of clustered regulatory interspaced short palindromic repeat, zinc-finger nucleases, and CRISPR-associated protein 9 (CRISPR/Cas9) techniques, and so on [23,24] . These techniques were useful to trace the lineage of CAR-T cell in vivo [25], and the functional activity was enhanced and the side effects were managed via the tetracycline regulatory system [26].…”

Section: The Essential Properties Of Car-t Cell Therapymentioning

confidence: 99%

A brief review concerning Chimeric Antigen Receptors T cell therapy

Li¹,

Yuan²,

Yang³

et al. 2020

J. Cancer

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The understanding concerning the function of immune system in cancer has achieved considerable advance with time passes by. Manipulating genetically engineered immune cells were investigated as a novel strategy for treating cancer. Chimeric antigen receptors (CARs) are recombinant protein molecules by merging the exquisite targeting the potent cytotoxicity of T cells and specificity of monoclonal antibodies and, which could trigger serial cascades of signal transduction and thereby activate T cells to directly destroy the tumor cells. Manufacturing CAR-modified T lymphocytes were successfully implemented in treating cancer derived from they could specifically retarget tumor-associated antigens, causing effective elimination of tumor cells, which spurred the optimization and development of new CART cell technology. The advancement of synthetic biology methodologies of cell therapy in CART would ultimately provide us with a much safer, reliable and efficient modality to against cancer. This review primarily described the emergence, development and application of cell therapy in CART , then discuss the side effects and the potential factors of tumor reccurrence caused by CART cell therapy, in addition to the corresponding countermeasure concerning complications.

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“…Combining this with scRNAseq has provided a balance between the high-dimensionality of arrayed screens, where knockouts are considered one-byone, with the throughput of pooled screens [49,86]. This technology depends on sequencing either a barcode associated with the CRISPR guide RNA [49,86] or by sequencing the guide RNA itself after capture onto microbeads [87]. Several CRISPR knockout screens coupled with scRNAseq and tumor infiltration models have identified regulators of CD8 + T cell fitness in mice, including RE-GNASE-1 [87][88][89].…”

Section: Multi-omic and Screening Approaches To Tackle T Cell Exhaustionmentioning

confidence: 99%

The progression & delivery of adoptive cellular immune therapies: leveraging single-cell resolution & novel algorithms to overcome the challenges associated with allogeneic & autologous immune cell therapies

Moignard¹,

Riva²,

Elgueta³

2020

Cell Gene Therapy Insights

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Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells

Cited by 216 publications

References 115 publications

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

A brief review concerning Chimeric Antigen Receptors T cell therapy

The progression & delivery of adoptive cellular immune therapies: leveraging single-cell resolution & novel algorithms to overcome the challenges associated with allogeneic & autologous immune cell therapies

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