The immunostimulatory RNA RN7SL1 enables CAR-T cells to enhance autonomous and endogenous immune function

Johnson, Lexus R.; Lee, Daniel Y.; Eacret, Jacqueline S.; Ye, Darwin; June, Carl H.; Minn, Andy J.

doi:10.1016/j.cell.2021.08.004

Cited by 118 publications

(90 citation statements)

References 57 publications

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“…A recent study published in Cell by Lexus et al presented CAR-T cell as a carrier that could secrete extracellular vesicles (EVs) containing immunostimulatory RNA RN7SL1, which could be specifically taken in by immune cells to enhance endogenous immunity against solid tumor. 1 …”

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confidence: 99%

“…For example, PRR and IFN signaling in immune cells are immunostimulatory, while the same signaling in cancer cells drives cancer progression and immunotherapy resistance. 1 Hence, a delivery system specific for immune cells is urgently needed for gene therapy targeting TME.…”

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confidence: 99%

“…In a recent study in Cell , Lexus et al put forward that delivering the pattern recognition receptor agonists was an effective way to stimulate anti-tumor immunity. 1 However, it’s hard to deliver them to immune cells directly and it often initiates cancer cell-intrinsic detrimental pathways on the contrary. Hence, Lexus et al engineered CAR-T cells to deliver immunostimulatory non-coding RNA RN7SL1 with EVs, which functions as a damage-associated molecular pattern (DAMP) to activate RNA PRRs in immune cells.…”

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confidence: 99%

“…Hence, Lexus et al engineered CAR-T cells to deliver immunostimulatory non-coding RNA RN7SL1 with EVs, which functions as a damage-associated molecular pattern (DAMP) to activate RNA PRRs in immune cells. 1 Lexus et al considered that CAR-T cells could kill target cancer cells within the scope of the EVs and thus realize selective tumor-infiltrated immune cells delivery, which avoids the initiation of cancer cell-intrinsic detrimental pathways. In immune cells, RN7SL1 limits the accumulation of myeloid-derived suppressor cells (MDSCs) and inhibits TGF-β1 signaling pathway.…”

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confidence: 99%

“…This strategy simultaneously employs CAR-T cells, enhances endogenous T cell function, and counteracts common suppressive mechanisms, offering effective combinatorial approaches to improve solid tumor response. 1 …”

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confidence: 99%

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CAR-T: a potential gene carrier targeting solid tumor immune microenvironment

Wang

Zhang

Jiang

2021

Sig Transduct Target Ther

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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CAR-T: a potential gene carrier targeting solid tumor immune microenvironment

Wang

Zhang

Jiang

2021

Sig Transduct Target Ther

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Nanomaterials Boost CAR‐T Therapy for Solid Tumors

Long,

Wang,

Jiang

et al. 2024

Adv Healthcare Materials

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T cell engineering, particularly via chimeric antigen receptor (CAR) modifications for enhancing tumor specificity, has shown efficacy in treating hematologic malignancies. The extension of CAR‐T cell therapy to solid tumors, however, is impeded by several challenges: the absence of tumor‐specific antigens, antigen heterogeneity, a complex immunosuppressive tumor microenvironment, and physical barriers to cell infiltration. Additionally, limitations in CAR‐T cell manufacturing capacity and the high costs associated with these therapies restrict their widespread application. The integration of nanomaterials into CAR‐T cell production and application offers a promising avenue to mitigate these challenges. Utilizing nanomaterials in the production of CAR‐T cells could decrease product variability and lower production expenses, positively impacting the targeting and persistence of CAR‐T cells in treatment and minimizing adverse effects. This review comprehensively evaluates the use of various nanomaterials in the production of CAR‐T cells, genetic modification, and in vivo delivery. It discusses their underlying mechanisms and potential for clinical application, with a focus on improving specificity and safety in CAR‐T cell therapy.This article is protected by copyright. All rights reserved

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Thermoresponsive Polypeptide Fused L‐Asparaginase with Mitigated Immunogenicity and Enhanced Efficacy in Treating Hematologic Malignancies

et al. 2023

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L‐Asparaginase (ASP) is well‐known for its excellent efficacy in treating hematological malignancies. Unfortunately, the intrinsic shortcomings of ASP, namely high immunogenicity, severe toxicity, short half‐life, and poor stability, restrict its clinical usage. Poly(ethylene glycol) conjugation (PEGylation) of ASP is an effective strategy to address these issues, but it is not ideal in clinical applications due to complex chemical synthesis procedures, reduced ASP activity after conjugation, and pre‐existing anti‐PEG antibodies in humans. Herein, the authors genetically engineered an elastin‐like polypeptide (ELP)‐fused ASP (ASP‐ELP), a core‐shell structured tetramer predicted by AlphaFold2, to overcome the limitations of ASP and PEG‐ASP. Notably, the unique thermosensitivity of ASP‐ELP enables the in situ formation of a sustained‐release depot post‐injection with zero‐order release kinetics over a long time. The in vitro and in vivo studies reveal that ASP‐ELP possesses increased activity retention, improved stability, extended half‐life, mitigated immunogenicity, reduced toxicity, and enhanced efficacy compared to ASP and PEG‐ASP. Indeed, ASP‐ELP treatment in leukemia or lymphoma mouse models of cell line‐derived xenograft (CDX) shows potent anti‐cancer effects with significantly prolonged survival. The findings also indicate that artificial intelligence (AI)‐assisted genetic engineering is instructive in designing protein‐polypeptide conjugates and may pave the way to develop next‐generation biologics to enhance cancer treatment.

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The immunostimulatory RNA RN7SL1 enables CAR-T cells to enhance autonomous and endogenous immune function

Cited by 118 publications

References 57 publications

CAR-T: a potential gene carrier targeting solid tumor immune microenvironment

CAR-T: a potential gene carrier targeting solid tumor immune microenvironment

Nanomaterials Boost CAR‐T Therapy for Solid Tumors

Thermoresponsive Polypeptide Fused L‐Asparaginase with Mitigated Immunogenicity and Enhanced Efficacy in Treating Hematologic Malignancies

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