Sonodynamic Therapy Induces Pyroptosis and Recruits CAR-NK Cells to Enhance the Treatment of Oral Squamous Cell Carcinoma DOI Creative Commons
Jing Meng,

Jiaxin Zuo,

Luyu Li

et al.

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: May 8, 2025

Background: Immunotherapy strategies have demonstrated promising efficacy in treating various cancers. However, cancer cells often evade immune surveillance by reducing their immunogenicity, which limits cell infiltration into the tumor microenvironment. Pyroptosis, a proinflammatory form of programmed death, is characterized formation plasma membrane pores that lead to release intracellular contents and stimulate robust response. Results: To exploit this mechanism, we developed hematoporphyrin monomethyl ether (HMME)-loaded nanoliposomes capable efficiently accumulating at site. Upon ultrasound irradiation, these nanomedicines generate reactive oxygen species (ROS) activate Caspase-3, cleaves Gasdermin E (GSDME) induces pyroptosis. Notably, sonodynamic therapy (SDT) based on nanosonosensitizers enhanced targeted enrichment chimeric antigen receptor (CAR)-engineered natural killer (NK) ultrasound-irradiated site, significantly improved response, effectively inhibited growth proliferation oral squamous carcinoma (OSCC) both vivo vitro. Conclusions: Given NK immunotherapy has an excellent safety profile with minimal risks cytokine syndrome neurotoxicity, approach holds promise as adjunct cell-based immunotherapies through SDT-induced

Language: Английский

Intracranial injection of natural killer cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma DOI Creative Commons
Michael C. Burger, Marie-Thérèse Forster,

A Romański

et al.

Neuro-Oncology, Journal Year: 2023, Volume and Issue: 25(11), P. 2058 - 2071

Published: May 6, 2023

Abstract Background Glioblastoma (GB) is incurable at present without established treatment options for recurrent disease. In this phase I first-in-human clinical trial we investigated safety and feasibility of adoptive transfer clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2, which expressed elevated levels by a subset glioblastomas. Methods Nine patients with HER2-positive GB were treated single doses 1 × 107, 3 or 108 irradiated CAR-NK injected into the margins surgical cavity during relapse surgery. Imaging baseline follow-up, peripheral blood lymphocyte phenotyping analyses immune architecture multiplex immunohistochemistry spatial digital profiling performed. Results There no dose-limiting toxicities, none developed cytokine release syndrome effector cell-associated neurotoxicity syndrome. Five showed stable disease after surgery injection that lasted 7 to 37 weeks. Four had progressive Pseudoprogression was found sites in 2 patients, suggestive treatment-induced response. For all median progression-free survival weeks, overall 31 Furthermore, level CD8+ T-cell infiltration tumor tissue prior cell positively correlated time progression. Conclusions Intracranial HER2-targeted feasible safe GB. NK-92/5.28.z determined as maximum dose subsequent expansion cohort repetitive local injections cells.

Language: Английский

Citations

52
Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders DOI

Panrui Lu,

Y. Cheng, Lei Xue

et al.

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

Citations

18
Enhancement of anti‐sarcoma immunity by NK cells engineered with mRNA for expression of a EphA2‐targeted CAR DOI Creative Commons
Pui Yeng Lam, Natacha Omer,

J. Wong

et al.

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 1, 2025

Abstract Background Paediatric sarcomas, including rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, represent a group of malignancies that significantly contribute to cancer‐related morbidity mortality in children young adults. These cancers share common challenges, high rates metastasis, recurrence or treatment resistance, leading 5‐year survival rate approximately 20% for patients with advanced disease stages. Despite the critical need, therapeutic advancements have been limited over past three decades. The advent chimeric antigen receptor (CAR)‐based immunotherapies offers promising avenue novel treatments. However, CAR‐T cells faced significant challenges success treating solid tumours due issues such as poor tumour infiltration, immunosuppressive microenvironments off‐target effects. In contrast, adaptation CAR technology natural killer (NK) has demonstrated potential both haematological tumours, suggesting new strategy paediatric sarcomas. Methods This study developed validated CAR‐NK cell therapy targeting ephrin type‐A receptor‐2 (EphA2) antigen, which is highly expressed various Results expression was successfully detected on surface NK post‐electroporation, indicating successful transfection. Significantly, EphA2‐specific enhanced cytotoxic activity against several lines vitro, those compared unmodified cells. Transient messenger RNA (mRNA) transfection safe approach genetic engineering, further chemical modifications mRNA enhancing stability temporal EphA2‐CAR cells, thereby promoting prolonged protein expression. Additionally, vivo EphA2‐CAR‐NK showed anti‐cancer rhabdomyosarcoma osteosarcoma mouse models. Conclusions provides foundational basis clinical evaluation EphA2‐targeted across spectrum anti‐tumour effects observed vitro/vivo suggests improved outcomes hard‐to‐cure Key points Addressing unmet needs Sarcomas. sarcoma, exhibit lack progress decades necessitates innovative approaches. Advancing immunotherapy Natural modified receptors (CARs) overcome limitations particularly tumours. are associated targeting, reduced effects, safety profiles. EphA2 target. EphA2, overexpressed multiple identified viable target CAR‐based its role progression angiogenesis. Innovations mRNA‐based engineering. demonstrates feasibility transient engineer expression, offering non‐integrative safer alternative viral transduction. Enhancements through modifications, can optimise Preclinical efficacy superior cytotoxicity vitro demonstrate models osteosarcoma. Clinical translation potential. findings establish strong preclinical rationale immunotherapeutic option Future research directions: Combining immune checkpoint inhibitors other immunomodulatory agents could enhance durability. Advanced mimicking human needed refine this approach.

