Lenalidomide Enhances CAR-T Cell Activity Against Solid Tumor Cells

Wang, Zhixiong; Zhou, Guomin; Na, Risu; Fu, Jiayu; Zou, Yan; Tang, Jiaxing; Long, Li; Liu, Hui; Liu, Qian; Zhu, Xuekai

doi:10.1177/0963689720920825

Cited by 32 publications

(31 citation statements)

References 51 publications

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“…Supporting a similar role for Ikaros in CD8 + T cells, a recent study in CAR T cell populations found that treatment of these cells with the immunomodulatory drug lenalidomide, which is known to semi‐selectively degrade Ikaros and Aiolos proteins, resulted in increased proliferation and function of these cells. This included both increased cytotoxicity and augmented expression of IL‐2, IFN‐γ, TNF‐α, and GM‐CSF, similar to the phenotype observed in T‐helper cell populations upon loss of Ikaros 88 . Finally, Ikaros may also play a role in regulating responsiveness to cytokine signals, including IL‐2, as overexpression of the dominant negative form of Ikaros resulted in increased expression of the IL‐2 receptor alpha subunit (CD25) in IL‐12 treated CD8 + cells 89 .…”

Section: Regulation Of Mature T Cell Populations By Ikaros Factorsmentioning

confidence: 66%

“…However, whether this effect is due to loss of Aiolos, Ikaros, or another lenalidomide-sensitive factor is yet to be determined. 88 Regardless, the above data are supportive of a role for Aiolos, like Ikaros, in the differential regulation of pro-and anti-inflammatory cytokine production in a number of individual T-helper cell subsets.…”

Section: Ikarosmentioning

confidence: 83%

“…Finally, as discussed above, recent work in CD8 + CAR T cell populations indicated that Aiolos may positively regulate their cytotoxicity and pro‐inflammatory cytokine production, as lenalidomide treatment caused increases in both. However, whether this effect is due to loss of Aiolos, Ikaros, or another lenalidomide‐sensitive factor is yet to be determined 88 . Regardless, the above data are supportive of a role for Aiolos, like Ikaros, in the differential regulation of pro‐ and anti‐inflammatory cytokine production in a number of individual T‐helper cell subsets.…”

Section: Regulation Of Mature T Cell Populations By Ikaros Factorsmentioning

confidence: 92%

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Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function

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Jones

Freud

et al. 2020

Immunological Reviews

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Ikaros zinc finger transcription factors are important regulators of the gene programs underlying the development of hematopoietic cell lineages. The family consists of five members: Ikaros, Helios, Aiolos, Eos, and Pegasus, which engage in both homo-and heterotypic intrafamilial interactions to exert diverse functional effects. Pioneering studies focused on the role of these factors in early lymphoid development, as their absence resulted in severe defects in lymphocyte populations. More recent work has now begun to define nuanced, stage-specific roles for Ikaros family members in the differentiation and function of mature T, B, and innate lymphoid cell populations including natural killer (NK) cells. The precise transcriptional mechanisms by which these factors function, both independently and collaboratively, is an area of active investigation. However, several key themes appear to be emerging regarding the pathways influenced by Ikaros family members, including the end-to-end regulation of cytokine signaling. Here, we review roles for Ikaros factors in lymphoid cell development, differentiation, and function, including a discussion of the current understanding of the transcriptional mechanisms they employ and considerations for the future study of this important transcription factor family.

