Chimeric antigen receptor macrophages targeting c-MET(CAR-M-c-MET) inhibit pancreatic cancer progression and improve cytotoxic chemotherapeutic efficacy DOI Creative Commons

Huaijin Zheng,

Xinzhe Yang,

Nan Huang

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Dec. 6, 2024

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors. Macrophages are abundant in tumor microenvironment, making them an attractive target for therapeutic intervention. While current immunotherapies, including immune checkpoint inhibition (ICI) and chimeric antigen receptor T (CAR-T) cells, have shown limited efficacy pancreatic cancer, a novel approach involving macrophages (CAR-M) has, although promising, not been explored cancer. In this study, we first investigated role CAR-M cells targeting c-MET The effectiveness rationality as cancer were validated through bioinformatic analyses immunohistochemical staining samples from patients. We utilized flow cytometry bioluminescence detection methods to demonstrate specific binding phagocytic killing effect on cells. Additionally, observed process engulfing using confocal microscopy long-term fluorescence live cell imaging system. situ model transplanted into NOD/SCID mice, administered intraperitoneal injections confirm its inhibitory function Furthermore, these findings human monocyte-derived (hMDM). Bioinformatics tissue microarray revealed significantly higher expression levels tissues, compared paired peritumoral correlated with worse patient survival. engineered monocytic THP-1 line hMDM (CAR-M-c-MET). CAR-M-c-MET demonstrated highly exhibited more phagocytosis abilities than pro-inflammatory polarized control macrophages. addition, synergized various cytotoxic chemotherapeutic drugs. murine model, intraperitoneally injected rapidly migrated substantially inhibited growth, which did lead obvious side effects. Cytokine arrays mRNA sequencing showed that produced activators This study provides compelling evidence safety therapy treating results suppresses progression enhances chemotherapy. Remarkably, no discernible effects occur. Further clinical trials warranted

Language: Английский

Emerging Therapeutic Strategies to Overcome Drug Resistance in Cancer Cells DOI Open Access
Pankaj Garg, Jyoti Malhotra, Prakash Kulkarni

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(13), P. 2478 - 2478

Published: July 7, 2024

The rise of drug resistance in cancer cells presents a formidable challenge modern oncology, necessitating the exploration innovative therapeutic strategies. This review investigates latest advancements overcoming mechanisms employed by cells, focusing on emerging modalities. intricate molecular insights into resistance, including genetic mutations, efflux pumps, altered signaling pathways, and microenvironmental influences, are discussed. Furthermore, promising avenues offered targeted therapies, combination treatments, immunotherapies, precision medicine approaches highlighted. Specifically, synergistic effects combining traditional cytotoxic agents with molecularly inhibitors to circumvent pathways examined. Additionally, evolving landscape immunotherapeutic interventions, immune checkpoint adoptive cell is explored terms bolstering anti-tumor responses evasion mechanisms. Moreover, significance biomarker-driven strategies for predicting monitoring treatment underscored, thereby optimizing outcomes. For future direction paradigms, current focused prevailing challenges improving patient outcomes, through an integrative analysis these

Language: Английский

Citations

49
Antigen escape in CAR-T cell therapy: Mechanisms and overcoming strategies DOI Open Access
Haolong Lin,

Xiuxiu Yang,

Shanwei Ye

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 178, P. 117252 - 117252

Published: Aug. 3, 2024

Chimeric antigen receptor T (CAR-T) cell therapy has shown promise in treating hematological malignancies and certain solid tumors. However, its efficacy is often hindered by negative relapses resulting from escape. This review firstly elucidates the mechanisms underlying escape during CAR-T therapy, including enrichment of pre-existing target-negative tumor clones, gene mutations or alternative splicing, deficits processing, redistribution, lineage switch, epitope masking, trogocytosis-mediated loss. Furthermore, we summarize various strategies to overcome escape, evaluate their advantages limitations, propose future research directions. Thus, aim provide valuable insights enhance effectiveness therapy.

Language: Английский

Citations

14
The next frontier in immunotherapy: potential and challenges of CAR-macrophages DOI Creative Commons
Jing Li,

Ping Chen,

Wenxue Ma

et al.