Language: Английский

Citations

2
Integration of ζ-deficient CARs into the CD3 ζ gene conveys potent cytotoxicity in T and NK cells DOI Creative Commons
Jonas Kath, Clemens Franke, Vanessa Drosdek

et al.

Blood, Journal Year: 2024, Volume and Issue: 143(25), P. 2599 - 2611

Published: March 17, 2024

Abstract Chimeric antigen receptor (CAR)-redirected immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in nonphysiological regulation of CAR-signaling limits their accessibility due to logistical challenges, high costs biosafety requirements. Random transfer modalities pose a risk malignant transformation by insertional mutagenesis. Here, we propose novel approach utilizing CRISPR-Cas editing redirect T natural killer (NK) with CARs. By transferring shorter, truncated CAR-transgenes lacking main activation domain into the human CD3ζ (CD247) gene, functional CAR fusion-genes are generated that exploit endogenous as CAR’s domain. Repurposing this T/NK-cell lineage facilitated physiological expression redirection various cell types, including conventional cells, TCRγ/δ regulatory NK cells. In in-frame fusion eliminated TCR surface expression, reducing graft-versus-host disease allogeneic off-the-shelf settings. CD3ζ-CD19-CAR-T exhibited comparable leukemia control TCRα chain constant (TRAC)-replaced lentivirus-transduced vivo. Tuning CD3ζ-CAR-expression levels significantly improved vivo efficacy. Notably, enabled without impairing canonical functions. Thus, is promising platform development redirected lymphocytes.

Language: Английский

Citations

14
Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization DOI Creative Commons

Sumei Chen,

Haitao Zhu, Youssef Jounaïdi

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 8, 2024

Abstract Natural killer (NK) cells, initially identified for their rapid virus-infected and leukemia cell killing tumor destruction, are pivotal in immunity. They exhibit multifaceted roles cancer, viral infections, autoimmunity, pregnancy, wound healing, more. Derived from a common lymphoid progenitor, they lack CD3, B-cell, or T-cell receptors but wield high cytotoxicity via perforin granzymes. NK cells orchestrate immune responses, secreting inflammatory IFNγ immunosuppressive TGFβ IL-10. CD56 dim bright execute cytotoxicity, while also regulate However, beyond the dichotomy, detailed phenotypic diversity reveals many functional subsets that may not be optimal cancer immunotherapy. In this review, we provide comprehensive snapshots of cells’ functions states activation inhibitions angiogenesis, pregnancy fertility, aging, senescence mediated by complex signaling ligand-receptor interactions, including impact environment. As use engineered immunotherapy accelerates, often footsteps T-cell-derived engineering, examine interactions with other effectors relevant limitations microenvironment, intending to understand how enhance cytolytic activities specifically

Language: Английский

Citations

13
Chimeric antigen receptor-natural killer cell therapy: current advancements and strategies to overcome challenges DOI Creative Commons
Jun Kong, Mohammad Auwal Sa’ad,

Hema Manusri Vijayan

et al.

