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Immunotherapy for pediatric solid tumors: overcoming biological barriers through rational multimodal combinations.

Pediatric solid tumors remain among the most treatment-refractory childhood malignancies, defined by biological features that have largely resisted the immunotherapeutic advances transforming adult oncology. Exceptionally low tumor mutational burden, sparse neoantigen landscapes, and profoundly immunosuppressive tumor microenvironments collectively undermine the T cell-dependent mechanisms on which most current immunotherapies depend. Yet the field is undergoing a meaningful shift. Anti-GD2 monoclonal antibodies have established a survival benchmark in high-risk neuroblastoma, and next-generat

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… Pang N, Shi J, Qin L, Chen A, Tang Y, Yang H, Huang Y, Wu Q, Li X, He B (2021) IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J Hematol Oncol 14(1):118 94. …

USP33 Promotes Lung Adenocarcinoma Brain Metastasis by Inhibiting the K48-Linked Ubiquitination and Degradation of S100A9 and Facilitating Vimentin Secretion.

Brain metastasis has a deterministic influence on the evolutionary trajectory of lung adenocarcinoma (LUAD). Given the profound clinical importance of LUAD brain metastases and the formidable obstacles that hinder their precise prediction, novel therapeutic targets are urgently needed. Notably, a substantial fraction of lung carcinoma cells in brain metastatic foci demonstrates marked S100A9 overexpression. However, whether these cells represent the primary drivers of brain metastasis requires further elucidation. Coculture of S100A9-overexpressing LUAD cells with human brain microvascular end

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… Macrophages Under the Influence of Tumor Mesothelin Weaken Host Defenses against Pancreatic Cancer Metastasis. Cancer Res. 2024;84:513–4. doi: 10.1158/0008-5472.CAN-23-4036. 16. Chen JM, He J, Qiu JM, Yang GG, Wang D, Shen Z. …

Engineered cell therapies for autoimmune diseases: evaluating CAR-T and CAR-M progress and prospects.

Autoimmune diseases (AID) comprise a diverse group of disorders driven by aberrant B-cell and T-cell reactivity against self-tissues. In recent years, cell-based therapies utilizing engineered T cells have emerged as a promising therapeutic strategy for AIDs. Notably, chimeric antigen receptor (CAR)-T cells have demonstrated the ability to selectively target and eliminate autoreactive immune populations, including pathogenic B cells and antibody-producing plasma cells. Beyond T-cell modulation, macrophages (MΦs) exhibit remarkable plasticity, differentiating into pro-inflammatory (M1) or anti-

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… A clinical study of autologous chimeric antigen receptor macrophage targeting mesothelin shows safety in ovarian cancer therapy . J Hematol Oncol . ( 2024 ) 17 : 116 . doi: 10.1186/s13045-024-01635-5 , PMID: 39609867 PMC11603993 107 Zhu X Fang Y Chen Y Chen Y Hong W Wei W . …

Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments.

Glioblastoma (GBM) tumors are the most aggressive primary brain tumors in adults that, despite maximum treatment, carry a dismal prognosis. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness and maintenance of glioma stem cells and creates an overall immunosuppressive landscape. This article reviews how hypoxic conditions overlap with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, represent promising avenues f

Integrating oncolytic adenoviruses into combination cancer therapy: Mechanisms, advances and clinical outlook.

BACKGROUND: Cancer represents a major global public health issue, and recent research has focused on improving the efficacy of existing therapeutic approaches. In this context, oncolytic viruses have emerged as promising treatment options for advanced and treatment-resistant malignancies. Among them, adenoviruses are the most extensively studied due to their favourable safety profile, biological versatility and ease of genetic modification to enhance therapeutic performance. MAIN BODY: Combination-based strategies integrating virotherapy with chemotherapy, radiotherapy or immunotherapy have b

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… Pancreatic cancer therapy with combined mesothelin‐redirected chimeric antigen receptor T cells and cytokine‐armed oncolytic adenoviruses. JCI Insight. 2018;3(7):e99573. 10.1172/jci.insight.99573 93. Cervera‐Carrascon V, Siurala M, Santos JM, et al. …

Mechanisms and Functions of γδ T Cells in Tumor Cell Recognition.