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Section: Regulation Of Mature T Cell Populations By Ikaros Factorsmentioning

confidence: 66%

Section: Ikarosmentioning

confidence: 83%

Section: Regulation Of Mature T Cell Populations By Ikaros Factorsmentioning

confidence: 92%

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Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function

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Jones

Freud

et al. 2020

Immunological Reviews

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“…Besides, the loss of IKZFs is the reason for the increase of IFN-γ, IL-21, and IL-2 production by T cells treated with IMiDs ( Gandhi et al, 2014 ; Brissot et al, 2015 ). In addition, Len also decreased the levels of Ikaros and Aiolos in chimeric antigen receptor (CAR) T-cells, which helped to enhance the ability of CAR T-cells to restore IL-2 gene transcription and facilitate IL-2 secretion against solid cancer cells ( Wang et al, 2020b ).…”

Section: Targeted Therapy For Ikarosmentioning

confidence: 99%

Ikaros Proteins in Tumor: Current Perspectives and New Developments

Xia

Yuan

Han

et al. 2021

Front. Mol. Biosci.

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Ikaros is a zinc finger transcription factor (TF) of the Krüppel family member, which significantly regulates normal lymphopoiesis and tumorigenesis. Ikaros can directly initiate or suppress tumor suppressors or oncogenes, consequently regulating the survival and proliferation of cancer cells. Over recent decades, a series of studies have been devoted to exploring and clarifying the relationship between Ikaros and associated tumors. Therapeutic strategies targeting Ikaros have shown promising therapeutic effects in both pre-clinical and clinical trials. Nevertheless, the increasingly prominent problem of drug resistance targeted to Ikaros and its analog is gradually appearing in our field of vision. This article reviews the role of Ikaros in tumorigenesis, the mechanism of drug resistance, the progress of targeting Ikaros in both pre-clinical and clinical trials, and the potential use of associated therapy in cancer therapy.

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“…In T cells, siRNA-mediated knockdown of either IKZF1 or IKZF3 is sufficient to enhance the expression of IL-2 and multiple other cytokines, reminiscent of the effects of LENA treatment 29 . We have recently demonstrated that in vitro, LENA can enhance cytokine expression and killing of solid tumors by CAR T cells, suggesting that LENA might be used for boosting the efficacy of CAR T cells targeting solid tumors 31 . However, LENA has been FDA-approved only for treating several hematological cancers (namely multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma), but not for any solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Impact of genomic preselection on subsequent genetic evaluations with ssGBLUP - using real data from pigs

Jibrila

Vandenplas

Napel

et al. 2021

Preprint

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Background: Empirically assessing the impact of preselection on subsequent genetic evaluations of preselected animals requires comparison of scenarios with and without preselection. However, preselection almost always takes place in animal breeding programs, so it is difficult, if not impossible, to have a dataset without preselection. Hence most studies on preselection used simulated datasets, concluding that subsequent genomic estimated breeding values (GEBV) from single-step genomic best linear unbiased prediction (ssGBLUP) are unbiased. The aim of this study was to investigate the impact of genomic preselection, using real data, on accuracy and bias of GEBV of validation animals. Methods: We used data on four pig production traits from one sire-line and one dam-line, with more intense original preselection in the dam-line than in the sire-line. The traits are average daily gain during performance testing, average daily gain throughout life, backfat, and loin depth. Per line, we ran ssGBLUP with the entire data until validation generation and considered this scenario as the reference scenario. We then implemented two scenarios with additional layers of genomic preselection by removing all animals without progeny either i) only in the validation generation, or ii) in all generations. In computing accuracy and bias, we compared GEBV against progeny yield deviation of validation animals. Results: Results showed only a limited loss in accuracy due to the additional layers of genomic preselection. This is true in both lines, for all traits, and regardless of whether validation animals had records or not. Bias too was largely absent, and did not differ greatly among corresponding scenarios with or without additional layers of genomic preselection. Conclusion: We concluded that impact of recent and/or historical genomic preselection is minimal on subsequent genetic evaluations of selection candidates, if these subsequent genetic evaluations are done using ssGBLUP.

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Lenalidomide Enhances CAR-T Cell Activity Against Solid Tumor Cells

Cited by 32 publications

References 51 publications

Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function

Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function

Ikaros Proteins in Tumor: Current Perspectives and New Developments

Impact of genomic preselection on subsequent genetic evaluations with ssGBLUP - using real data from pigs

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