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: Aug. 5, 2024

Abstract Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers promising approach to target and eradicate tumor cells by utilizing macrophages’ phagocytic antigen-presenting abilities. However, challenges such as the complex microenvironment (TME), variability expression, immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of action, optimal construct designs, interactions within TME. It also delves into ex vivo manufacturing CAR-MΦ, discussing autologous allogeneic sources importance stringent quality control. The potential synergies integrating with existing cancer like checkpoint inhibitors conventional chemotherapeutics are examined highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways scrutinized alongside established protocols cells, identifying unique considerations essential clinical trials market approval. Proposed safety monitoring frameworks aim manage adverse events, cytokine release syndrome, crucial patient safety. Consolidating current research insights, this seeks refine therapeutic applications, overcome barriers, suggest future directions transition from experimental platforms standard care options.

Language: Английский

Citations

13
Exploring CAR-macrophages in non-tumor diseases: Therapeutic potential beyond cancer DOI Creative Commons

Yizhao Chen,

Qianling Xin,

Mengjuan Zhu

et al.

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

After significant advancements in tumor treatment, personalized cell therapy based on chimeric antigen receptors (CAR) holds promise for transforming the management of various diseases. CAR-T therapy, first approved CAR product, has demonstrated therapeutic potential treating infectious diseases, autoimmune disorders, and fibrosis. CAR-macrophages (CAR-Ms) are emerging as a promising approach immune particularly solid highlighting feasibility using macrophages to eliminate pathogens abnormal cells.

Language: Английский

Citations

2
CAR-macrophage: Breaking new ground in cellular immunotherapy DOI Creative Commons

Ting Huang,

Chenqi Bei,

Zhenhua Hu

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: Oct. 3, 2024

Chimeric Antigen Receptor (CAR) technology has revolutionized cellular immunotherapy, particularly with the success of CAR-T cells in treating hematologic malignancies. However, have limited efficacy against solid tumors. To address these limitations, CAR-macrophages (CAR-Ms) leverage innate properties macrophages specificity and potency CAR technology, offering a novel promising approach to cancer immunotherapy. Preclinical studies shown that CAR-Ms can effectively target destroy tumor cells, even within challenging microenvironments, by exhibiting direct cytotoxicity enhancing recruitment activation other immune cells. Additionally, favorable safety profile their persistence tumors position as potentially safer more durable therapeutic options compared This review explores recent advancements including engineering strategies optimize anti-tumor preclinical evidence supporting use. We also discuss challenges future directions developing therapies, emphasizing potential revolutionize By harnessing unique macrophages, offer groundbreaking overcoming current limitations cell paving way for effective sustainable treatments.

Language: Английский

Citations

8
Macrophages: a double-edged sword in female reproduction and disorders DOI Creative Commons

Mira Park,

Yeon Sun Kim,

Haengseok Song

et al.

Experimental & Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Reproduction consists of sequential inflammation-like events, primarily within the endometrium, from ovulation to embryo implantation, decidualization and delivery. During reproductive cycle, endometrium repeatedly undergoes cyclic periods proliferation, differentiation, tissue breakdown repair without scarring. Owing their phagocytic activity, macrophages, key players in innate immunity, are thought play crucial roles endometrium. Endometrial macrophages actively participate various stages remodeling, particularly during pregnancy establishment. Traditionally considered simple bystanders that clear debris prevent autoimmune responses homeostasis, now recognized as main actors with broad functional plasticity allows them fine tune balance between pro- anti-inflammatory inflammation, remodeling repair. Homeostatic is determined by sum mediators produced two distinctly polarized macrophage subpopulations. The biased polarization tissue-resident may contribute pathogenesis diseases, such inflammation cancer. Thus, understanding how endometrial homeostasis for deciphering underlying mechanisms disorders. Nanomedicines using extracellular vesicles, nanoparticles noncoding RNAs have recently been applied modulate alleviate disease phenotypes. Despite these advances, functions under physiological pathophysiological conditions remain poorly understood, which complicates development targeted therapies. Here we update current homeostatic function putative contribution dysfunction disorders women, along innovative molecular therapeutics resolve this issue.

