CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Jan. 30, 2023

In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This consists of genetically engineered immune cells expressing surface receptor, called CAR, that specifically targets antigens expressed on tumor cells. hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T shown efficacy in treating chemotherapy refractory patients. However, value this remains inconclusive context solid tumors is restrained by several obstacles including limited trafficking infiltration, presence an immunosuppressive microenvironment, well adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) CAR-macrophages (CAR-M) were introduced complement/alternative for tumors. CAR-NK could be favorable substitute since they do not require HLA compatibility have toxicity. Additionally, might generated large scale from sources which would suggest them off-the-shelf product. CAR-M immunotherapy its capabilities phagocytosis, tumor-antigen presentation, broad currently being investigated. Here, we discuss emerging role CAR-T, CAR-NK, We also highlight advantages drawbacks compared Finally, prospective solutions potential combination therapies enhance CAR-cells immunotherapy.

Language: Английский

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Emerging roles of CAR-NK cell therapies in tumor immunotherapy: current status and future directions

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: July 10, 2024

Abstract Cancer immunotherapy harnesses the body’s immune system to combat malignancies, building upon an understanding of tumor immunosurveillance and evasion mechanisms. This therapeutic approach reactivates anti-tumor responses can be categorized into active, passive, combined immunization strategies. Active engages recognize attack cells by leveraging host immunity with cytokine supplementation or vaccination. Conversely, passive employs exogenous agents, such as monoclonal antibodies (anti-CTLA4, anti-PD1, anti-PD-L1) adoptive cell transfers (ACT) genetically engineered chimeric antigen receptor (CAR) T NK cells, exert effects. Over past decades, CAR-T therapies have gained significant traction in oncological treatment, offering hope through their targeted approach. However, potential adverse effects associated including release syndrome (CRS), off-tumor toxicity, neurotoxicity, warrant careful consideration. Recently, CAR-NK therapy has emerged a promising alternative landscape immunotherapy, distinguished its innate advantages over modalities. In this review, we will synthesize latest research clinical advancements therapies. We elucidate benefits employing oncology critically examine developmental bottlenecks impeding broader application. Our discussion aims provide comprehensive overview current status future cancer immunotherapy.

Language: Английский

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CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 9, 2025

Chimeric Antigen Receptor (CAR)-T cell therapy has rapidly emerged as a groundbreaking approach in cancer treatment, particularly for hematologic malignancies. However, the application of CAR-T solid tumors remains challenging. This review summarized development technologies, emphasized challenges and solutions tumors. Also, key innovations were discussed including specialized CAR-T, combination therapies novel use CAR-Treg, CAR-NK CAR-M cells. Besides, CAR-based have extended its reach beyond oncology to autoimmune disorders. We reviewed preclinical experiments clinical trials involving Car-Treg CAAR-T various diseases. By highlighting these cutting-edge developments, this underscores transformative potential CAR technologies practice.

Language: Английский

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Chimeric Cytokine Receptor TGF-β RⅡ/IL-21R Improves CAR-NK Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Gastric Cancer

Pharmacological Research, Journal Year: 2025, Volume and Issue: 212, P. 107637 - 107637

Published: Jan. 29, 2025

Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects advanced stages. Natural killer (NK) cells play crucial role the body's anti-cancer defense, chimeric antigen receptor (CAR)-NK cell therapy is gaining attention as cutting-edge promising treatment method. This study aims to tackle challenge of TGF-β-mediated tumor immune evasion within immunosuppressive microenvironment designing novel cytokine TRII/21R, which consists extracellular domains TGF-β II (TRII) transmembrane intracellular IL-21 (21R) can convert signal from (TME) into an NK activation through IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK expressing TRII/21R demonstrated strong anti-tumor activity against both vitro vivo. The co-expression CAR-NK enhanced cytotoxicity, promoted proliferation capabilities, reduced expression exhaustion markers. In xenograft mouse model, TRII/21R-CAR-NK significantly inhibited growth improved rate tumor-bearing mice compared receiving control cells. Additionally, cells' infiltration, activation, persistence tumor, indicating robust response mediated JAK-STAT3 signaling underscores therapeutic potential TRII/21R-modified breakthrough strategy for combating cancer.

Language: Английский

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Chimeric antigen receptor engineered natural killer cells for cancer therapy

Experimental Hematology and Oncology, Journal Year: 2023, Volume and Issue: 12(1)

Published: Aug. 10, 2023

Abstract Natural killer (NK) cells, a unique component of the innate immune system, are inherent killers stressed and transformed cells. Based on their potent capacity to kill cancer cells good tolerance healthy NK have been successfully employed in adoptive cell therapy treat patients. In recent years, clinical success chimeric antigen receptor (CAR)-T has proven vast potential gene-manipulated as main force fight cancer. Following lessons learned from mature gene-transfer technologies advanced strategies CAR-T therapy, rapidly explored promising candidate for CAR-based therapy. An exponentially growing number studies multiple sources CAR-NK target wide range cancer-related antigens, showing remarkable outcomes encouraging safety profiles. Clinical trials also shown impressive therapeutic efficacy treatment hematological tumors, but solid tumors is still initial stages. this review, we present favorable profile platform engineering then summarize therapies up-to-date preclinical investigations. Finally, evaluate challenges remaining describe existing that can assist us devising future prospective solutions.

