Plasma membrane-coated nanoparticles and membrane vesicles to orchestrate multimodal antitumor immunity

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(1), С. e010005 - e010005

Опубликована: Янв. 1, 2025

Background A number of immunotherapeutic approaches have been developed and are entering the clinic. Bispecific antibodies (BsAbs) one these modalities induce robust efficacy by endogenous T cells in several hematological malignancies. However, most treated patients experience only a temporary benefit. Currently available BsAbs provide anti-CD3 antibody-mediated T-cell stimulation, but not costimulation or cytokine signaling essential for full activation. Here, we hypothesized that simultaneous input more comprehensive signals would elicit durable effector functions. Methods We genetically engineered leukemia cell line K562 to express BsAbs, costimulatory ligands, cytokines, blocking against immune checkpoint molecules on surface, from which obtained plasma membrane fractions mechanical homogenization subsequent isolation steps. Plasma membranes were reconstituted poly (lactic-co-glycolic acid) surface generate membrane-coated nanoparticles (NPs). Alternatively, nano-sized vesicles (MVs) generated ultrasonic dispersion isolated membranes. The antitumor function NPs MVs loaded with various immunomodulatory factors was evaluated vitro vivo. Results Both induced BsAb-mediated antigen-specific cytotoxic activity non-specific cells, inducing slightly better response Importantly, activation elicited presence target tumor providing safety advantage clinical use. expressing (CD80/4-1BBL) cytokines (interleukin (IL)-7/IL-15) further enhanced therapeutic In addition, inflammatory IL-12 IL-18 objective responses solid models partly converting immunosuppressive macrophages proinflammatory phenotypes infiltration into tumor. Finally, showed also activate natural killer (NK) loading multiple ligands. 4-1BBL, IL-15, IL-21 NK-cell an manner. Conclusions efficiently vivo simultaneously delivering immunostimulatory cells. This platform enables delivery desired combinations NK

Язык: Английский

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Combined delivery of IL12 and an IL18 mutant without IL18BP-binding activity by an adenoviral vector enhances tumor specific immunity

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 28, 2025

Cytokines play pivotal roles in anticancer immune response. We previously reported that adenovirus armed with an IL18 variant (DR18) overcomes IL18BP neutralizing effect displayed powerful therapeutic effects local and distant tumors when delivered intratumorally. Here, we tested a combined delivery of IL12 DR18 tumor models since are known to act synergistically potentiating IFNγ production antitumor immunity. To minimize adverse associated systemic delivery, constructed oncolytic adenoviruses (oAd) harboring (oAd.DR18/IL12). was expressed as single chain (scIL12) peptide composed the IL12/p40 IL12/p35 subunits. Intratumoral administration oAd.DR18/IL12, oAd-expressing (oAd.DR18), or (oAd.IL12) showed syngeneic colorectal models. Compared oAd.DR18 oAd.IL12, oAd.DR18/IL12 improved well increased survival rate these detected enhanced infiltrating T lymphocytes NK cells oAd.DR18/IL12-treated mice than those from mock-treated individually treated groups. Moreover, received had more robust tumor-specific cytotoxicity. Importantly, regression after treatment established anti-tumor specific memory. These results show engineered cytokines boosts immunity effect.

Язык: Английский

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Cytokine-driven cancer immune evasion mechanisms

International review of cell and molecular biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

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The Interleukin-1 Family

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Therapeutic targets of armored chimeric antigen receptor T cells navigating the tumor microenvironment

Experimental Hematology and Oncology, Год журнала: 2024, Номер 13(1)

Опубликована: Сен. 30, 2024

Язык: Английский

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Cytotoxicity as a form of immunogenic cell death leading to efficient tumor antigen cross‐priming

Immunological Reviews, Год журнала: 2023, Номер 321(1), С. 143 - 151

Опубликована: Окт. 11, 2023

Summary Antigen cross‐priming of CD8 + T cells is a critical process necessary for the effective expansion and activation endowed with ability to recognize destroy tumor cells. The cross‐presentation antigens cross‐prime mainly mediated, if not only, by subset professional antigen‐presenting termed type‐1 conventional dendritic (cDC1). demise malignant can be immunogenic it occurs in context premortem stress. These ways dying are cell death (ICD) associated biochemical features favoring cDC1 efficient antigens. Immunosurveillance success immunotherapies heavily rely on cytotoxic immune cells, primarily NK detect eliminate through mechanisms collectively known as cytotoxicity. Recent studies have revealed significance NK‐ CTL‐mediated cytotoxicity prominent form death, resulting that promote sustain antigen‐specific responses. This review focuses underlying released during killing an emphasis role Indeed, cDC1s instrumental effectiveness most immunotherapies, underscoring antigen contexts death. notion potent immunogenicity from or lymphocyte (CTL)‐mediated has far‐reaching implications cancer immunotherapy.

