The Role of Gamma Delta T Lymphocytes in Physiological and Pathological Condition—Focus on Psoriasis, Atopic Dermatitis, Autoimmune Disorders, Cancer and Lymphomas

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7960 - 7960

Published: July 21, 2024

Gamma delta (γδ) T cells are a heterogeneous population of that play roles in inflammation, host tissue repair, clearance viral and bacterial pathogens, regulation immune processes, tumor surveillance. Recent research suggests these the main skin produce interleukin-17 (I-17). Furthermore, γδ exhibit memory-cell-like characteristics mediate repeated episodes psoriatic inflammation. found epithelial tissues, where many cancers develop. There, they participate antitumor immunity as cytotoxic or coordinators. also defense, surveillance, homeostasis. The aim this review is to present importance physiological pathological diseases, such psoriasis, atopic dermatitis, autoimmune cancer, lymphoma.

Language: Английский

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EGFR-Targeted Antibody–Drug Conjugate to Different Aminobisphosphonates: Direct and Indirect Antitumor Effects on Colorectal Carcinoma Cells

Cancers, Journal Year: 2024, Volume and Issue: 16(7), P. 1256 - 1256

Published: March 22, 2024

Antibody––drug conjugates (ADCs) are a promising delivery system that involves linking monoclonal antibody (mAb) to specific drug, such as cytotoxic agent, target tumor cells. This new class of antitumor therapy acts “biological missile” can destroy cells while increasing the therapeutic index and decreasing toxicity. One most critical factors in ADC design is selecting antigen highly expressed on surface cancer In this study, we conjugated Cetuximab (Cet), targets epidermal growth factor receptor (EGFR), aminobisphosphonates (N-BPs) ibandronate (IBA) or risedronate (RIS) zoledronate (ZA). administered patients with metastatic colorectal carcinoma (mCRC) wild-type (WT) EGFR transduction pathway. Also, it well established N-BPs trigger activity Vδ2 T both vitro vivo experimental models. The resulting ADCs were added co-culture assess effect CRC cell line proliferation sensitivity lymphocytes comparison native antibody. These assays have been performed conventional 3D spheroid cultures. We found all three increase inhibitory WT-EGFR Caco-2 only Cet-RIS Cet-ZA cytotoxicity mediated by against WT EGFR-mutated lines (Caco-2, DLD-1, HCT-116). present peripheral blood specimens. Our findings indicate anti-EGFR antibodies bound improve effects possibly effect.

Language: Английский

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TCR-T cell therapy for solid tumors: challenges and emerging solutions

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: March 10, 2025

With the use of T cell receptor cells (TCR-T cells) and chimeric antigen (CAR-T cells), T-cell immunotherapy for cancer has advanced significantly in recent years. CAR-T therapy demonstrated extraordinary success when used to treat hematologic malignancies. Nevertheless, there are several barriers that prevent this achievement from being applied solid tumors, such as challenges with tumor targeting inadequate transit adaption genetically modified T-cells, especially unfavorable microenvironments The deficiencies treatment tumors compensated by TCR-T cells, which have a stronger homing ability initiate intracellular commands, 90% proteins can be developmental targets, they recognize target antigens more broadly. As result, may effective treating tumors. In review, we discussed structure outlined drawbacks therapy, suggested potential remedies. This review is crucial understanding current state future therapy. We emphasize how important it combinatorial approaches, combining new combinations various emerging strategies over-the-counter therapies designed TCR-T, increase anti-tumor efficacy inside TME maximize safety, comes immunotherapies.

