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, Journal Year: 2022, Volume and Issue: 13

Published: July 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.

Language: Английский

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

Biomaterials Advances, Journal Year: 2022, Volume and Issue: 140, P. 213059 - 213059

Published: Aug. 3, 2022

Language: Английский

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

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(9), P. e007277 - e007277

Published: Sept. 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

Language: Английский

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

ACS Applied Bio Materials, Journal Year: 2024, Volume and Issue: 7(5), P. 2637 - 2659

Published: April 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.

Language: Английский

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The basic biology of NK cells and its application in tumor immunotherapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 16, 2024

Natural Killer (NK) cells play a crucial role as effector within the tumor immune microenvironment, capable of identifying and eliminating through expression diverse activating inhibitory receptors that recognize tumor-related ligands. Therefore, harnessing NK for therapeutic purposes represents significant adjunct to T cell-based immunotherapy strategies. Presently, strategies encompass various approaches, including adoptive cell therapy, cytokine antibody-based therapy (enhancing ADCC mediated by cells, engagers, checkpoint blockade therapy) utilization nanoparticles small molecules modulate anti-tumor functionality. This article presents comprehensive overview latest advances in immunotherapy, with aim offering insights methodologies clinical treatment cancer patients.

Language: Английский

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