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

Published: April 25, 2024

Chimeric antigen receptor-natural killer (CAR-NK) cell therapy is a novel immunotherapy targeting cancer cells via the generation of chimeric receptors on NK which recognize specific antigens. CAR-NK gaining attention nowadays owing to ability release potent cytotoxicity against without side effects such as cytokine syndrome (CRS), neurotoxicity and graft-versus-host disease (GvHD). do not require priming, thus enabling them be used “off-the-shelf” therapy. Nonetheless, still possesses several challenges in eliminating reside hypoxic immunosuppressive tumor microenvironment. Therefore, this review envisioned explore current advancements limitations well discuss strategies overcome faced by This also aims dissect status clinical trials future recommendations for improving effectiveness safety

Language: Английский

Citations

7
Advances in CAR‐Engineered Immune Cell Generation: Engineering Approaches and Sourcing Strategies DOI Creative Commons
Zhaozhao Chen, Yu Hu, Heng Mei

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(35)

Published: Oct. 31, 2023

Abstract Chimeric antigen receptor T‐cell (CAR‐T) therapy has emerged as a highly efficacious treatment modality for refractory and relapsed hematopoietic malignancies in recent years. Furthermore, CAR technologies cancer immunotherapy have expanded from CAR‐T to CAR‐natural killer cell (CAR‐NK), CAR‐cytokine‐induced (CAR‐CIK), CAR‐macrophage (CAR‐MΦ) therapy. Nevertheless, the high cost complex manufacturing processes of ex vivo generation autologous products hampered broader application. There is an urgent need develop efficient economical paradigm shift exploring new sourcing strategies engineering approaches toward generating CAR‐engineered immune cells benefit patients. Currently, researchers are actively investigating various optimize preparation these potent immunotherapeutic agents. In this work, latest research progress summarized. Perspectives on future provided, approaches, diverse sources used their development focused upon.

Language: Английский

Citations

16
The impact of, and expectations for, lipid nanoparticle technology: From cellular targeting to organelle targeting DOI
Yusuke Sato, Takashi Nakamura, Yuma Yamada

et al.

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 370, P. 516 - 527

Published: May 9, 2024

Language: Английский

Citations

6
Next-Generation CEA-CAR-NK-92 Cells against Solid Tumors: Overcoming Tumor Microenvironment Challenges in Colorectal Cancer DOI Open Access
Alexander Sebastian Franzén,

Abdelhadi Boulifa,

Clarissa Radecke

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(2), P. 388 - 388

Published: Jan. 16, 2024

Colorectal carcinoma (CRC) presents a formidable medical challenge, demanding innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has emerged as promising alternative to CAR T-cell for cancer. A suitable tumor target on CRC is carcinoembryonic (CEA), given its widespread expression and role in tumorigenesis metastasis. CEA known be prolifically shed from cells soluble form, thus hindering recognition of tumors migration through the TME. We have developed next-generation construct exclusively targeting cell-associated CEA, incorporating PD1-checkpoint inhibitor CCR4 chemokine enhance homing infiltration CAR-NK-92 line TME, which does not induce fratricidal killing CAR-NK-92-cells. To evaluate this approach, we harnessed intricate 3D multicellular spheroid models (MCTS), emulate key elements Our results demonstrate effective cytotoxicity CEA-CAR-NK-92 against colorectal lines MCTS models. Importantly, minimal off-target activity non-cancerous underscores precision therapy. Furthermore, integration augments by recognizing ligands, CCL17 CCL22. Notably, our design no significant trogocytosis-induced fratricide. In summary, proposed CEA-targeting CAR-NK could offer solution treatment, combining efficacy tailored approach.

Language: Английский

Citations

5
CD44v6 specific CAR-NK cells for targeted immunotherapy of head and neck squamous cell carcinoma DOI Creative Commons
Ioana Sonya Ciulean,

Joe Fischer,

Andrea Quaiser

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 10, 2023

Head and neck squamous cell carcinoma (HNSCC) is a major challenge for current therapies. CAR-T cells have shown promising results in blood cancers, however, their effectiveness against solid tumors remains hurdle. Recently, CD44v6-directed demonstrated efficacy controlling tumor growth multiple myeloma such as HNSCC, lung ovarian adenocarcinomas. Apart from cells, CAR-NK offer safe allogenic alternative to autologous therapy. In this paper, we investigated the capacity of redirected CD44v6 execute cytotoxicity HNSCC. Anti-CD44v6 were generated healthy donor peripheral blood-derived NK using gamma retroviral vectors (gRVs). The transduction was optimized by exploring virus envelope proteins derived baboon endogenous (BaEV), feline leukemia (FeLV, termed RD114-TR) gibbon ape (GaLV), respectively. BaEV pseudotyped gRVs induced highest rate compared RD114-TR GaLV envelopes measured EGFP surface CAR expression transduced cells. showed two- threefold increase killing various HNSCC lines unmodified, cytokine-expanded primary effective eliminating with high low levels. Overall, improved holds promise therapeutic option treatment However, further preclinical trials are necessary test vivo safety, well optimize regimen anti-CD44v6 tumors.

Language: Английский

Citations

11