Language: Английский

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γδT cells, a key subset of T cell for cancer immunotherapy

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 28, 2025

γδT cells represent a unique and versatile subset of T characterized by the expression T-cell receptors (TCRs) composed γ δ chains. Unlike conventional αβT cells, do not require major histocompatibility complex (MHC)-dependent antigen presentation for activation, enabling them to recognize respond wide array antigens, including phosphoantigens, stress-induced ligands, tumor-associated antigens. While are relatively rare in peripheral blood, they enriched tissues such as skin, intestine, lung. These play crucial role tumor immunotherapy exerting direct cytotoxicity through production inflammatory cytokines (e.g., interferon-gamma (IFN-γ), necrosis factor-alpha (TNF-α), interleukin-17 (IL-17)) cytotoxic molecules perforin granzyme). Recent advances cell research have elucidated their mechanisms recognition, detection phosphoantigens ligands like MICA (MHC class I polypeptide-related sequence A), MICB B), ULBP (UL16-binding protein). Furthermore, various strategies enhance cell-based been developed, vitro expansion using phosphoantigen-based therapies, cytokine stimulation, chimeric receptor (CAR)-γδT engineering. advancements shown promising results both preclinical clinical settings, paving way become powerful tool cancer immunotherapy. This review highlights key mechanisms, functions, harness potential effective

Language: Английский

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The clinical landscape of CAR-engineered unconventional T cells

Trends in cancer, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Unconventional T cells, such as invariant natural killer (iNKT), γδ T, and mucosal-associated (MAIT) play a pivotal role in bridging innate adaptive immunity. Their capacity for rapid tumor targeting effective modulation of the microenvironment (TME) makes them promising candidates cancer immunotherapy. Advances chimeric antigen receptor (CAR) engineering have further highlighted their therapeutic potential, particularly treating challenging cancers. Notably, these cells exhibit favorable safety profiles, enhancing viability off-the-shelf options. We provide comprehensive analysis clinical applications CAR-engineered unconventional focusing on genetic modifications, manufacturing processes, preconditioning regimens, dosing strategies. discuss successful examples from recent trials explore future directions utilizing therapy beyond.

Language: Английский

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Tricking the Trickster: Precision Medicine Approaches to Counteract Leukemia Immune Escape after Transplant

Blood, Journal Year: 2024, Volume and Issue: 143(26), P. 2710 - 2721

Published: May 10, 2024

Language: Английский

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A positive take on negative selection for CAR-T manufacturing

Molecular Therapy — Methods & Clinical Development, Journal Year: 2024, Volume and Issue: 32(1), P. 101218 - 101218

