DNAM-1-chimeric receptor-engineered NK cells, combined with Nutlin-3a, more effectively fight neuroblastoma cells in vitro: a proof-of-concept study

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Июль 28, 2022

Adoptive transfer of engineered NK cells, one clinical approaches to fight cancer, is gaining great interest in the last decade. However, development new strategies needed improve efficacy and safety cell-based immunotherapy. cell-mediated recognition lysis tumor cells are strictly dependent on expression ligands for cell-activating receptors NKG2D DNAM-1 cells. Of note, PVR/CD155 Nectin-2/CD112 expressed primarily solid poorly normal tissue Here, we generated human expressing either full length receptor or three different DNAM-1-based chimeric that provide fused a costimulatory molecule such as 2B4 CD3ζ chain. Upon transfection into primary isolated from healthy donors, evaluated surface and, functional readout, assessed extent degranulation, cytotoxicity production IFNγ TNFα response leukemic K562 cell line. In addition, explored effect Nutlin-3a, MDM2-targeting drug able restoring p53 functions known have an immunomodulatory effect, degranulation DNAM-1-engineered neuroblastoma (NB) LA-N-5 SMS-KCNR lines. By comparing transfected with four plasmid vectors through blocking experiments, DNAM-1-CD3ζ-engineered showed strongest response. Furthermore, both pretreated Nutlin-3a were significantly more susceptible than empty vector. Our results proof-of-concept suggesting combined use DNAM-1-chimeric receptor-engineered may represent novel therapeutic approach treatment tumors, NB, carrying dysfunctional p53.

Язык: Английский

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Lipid-mediated ex vivo cell surface engineering for augmented cellular functionalities

Biomaterials Advances, Год журнала: 2022, Номер 140, С. 213059 - 213059

Опубликована: Авг. 3, 2022

Язык: Английский

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Targeting T-cell malignancies using allogeneic double-negative CD4-CAR-T cells

Journal for ImmunoTherapy of Cancer, Год журнала: 2023, Номер 11(9), С. e007277 - e007277

Опубликована: Сен. 1, 2023

Background Patients with relapsed/refractory T-cell malignancies have limited treatment options. The use of chimeric antigen receptor (CAR)-T cell therapy for is challenging due to possible blast contamination autologous products and fratricide CAR-T cells targeting T-lineage antigens. Recently, allogeneic double-negative T (DNTs) been shown be safe as an off-the-shelf adoptive amendable CAR transduction. Here, we explore the antitumor activity DNTs against potential using anti-CD4-CAR (CAR4)-DNTs malignancies. Methods Healthy donor-derived were ex vivo expanded or without CAR4 CAR4-DNTs acute lymphoblastic leukemia (T-ALL) peripheral lymphoma (PTCL) examined flow cytometry-based cytotoxicity assays xenograft models. Mechanisms action investigated transwell blocking assays. Results Allogeneic induced endogenous T-ALL PTCL in vitro, but high doses required attain therapeutic effects vivo. potency was significantly enhanced by transducing a third-generation CAR4. manufactured showed superior CD4 + vitro relative empty-vector transduced-DNTs. eliminated lines primary blasts vitro. effectively infiltrated tumors, delayed tumor progression, prolonged survival xenografts. Further, pretreatment PI3Kδ inhibitor idelalisib promoted memory phenotype their persistence antileukemic efficacy Mechanistically, LFA-1, NKG2D, perforin/granzyme B degranulation pathways involved DNT-mediated CAR4-DNT-mediated killing PTCL. Conclusions These results demonstrate that can target support

Язык: Английский

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T Cell and Natural Killer Cell Membrane-Camouflaged Nanoparticles for Cancer and Viral Therapies

ACS Applied Bio Materials, Год журнала: 2024, Номер 7(5), С. 2637 - 2659

Опубликована: Апрель 30, 2024

Extensive research has been conducted on the application of nanoparticles in treatment cancer and infectious diseases. Due to their exceptional characteristics flexible structure, they are classified as highly efficient drug delivery systems, ensuring both safety targeted delivery. Nevertheless, still encounter obstacles, such biological instability, absence selectivity, recognition unfamiliar elements, quick elimination, which restrict remedial capacity. To surmount these drawbacks, biomimetic nanotechnology developed that utilizes T cell natural killer (NK) membrane-encased sophisticated methods administering drugs. These can extend duration circulation avoid immune system clearance. During membrane extraction coating procedure, surface proteins immunological cells transferred nanoparticles. Such present confer several benefits nanoparticles, including prolonged circulation, enhanced targeting, controlled release, specific cellular contact, reduced vivo toxicity. This review focuses nanosystems derived from membranes NK comprehensive manufacture, applications viral infections. Furthermore, potential applications, prospects, existing challenges medical implementation highlighted.

Язык: Английский

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Stealth transgenes enable CAR-T cells to evade host immune responses

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(5), С. e008417 - e008417

Опубликована: Май 1, 2024

Background Adoptive cell therapy, such as chimeric antigen receptor (CAR)-T has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T products use FMC63-based αCD19 single-chain variable fragment, derived from a murine monoclonal antibody, extracellular binding domain. Clinical studies demonstrate that patients develop humoral and cellular immune responses to non-self CAR components autologous cells or donor-specific antigens allogeneic cells, which is thought potentially limit persistence success repeated dosing. Methods In this study, we implemented one-shot approach prevent rejection engineered T by simultaneously reducing presentation surface expression both Classes major histocompatibility complex (MHC) via viral inhibitors transporter associated with processing (TAPi) in combination transgene coding shRNA targeting class II MHC transactivator (CIITA). The optimal was screened vitro flow cytometric analysis mixed lymphocyte reaction assays validated vivo mouse models leukemia lymphoma. Functionality assessed an setting using samples model. Results Epstein-Barr virus TAPi CIITA efficient effective at classes I ‘stealth’ while retaining antitumor functionality. Mixed IFNγ ELISpot performed previously treated confirm expressing stealth transgenes evade anti-CAR responses, further vivo. Importantly, noted anti-CAR-T who had received multiple infusions, response reduced on restimulation CARs containing transgenes. Conclusions Together, these data suggest proposed may reduce immunogenicity therapeutics. Moreover, indicate doses significantly increased patients.

Язык: Английский

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