Язык: Английский

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ARI0003: Co-transduced CD19/BCMA Dual-targeting CAR-T Cells for the Treatment of Non-Hodgkin Lymphoma

Molecular Therapy, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

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In Synergy: Optimizing CAR T Development and Personalizing Patient Care Using Single-Cell Technologies

Cancer Discovery, Год журнала: 2023, Номер 13(7), С. 1546 - 1555

Опубликована: Май 23, 2023

Chimeric antigen receptor (CAR) T therapies hold immense promise to revolutionize cancer treatment. Nevertheless, key challenges, primarily in solid tumor settings, continue hinder the application of this technology. Understanding CAR T-cell mechanism action, vivo activity, and clinical implications is essential for harnessing its full therapeutic potential. Single-cell genomics cell engineering tools are becoming increasingly effective comprehensive research complex biological systems. The convergence these two technologies can accelerate development. Here, we examine potential applying single-cell multiomics development next-generation therapies. Although have demonstrated remarkable results treating cancer, their effectiveness most patients types remains limited. technologies, which transforming our understanding molecular biology, provide new opportunities overcome challenges Given therapy tip balance fight against it important understand how multiomic approaches be leveraged develop next generations more less toxic products powerful decision-making clinicians optimize treatment improve patient outcomes.

Язык: Английский

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Interleukin-18 in cancer immunology and immunotherapy

Expert Opinion on Therapeutic Targets, Год журнала: 2023, Номер 27(11), С. 1035 - 1042

Опубликована: Ноя. 2, 2023

ABSTRACTIntroduction Interleukin-18 (IL-18) is a myeloid leukocyte inflammatory mediator whose main known function to elicit IFNγ secretion from T and NK cells.Areas covered This offers potential in cancer immunotherapy but as single treatment, preclinical clinical antitumor activities are modest. IL-18 bioactivity chiefly downregulated by decoy soluble receptor named IL18-binding protein (IL-18BP) that induced negative feedback mechanism. Recent advances indicate promising efficacy of at armoring CAR-T cells for the treatment hematological malignancies. Preclinical research has also yielded constructs do not bind IL-18BP have preserved activity on exert markedly increased effects. Indeed, agents this kind undergoing trials. The synergistic effects IL-12 combination induce extremely potent toxic if systemically delivered. In mouse models, decoy-resistant variants can be efficaciously used local treatments tumors exploiting mRNA intratumoral co-delivery. Moreover, transiently engineered with mRNAs encoding cytokines attain efficacious upon delivery.Expert opinion certainly holds promise other approaches.KEYWORDS: Interleukin-18decoy resistant IL-18combination strategiesmRNACAR-T cellsDisclaimerAs service authors researchers we providing version an accepted manuscript (AM). Copyediting, typesetting, review resulting proofs will undertaken before final publication Version Record (VoR). During production pre-press, errors may discovered which could affect content, all legal disclaimers apply journal relate these versions also. Article highlightsIL-18 play double-edged roles immunobiologyApplicability recombinant been tested studies trials.The therapeutic limited IL-18BP, natural regulator bioactivity.Decoy-resistant (DR-18), cannot developed novel treat being clinic.IL-18 gene-transfer increases various adoptive T-cell therapies models.Armoring safe preliminary results against malignancies promising.Combination approaches based delivery DR-18 achieved tumor models.Engineering achieves activity.AbbreviationsInterleukin-18 (IL-18), interferon-γ (IFNγ), interleukin-12 (IL-12), binding (IL-18BP), necrosis factor (TNF), dendritic (DCs), dextran sulfate sodium (DSS), vascular endothelial growth (VEGF), Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), chimeric antigen (CAR), cell (TCR), programmed death protein-1 (PD-1), Cancer Genome Atlas (TCGA), Food Drug Administration (FDA), infiltrating lymphocytes (TILs), therapy (ACT)Declaration interestI Melero reports grants personal fees Genmab, Bristol Myers Squibb, Roche, AstraZeneca, Pharmamar F-Star, Numab, Pieris, Boehringer Ingelheim, Gossamer, Alligator, Hotspot, Biolinerx, Bioncotech, Dompe, Highlight therapeutics, Bright Peaks Boston Therapeutics outside submitted work.Reviewer disclosuresPeer reviewers no relevant financial or relationships disclose.AcknowledgementsCritical reading scientific discussion Drs Miguel F. Sanmamed, Alvaro Teijeira, Maite Alvarez acknowledged well support Dr. Belen Palencia.Figure 1. Scheme biosynthesis, signal transduction target microenvironment neutralized IL-18BP.Display full sizeFigure 2. Ways exploit forms resist strategies.Display sizeAdditional informationFundingThis project received funding European Union's Horizon 2020 innovation program under Marie Sklodowska-Curie grant agreement No 765394. study was supported Spanish Ministry Economy Competitiveness Research (MINECO SAF2014-52361-R SAF 2017-83267-C2-1R MCIN/AEI/10.13039/501100011033/y por FEDER Una manera de hacer Europa PID2020-112892RB-100, PID2020-113174-RA-100 MCIN/AEI/10.13039/501100011033, Institute CRI-CLIP, work Instituto Salud Carlos III (AC16/00015) Funds Regional Development (EFRD) TRANSCAN-2 Programme, UK [C18915/A29362], FCAECC AIRC Accelerator Award Gobierno Navarra Salud, Proyecto ARNMUNE Ref: 0011–1411-2023, Mark Foundation "MINCITH. Metabolic requirements immune INfiltration effective ImmunoTHerapy" AYUDAS FUNDACIÓN BBVA A EQUIPOS DE INVESTIGACION CIENTIFICA 2019" Fundación Olga Torres. (PI22/00147) co-financed Fondos Feder. Work produced 2022 Leonardo Grant Researchers Cultural Creators, Foundation.

Язык: Английский

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Regional and intratumoral adoptive T-cell therapy

Immuno-Oncology Technology, Год журнала: 2024, Номер 24, С. 100715 - 100715

Опубликована: Июнь 13, 2024

Язык: Английский

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