Published: March 1, 2024

Adoptive immunotherapy with engineered T cells has progressed at a lightning pace, resulting in approved indications for B cell malignancies, such as leukemia, lymphoma, and multiple myeloma, both pediatric adult populations. Due to this rapid many fundamental questions have yet be adequately addressed, including seemingly obvious one: which should we use? While the processes commercial chimeric antigen receptor (CAR)-T manufacturing remain trade secret, team of investigators National Institutes Health, led by Dr. Steven Highfill, begun pull back curtain. Song et al. demonstrate that how are selected genetic engineering leads differences collection phenotypes broadly grouped "T cells" well activation state these cells.1Song H.W. Benzaoui M. Dwivedi A. Underwood S. Shao L. Achar Posarac V. Remley V.A. Prochazkova Cai Y. al.Manufacture CD22 following positive versus negative selection results distinct cytokine secretion profiles γδ output.Mol Ther Methods Clin Dev. 2024; 32101171https://doi.org/10.1016/j.omtm.2023.101171Abstract Full Text PDF PubMed Google Scholar This implications success CAR-T cells, activity against disease, toxicity associated therapy. begins large number peripheral blood mononuclear (PBMCs), usually means leukapheresis. Following leukapheresis, one may proceed directly centrifugation over density gradient media, fractionated PBMC population majority platelets, granulocytes, serum removed. The comprised monocytes, natural killer lymphocytes, lymphocytes. At stage, can begin. However, some types been demonstrated detrimental. Work group NIH others clearly presence myeloid (expressing CD14 surface marker) inhibit expansion during manufacturing.2Stroncek D.F. Ren J. Lee D.W. Tran Frodigh S.E. Sabatino Khuu H. Merchant M.S. Mackall C.L. Myeloid concentrates cells.Cytotherapy. 2016; 18: 893-901https://doi.org/10.1016/j.omtm.2023.101171Abstract Scholar,3Wang Tsao S.-T. Gu Fu C. He F. Li X. Zhang N. Hu H.-M. A simple effective method purify activate successful generation (CAR-T) from patients high monocyte count.J. Transl. Med. 2022; 20: 608https://doi.org/10.1016/j.omtm.2023.101171Abstract Researchers University Pennsylvania that, on occasion, transduced CAR-encoding gene vector—resulting leukemia target (CD19) down-modulated virtue co-expressing CD19-specific CAR, render leukemic resistant very CAR designed treat them.4Ruella Xu Barrett D.M. Fraietta J.A. Reich T.J. Ambrose D.E. Klichinsky Shestova O. Patel P.R. Kulikovskaya I. al.Induction resistance therapy transduction single cell.Nat. 2018; 24: 1499-1503https://doi.org/10.1016/j.omtm.2023.101171Abstract Scopus (0) Thus, need remove is paramount Further purification starting approached either or selection. Positive uses antibody-coated beads an iron core used select passing treated through column other matrix magnetic field. Smaller biodegradable matrices embedded particles antibody also advantage not having removed population. Negative refers selecting away unwanted populations leaving desired untouched. aspect ability specify markers will most often employs containing anti-CD4 anti-CD8 antibodies, thus only expressing markers. It would seem added specificity exactly what required. there two caveats. first anytime bound, it potential signal being selected. why CD3-based binding never positively In report al., was using CD4 CD8 approaches does impact biology. previous reports shown engaging increases basal level Erk phosphorylation 3-fold higher expression CXCR4 account levels administered, especially given interferon γ interleukin-8 production population, demonstrate.5Bernard Jaleco Dardalhon Steinberg Yssel Noraz Taylor Kinet Ex vivo isolation protocols differentially affect phenotype human CD4+ cells.J. Immunol. Methods. 2002; 271: 99-106https://doi.org/10.1016/s0022-1759(02)00412-xCrossref Scholar,6Shah N.N. Highfill S.L. Shalabi Yates B. Jin Wolters P.L. Ombrello S.M. Martin Delbrook al.CD4/CD8 T-Cell affects (CAR) potency toxicity: updated phase I anti-CD22 T-cell trial.J. Clin. Oncol. 2020; 38: 1938-1950https://doi.org/10.1200/JCO.19.03279Crossref (251) side further highlighted report. Cell assigned anti-tumor left notably cells. malignancy, recently reviewed Wang area active investigation, generally viewed positive.7Wang C.Q. Lim P.Y. Tan A.H.-M. Gamma/delta cellular vehicles immunity.Front. 2023; 141282758https://doi.org/10.3389/fimmu.2023.1282758Crossref their lack αβ receptor, tested additions allogenic protocols. They substrates mediators antibody-guided redirected killing (Table 1). do definitively prove association anti-leukemic effect, "untouched" comes along ride effect mediated expression, they show express serve killers vitro.Table 1Inclusion enhances immunityγδ therapyIndicationReference/clinical trialNeuroblastomaγδ anti-GD2 (dinutuximab) therapyNCT05400603, Jonus al.9Jonus H.C. Burnham R.E. Ho Pilgrim A.A. Shim Doering C.B. Spencer H.T. Goldsmith K.C. Dissecting components ex expansions optimize potent donors neuroblastoma trials.OncoImmunology. 112057012Crossref (9) ScholarAllo-HSCTinfusion post-transplant cyclophosphamideNCT03533816, McGuirk 2023, ASH no. 4853AML post-allo-HSCTpresence bone marrow complete responseMathioudaki al.10Mathioudaki Sedloev D.N. Huth R. Kamal Hundemer Liu Vasileiou Lulla P.D. Müller-Tidow remission status AML post alloSCT single-cell signature.Blood. (blood.2023021815)Crossref ScholarSpatial biology investigationcolorectal carcinoma tissue studyHerold al.11Herold Bruhns Babaei Spreuer Castagna Yurttas Scheuermann Seitz Ruf Königsrainer High-dimensional situ proteomics imaging assess spatial biology.J. Leukoc. Biol. 29qiad167Google ScholarCD7 CAR-TT leukemia/lymphomaNCT04702841NKG2DL CAR-Tsolid tumors heme-malignanciesNCT05302037CD19 CAR-TB-ALL CLLNCT02656147 Open table new tab investigative carried out work established track record iterative improvement therapeutic analysis its impact. Here, us important ways analyze donor variability, normalization according protocol, again "process product" manufacturing, opened door innovation. limited pre-determined mix depletion supplier. changing antibodies approach difficult due requirement good practice sourcing, beginning evaluate optimized simplified.8Xiong Xie Zhu Z. Oparaocha Sleesareva Dropulić Orentas Technological innovation drive improved access therapies.Med. Res. Arch. 11: 11https://doi.org/10.18103/mra.v11i11.4759Crossref Given chance define opens continued investigation contribution different make anti-cancer R.J.O. serves scientific advisory board Umoja Biopharma Galapagos NV.