Language: Английский

Citations

1
Intraperitoneal programming of tailored CAR macrophages via mRNA-LNP to boost cancer immunotherapy DOI Creative Commons
Sitao Xie,

Kedan Gu,

Ting Liang

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Abstract Therapeutic strategies for peritoneal metastasis in solid tumors are urgently needed the clinic. Programming chimeric antigen receptor macrophages (CAR-Ms) in situ offers opportunities an unmet demand. However, potential intracellular domains (ICDs) CAR design and their antitumor mechanisms macrophage empowerment remain to be explored systematically. By developing a targeted mRNA-LNP delivery system macrophages, we have investigated 36 combinations determine impact of CAR-Ms on immune regulation vitro vivo. In two tumor mouse models, intraperitoneal programming was shown elicit robust adaptive activation significantly synergize with PD-1/L1 therapy. Single-cell RNA sequencing (scRNA-seq) analysis revealed that could reshape immunosuppressive microenvironment (TME) boost TCF1+PD-1+ progenitor-exhausted CD8+ T cells (Tpex) population. Meanwhile, found tailored CAR-M CD3ζ/TLR4 ICDs favorably maintain proinflammatory phenotype simultaneously upregulate MHC I PD-L1 expression by perturbing NF-κB pathways. Moreover, synergism between knockdown therapy highlighted need block axis cross-presentation. short, developed vivo broadened understanding both regulatory feedback therapies against tumors.

Language: Английский

Citations

1
Are monocytes a preferable option to develop myeloid cell-based therapies for solid tumors? DOI Creative Commons

Daisy Bhatia,

Riccardo Dolcetti, Roberta Mazzieri

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: March 15, 2025

Abstract In the last two decades, novel and promising cell-based therapies have populated treatment landscape for haematological tumors. However, commonly exploited T NK show limited applicability to solid This is mainly given by impaired tumor trafficking capability effector activity of these cells within a highly immunosuppressive microenvironment. Myeloid spontaneously home tumors can thus be reprogrammed and/or engineered directly attack or locally selectively deliver therapeutically relevant payloads that may improve efficacy immunotherapy against difficult-to-access context myeloid therapies, adoptive transfer monocytes has often been overshadowed infusion differentiated macrophages hematopoietic stem cell transplantation despite their therapeutic potential. Here, we summarize recent improvements benefits using tumors, current clinical applications challenges use as well some possible strategies overcome them.

Language: Английский

Citations

1
Immunocyte membrane-derived biomimetic nano-drug delivery system: a pioneering platform for tumour immunotherapy DOI

Y Zeng,

Qing Gu, Dan Li

et al.

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: 45(12), P. 2455 - 2473

Published: July 31, 2024

Language: Английский

Citations

5
Intraperitoneal programming of tailored CAR macrophages via mRNA-LNP to boost cancer immunotherapy DOI Creative Commons

Kedan Gu,

Ting Liang,

Luting Hu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 30, 2024

ABSTRACT Therapeutic strategies for peritoneal metastasis in solid tumors are urgently needed the clinic. Programming chimeric antigen receptor macrophages (CAR-Ms) situ offers opportunities an unmet demand. However, potential intracellular domains (ICDs) CAR design and their antitumor mechanisms macrophage empowerment remain to be explored systematically. By developing a targeted mRNA-LNP delivery system macrophages, we have investigated 36 combinations determine impact of CAR-Ms on immune regulation vitro vivo . In two tumor mouse models, intraperitoneal programming was shown elicit robust adaptive activation significantly synergize with PD-1/L1 therapy. Single-cell RNA sequencing (scRNA-seq) analysis revealed that could reshape immunosuppressive microenvironment (TME) boost TCF1 + PD-1 progenitor- exhausted CD8 T cells (Tpex) population. Meanwhile, found tailored CAR-M CD3ζ/TLR4 ICDs favorably maintain proinflammatory phenotype simultaneously upregulate MHC I PD-L1 expression by perturbing NF-κB pathways. Moreover, synergism between knockdown therapy highlighted need block axis cross-presentation. short, developed broadened understanding both regulatory feedback therapies against tumors.

Language: Английский

Citations

3