γδ T cells are among the first line of defense in the immune system, playing a crucial role in bridging innate and adaptive immunity. Although γδ T cells are crucial for tumor immune surveillance, the complete mechanism by which γδ T cell receptors identify molecular targets in target cells remains unknown. Target cells can produce phosphoantigens (PAgs) via the mevalonate pathway or the methylerythritol phosphate pathway. The BTN3A1-BTN2A1 complex undergoes conformational changes in its extracellular domains upon binding to PAgs, leading to Vγ9Vδ2 T cell recognition. However, the structural b

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… Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors Cell Mol. Immunol. 2021 18 2188 2198 10.1038/s41423-021-00749-x 34381179 PMC8429583 104. Moradi V. Khodabandehloo E. Alidadi M. Omidkhoda A. Ahmadbeigi N. …

Constructing the cure: engineering the next wave of antibody and cellular immune therapies.

Immuno-oncology has revolutionized cancer treatment by mobilizing the immune system to eliminate tumors. Although immune checkpoint inhibitors and T cell therapies have mediated durable responses in hematologic malignancies and select solid tumors, most patients still relapse or fail to respond. To overcome these limitations, novel, next-generation immune constructs, including bispecific-cell therapy combinations, armored cells, tethered cytokines, immune-stimulatory antibody conjugates, and in vivo gene editing, are being developed to enhance specificity, persistence, and immune activation. T

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… 33211575 PMC7957378 230 Choe JH Watchmaker PB Simic MS et al SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma Sci Transl Med 2021 13 10.1126/scitranslmed.abe7378 PMC8362330 33910979 231 Yang Y Vedvyas Y Alcaina Y et al Affinity-tuned mesothelin …

Changing lanes: extending CAR T-cell therapy to high-risk plasma cell dyscrasias.

Chimeric antigen receptor (CAR) cellular therapies have advanced outcomes in challenging hematologic malignancies like leukemia, lymphoma, and multiple myeloma. Plasma cell-directed CAR T-cell therapies have been particularly beneficial in multiple myeloma, suggesting that these agents may have a role in other challenging plasma cell disorders such as systemic AL amyloidosis and plasma cell leukemia. AL amyloidosis is a monoclonal plasma cell disorder resulting in the deposition of protein fibrils that compromise end-organ function. Delays in diagnosis can result in end-organ dysfunction and o

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… Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results. Nat Med. (2023) 29:2099–109. doi: 10.1038/s41591-023-02452-y 15. Chen N, Pu C, Zhao L, Li W, Wang C, Zhu R, et al. …

Навигатор биомаркеров человека.

Биомаркеры играют ключевую роль в современных исследованиях медицины, особенно в ранней диагностике заболеваний и персонализированном лечении. Несмотря на то, что предыдущие исследования систематически обзоры маркеров в различных областях заболеваний, интегрированная система, которая связывает основные физиологические системы, охватывает множество органов и охватывает широкий спектр заболеваний, все еще отсутствует. В контексте современных вызовов здоровья, характеризующихся высокой распространенностью хронических заболеваний и широкими сопутствующими заболеваниями, создание панорамной системы

Antibody drug conjugates in the clinic.

Antibody-drug conjugates (ADCs), chemotherapeutic agents conjugated to an antibody to enhance their targeted delivery to tumors, represent a significant advancement in cancer therapy. ADCs combine the precise targeting capabilities of antibodies and the potent cell-killing effects of chemotherapy, allowing for enhanced cytotoxicity to tumors while minimizing damage to healthy tissues. Here, we provide an overview of the current clinical landscape of ADCs, highlighting 11 U.S. Food and Drug Administration (FDA)-approved products and discussing over 500 active clinical trials investigating newer

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… Tesirine | Cleavable | 1 | Advanced solid tumors | NCT04972981 BAY 94–9343 | MF‐T | DM4 | Maytansinoid | Cleavable | 1 | NSCLC | NCT03455556 SOT102 | Claudin‐18.2 | PNU‐159682 | TOPi | Noncleavable | 1 | Gastric cancer; pancreatic cancer; gastro‐esophageal junction cancer | NCT05525286 BMS‐986148 | Mesothelin …

Current advances of CRISPR-Cas technology in cell therapy.