Language: Английский

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Engineered NKG2C+ NK-like T cells exhibit superior antitumor efficacy while mitigating cytokine release syndrome

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

Published: July 19, 2024

Engineered T and NK cell therapies have widely been used to treat hematologic malignancies solid tumors, with promising clinical results. Current chimeric antigen receptor (CAR) therapeutics have, however, associated treatment-related adverse events such as cytokine release syndrome (CRS) are prone immunologic exhaustion. CAR-NK therapeutics, while not CRS, limited in vivo persistence. We now demonstrate that an NK-like TCRαβ

Language: Английский

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Finding potential targets in cell-based immunotherapy for handling the challenges of acute myeloid leukemia

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

Published: Sept. 30, 2024

Acute myeloid leukemia (AML) is a hostile hematological malignancy under great danger of relapse and poor long-term survival rates, despite recent therapeutic advancements. To deal with this unfulfilled clinical necessity, innovative cell-based immunotherapies have surfaced as promising approaches to improve anti-tumor immunity enhance patient outcomes. In comprehensive review, we provide detailed examination the latest developments in for AML, including chimeric antigen receptor (CAR) T-cell therapy, (TCR)-engineered natural killer (NK) therapies. We critically evaluate unique mechanisms action, current challenges, evolving strategies efficacy safety these modalities. The review emphasizes how cutting-edge immune-based are overcoming inherent complexities heterogeneity AML. discuss identification optimal target antigens, importance mitigating on-target/off-tumor toxicity, need persistence functionality engineered immune effector cells. All things considered, offers thorough overview rapidly field immunotherapy underscoring significant progress made ongoing efforts translate into more effective durable treatments devastating disease.

Language: Английский

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Innovative Cancer Immunotherapy with MAGE-A3 mRNA Cancer Vaccines

Cancers, Journal Year: 2024, Volume and Issue: 16(19), P. 3428 - 3428

Published: Oct. 9, 2024

Cancer causes over 10 million deaths annually worldwide and remains a significant global health challenge. This study investigated advanced immunotherapy strategies, focusing on mRNA vaccines that target tumor-specific antigens to activate the immune system. We developed novel vaccine using O,O'-dimyristyl-N-lysyl aspartate (DMKD) improve stability phosphatidylserine (PS) enhance antigen presentation cells. vaccine, containing melanoma-associated A3 (MAGE-A3) encapsulated within lipid nanoparticles (LNPs), was evaluated for its therapeutic potential against colorectal cancer. Our findings demonstrated MAGE-A3 mRNA-containing DMKD-PS LNPs significantly reduced tumor size weight, effectively combating metastatic The elicited robust response, increasing specific immunoglobulin cytokine levels without causing histotoxicity in major organs. These results confirm DMKD-PS-based holds promise cancer prevention treatment.

Language: Английский

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