Language: Английский

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Natural killer cell-derived exosome-based cancer therapy: from biological roles to clinical significance and implications

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

Published: June 29, 2024

Abstract Natural killer (NK) cells are important immune in the organism and third major type of lymphocytes besides T B cells, which play an function cancer therapy. In addition to retaining tumor cell killing natural cell-derived exosomes also have characteristics high safety, wide source, easy preserve transport. At same time, modify, engineered can be used combination with a variety current therapies, not only enhances therapeutic efficacy, but significantly reduces side effects. Therefore, this review summarizes isolation modification strategies combined application other antitumor is expected accelerate clinical translation process

Language: Английский

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Advancing Immunotherapy in Pancreatic Cancer: A Brief Review of Emerging Adoptive Cell Therapies

Cancers, Journal Year: 2025, Volume and Issue: 17(4), P. 589 - 589

Published: Feb. 9, 2025

Pancreatic cancer has the lowest 5-year survival rate (13%) among major cancers and is third leading cause of cancer-related deaths in United States. The high lethality this attributed to its insidious onset, late-stage diagnosis, rapid progression, limited treatment options. Addressing these challenges requires a deeper understanding complex tumor microenvironment identify novel therapeutic targets. Newer approaches like adoptive cell therapy have shown remarkable success treating hematological malignancies, but their application solid tumors, particularly pancreatic cancer, still early stages development. ACT broadly involves isolating immune cells (T lymphocytes, Natural Killer cells, macrophages) from patient, followed by genetic engineering enhance mount specific anti-tumor response. Various modalities are under investigation for including chimeric antigen receptor T (CAR-T), NK (CAR-NK), tumor-infiltrating lymphocytes (TIL), T-cell (TCR)-engineered cytokine-induced killer (CIK). Major hurdles been identifying actionable antigens delivering focused cellular therapies overcome immunosuppressive dense fibrotic stroma surrounding cancer. Further studies needed explore limitations faced combination order improve clinical outcomes.

Language: Английский

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Low-Dose Non-Targeted Effects and Mitochondrial Control

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(14), P. 11460 - 11460

Published: July 14, 2023

Non-targeted effects (NTE) have been generally regarded as a low-dose ionizing radiation (IR) phenomenon. Recently, regarding long distant abscopal also observed at high doses of IR) relevant to antitumor therapy. IR is inducing NTE involving intracellular and extracellular signaling, which may lead short-ranging bystander long-ranging signaling effects. Internal “spontaneous” cellular stress mostly due metabolic oxidative mitochondrial energy production (ATP) through phosphorylation and/or anaerobic pathways accompanied by the leakage O2− other radicals from mitochondria during normal or increased requirements dysfunction. Among external stressors, has shown very rapidly perturb functions, leading supply demands ROS/NOS production. Depending on dose, this affects all types cell constituents, including DNA, RNA, amino acids, proteins, membranes, perturbing inner organization function, forcing cells reorganize metabolism network organelles. The reorganization implies cytoplasmic-nuclear shuttling important activation autophagy, mitophagy, well induction cycle arrest, DNA repair, apoptosis, senescence. It includes reprogramming genetic epigenetic control expression genes proteins in order ensure tissue survival. At low IR, directly irradiated already exert non-targeted release molecular mediators, such radicals, cytokines, fragments, small RNAs, (sometimes form vehicles exosomes), can induce damage unirradiated neighboring (abscopal) immune responses. Such are contributing phenomena, hormesis, adaptive responses, hypersensitivity, genomic instability, they promoting suppression cells. All these parts main defense systems tissues, IR-induced innate present review focused prominent role processes, determinants survival anti-tumor RT.

Language: Английский

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Soluble programmed death ligand‐1‐induced immunosuppressive effects on chimeric antigen receptor‐natural killer cells targeting Glypican‐3 in hepatocellular carcinoma

Immunology, Journal Year: 2023, Volume and Issue: 169(2), P. 204 - 218

Published: Jan. 14, 2023

Abstract Although the pre‐clinical study of chimeric antigen receptor (CAR)‐natural killer (NK) cell was effective against various tumours, immunosuppression mediated by tumour microenvironment hampers their application and several efforts have been explored to improve effect in combating solid tumours. Glypican 3 (GPC3) is a promising target for hepatocellular carcinoma (HCC), CAR‐T cells targeting GPC3 tested clinical trials. Based on an affinity‐enhanced antibody (hYP7) GPC3, we constructed GPC3‐CAR‐NK explore potential function treatment HCC. We found that patients with HCC secreted high levels soluble programmed death‐ligand 1 (sPD‐L1), which inhibits CAR‐NK GPC3. In addition, combined high‐affinity sPD‐L1 variant (L3C7c‐Fc) solve problem inhibition. Our studies demonstrated L3C7c‐Fc could enhance therapeutic reversing suppression sPD‐L1, provides experimental evidence subsequent development immunotherapy strategies.

Language: Английский

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Therapeutic effect of small extracellular vesicles from cytokine-induced memory-like natural killer cells on solid tumors

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: July 29, 2024

Abstract Small extracellular vesicles (sEV) derived from diverse natural killer (NK) cell lines have proven their exceptional antitumor activities. However, sEV human primary NK cells, especially memory-like are rarely utilized for cancer treatment. In this study, we obtained IL-12, IL-15 and IL-18 cultured cells (mNK-sEV) that showed strong cytokine-secretory ability. It was uncovered mNK-sEV entered via macropinocytosis induced apoptosis caspase-dependent pathway. Compared to conventionally (conNK-sEV), inhibited tumor growth a greater extent. Concomitantly, pharmacokinetics biodistribution results validated higher accumulation of than conNK-sEV in tumors xenografted murine models. Notably, elevated containment granulysin (GNLY) within mNK-sEV, at least part, may contribute the enhanced therapeutic effect. Herein our present can be novel class reagent effective Graphical

Language: Английский

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