CRISPR-Cas is a versatile genome editing technology that has been broadly applied in both basic research and translation medicine. Ever since its discovery, the bacterial derived endonucleases have been engineered to a collection of robust genome-editing tools for introducing frameshift mutations or base conversions at site-specific loci. Since the initiation of first-in-human trial in 2016, CRISPR-Cas has been tested in 57 cell therapy trials, 38 of which focusing on engineered CAR-T cells and TCR-T cells for cancer malignancies, 15 trials of engineered hematopoietic stem cells treating hemog

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… CD38 and expression of IL-15/IL-15R fusion protein | iPSC | NCT04614636 Leukemia | CD19 CAR insertion | iPSC | NCT04629729 Solid tumor | PD-1 knockout | T cell | NCT02793856 NCT03081715 NCT03525652 NCT03044743 NCT02863913 NCT04417764 Solid tumor | CISH knockout | T cell | NCT04426669 Solid tumor | Mesothelin-target …

Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy.

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening co

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… Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor. Cell Death Dis. 2019;10:476. doi: 10.1038/s41419-019-1711-1. 21. Zhang E, et al. …

NKG2D CAR-T cells for solid tumor immunotherapy: advances, challenges, and future directions.

Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in hematologic malignancies, but its efficacy in solid tumors remains limited, primarily due to the immunosuppressive tumor microenvironment (TME) that hinders CAR-T cell trafficking and function. NKG2D CAR-T cells, which target stress-induced NKG2D ligands (NKG2DLs) broadly expressed on tumor cells, have shown promising potential in overcoming the immunosuppressive barriers of the solid TME. This review highlights recent advances in NKG2D CAR-T cell strategies for solid tumors, including innovations in CAR archite

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… To further optimize functionality, a modified construct (M28z10) incorporating the DAP10 cytoplasmic domain into a second-generation mesothelin-targeting CAR enhanced cytotoxicity, cytokine secretion (IL-2, IFN-γ, granzyme B), and durable anti-tumor responses in both A549GL xenograft models and patient-derived …

The investigation of oncolytic viruses in the field of cancer therapy.

Oncolytic viruses (OVs) have emerged as a potential strategy for tumor treatment due to their ability to selectively replicate in tumor cells, induce apoptosis, and stimulate immune responses. However, the therapeutic efficacy of single OVs is limited by the complexity and immunosuppressive nature of the tumor microenvironment (TME). To overcome these challenges, engineering OVs has become an important research direction. This review focuses on engineering methods and multi-modal combination therapies for OVs aimed at addressing delivery barriers, viral phagocytosis, and antiviral immunity in

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… Generation of a novel mesothelin-targeted oncolytic herpes virus and implemented strategies for manufacturing . Int J Mol Sci . ( 2021 ) 22 ( 2 ): 477 . doi: 10.3390/ijms22020477 PMC7825047 33418877 68 Granot T Yamanashi Y Meruelo D . …

Retrospective analysis of the preparation and application of immunotherapy in cancer treatment (Review).

Monoclonal antibody technology plays a vital role in biomedical and immunotherapy, which greatly promotes the study of the structure and function of genes and proteins. To date, monoclonal antibodies have gone through four stages: murine monoclonal antibody, chimeric monoclonal antibody, humanised monoclonal antibody and fully human monoclonal antibody; thousands of monoclonal antibodies have been used in the fields of biology and medicine, playing a special role in the pathogenesis, diagnosis and treatment of disease. In this review, we compare the advantages and disadvantages of hybridoma te

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… More importantly, photoimmunotherapy could be applied to a range of cancers simply by altering mAbs in photo-immunoconjugates which have different targets, such as EGFR, HER2, PSMA, CD25, CEA, mesothelin, GPC3, CD47, CD20 and PD-L1 ( 139 , 229 , 238 ). …

Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours.

Central nervous system (CNS) tumours comprise 25% of the paediatric cancer diagnoses and are the leading cause of cancer-related death in children. Current treatments for paediatric CNS tumours are far from optimal and fail for those that relapsed or are refractory to treatment. Besides, long-term sequelae in the developing brain make it mandatory to find new innovative approaches. Chimeric antigen receptor T cell (CAR T) therapy has increased survival in patients with B-cell malignancies, but the intrinsic biological characteristics of CNS tumours hamper their success. The location, heterogen

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… The exosomes derived from CAR-T cell efficiently target mesothelin and reduce triple-negative breast cancer growth Cell. Immunol. 2021 360 104262 10.1016/j.cellimm.2020.104262 33373818 148. Fu W. Lei C. Liu S. Cui Y. Wang C. Qian K. Li T. Shen Y. Fan X. Lin F. …

The next frontier in antibody-drug conjugates: challenges and opportunities in cancer and autoimmune therapy.

Antibody-Drug Conjugates (ADCs) have achieved significant success in cancer therapy by combining the targeting specificity of monoclonal antibodies with cytotoxic payloads. However, the concomitant issue of drug resistance has become increasingly prominent, with primary mechanisms including alterations in target antigen expression, impaired drug transport, and inhibition of cell death pathways. ADCs have also shown emerging therapeutic potential in the treatment of autoimmune diseases; for instance, ABBV-3373 has achieved initial success in this area, yet it also faces unique challenges such a

A Comprehensive Review of Modern Cancer Therapies Utilizing Oncolytic Viruses.

Oncolytic viruses (OVs) are gaining traction as advanced tools in cancer therapy. They are distinguished by their ability to destroy malignant cells while sparing normal tissue specifically. In addition to their direct tumor-lysing properties, an essential benefit of oncolytic virus therapy is its capacity to activate both the innate and adaptive immune systems. To enhance these therapeutic actions, many OVs have been genetically engineered to encode immune-modulating factors that reestablish or strengthen antitumor immune responses. Recent studies show that combining OVs with other forms of i

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… A Phase 1 clinical trial is currently underway, in which the VCN-01 virus is administered intravenously, followed by an infusion of autologous CAR-T anti-mesothelin (huCART-meso) in patients with pancreatic and ovarian cancer ( NCT03740256 ). …

Non-viral approaches in CAR-NK cell engineering: connecting natural killer cell biology and gene delivery.

Natural Killer (NK) cells are exciting candidates for cancer immunotherapy with potent innate cytotoxicity and distinct advantages over T cells for Chimeric Antigen Receptor (CAR) therapy. Concerns regarding the safety, cost, and scalability of viral vectors has ignited research into non-viral alternatives for gene delivery. This review comprehensively analyses recent advancements and challenges with non-viral genetic modification of NK cells for allogeneic CAR-NK therapies. Non-viral alternatives including electroporation and multifunctional nanoparticles are interrogated with respect to CAR

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… Activity of iPSC-NK cells expressing a CAR targeting mesothelin comprising a NKG2D transmembrane domain, 2B4 co-stimulatory domain, and CD3ζ signalling domain (termed CAR-iPSC-NK) were compared to a T-cell based CAR comprising two CD28 domains with 4-1BB (CD137) and CD3ζ (termed T-CAR-NK) in a luciferase-expressing …

Emerging Therapies in the Management of Advanced-Stage Gastric Cancer.

Globally, gastric malignancy contributes to significant cancer-related morbidity and mortality. Despite a recent approval of two targeted agents, trastuzumab and ramucirumab, the treatment options for advanced-stage gastric cancer are limited. Consequently, the overall clinical outcomes for patients with advanced-stage gastric cancer remain poor. Numerous agents that are active against novel targets have been evaluated in the course of randomized trials; however, most have produced disappointing results because of the molecular heterogeneity of gastric cancer. The Cancer Genome Atlas (TCGA) pr

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… A modified form of CRS-207 expresses a tumor associated antigen mesothelin, which is expressed in GC. (Nemunaitis et al., 2008 ). …