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Facing challenges with hope: universal immune cells for hematologic malignancies.

Many patients have achieved a favorable overall survival rate since allogenic hematopoietic stem cell transplantation (allo-HSCT) has been widely implemented to treat hematologic malignancies. However, graft-versus-host disease (GVHD) and complications of immunosuppressive drugs after allo-HSCT are the main causes of non-relapse mortality and a poor quality of life. In addition, GVHD and infusion-induced toxicity still occur with donor lymphocyte infusions (DLIs) and chimeric antigen receptor (CAR) T-cell therapy. Because of the special immune tolerance characteristics and anti-tumor ability o

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… In contrast to conventional T cells, NKT cells possess characteristics of NK cells, including expression of NK cell markers (CD16 and CD56) and secretion of granzyme and perforin. …

The Trinity: Interplay among Cancer Cells, Fibroblasts, and Immune Cells in Pancreatic Cancer and Implication of CD8+ T Cell-Orientated Therapy.

The microenvironment in tumors is complicated and is constituted by different cell types and stromal proteins. Among the cell types, the abundance of cancer cells, fibroblasts, and immune cells is high and these cells work as the "Trinity" in promoting tumorigenesis. Although unidirectional or bidirectional crosstalk between two independent cell types has been well characterized, the multi-directional interplays between cancer cells, fibroblasts, and immune cells in vitro and in vivo are still unclear. We summarize recent studies in addressing the interaction of the "Trinity" members in the tu

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… While CD8 + T cell infiltration was not increased, its functions regrading memory subset and IFNγ/perforin expression were all boosted. In addition to IL6 and TGFβ, CXCR4-mediated signaling also affects pancreatic cancer treatment significantly. …

Chemokines in COPD: From Implication to Therapeutic Use.

: Chronic Obstructive Pulmonary Disease (COPD) represents the 3rd leading cause of death in the world. The underlying pathophysiological mechanisms have been the focus of extensive research in the past. The lung has a complex architecture, where structural cells interact continuously with immune cells that infiltrate into the pulmonary tissue. Both types of cells express chemokines and chemokine receptors, making them sensitive to modifications of concentration gradients. Cigarette smoke exposure and recurrent exacerbations, directly and indirectly, impact the expression of chemokines and chem

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… a decline of lung function in COPD patients is associated with a high percentage of T cells that express CXCR3 [ 115 ], suggesting that CXCL9, CXCL10, and CXCL11 may be involved in the recruitment of T cells and the subsequent immune mediated lung damage observed in COPD, through the production of perforins …

Esid 2014 oral presentations.

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Advancing CAR T-Cell Therapy in Solid Tumors: Current Landscape and Future Directions.

BackgroundChimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment of hematological malignancies, yet its application in solid tumors remains constrained by unique biological and logistical barriers.ObjectiveThis review critically examines the evolving landscape of CAR T-cell therapy in solid malignancies, with a focus on antigen heterogeneity, the immunosuppressive tumor microenvironment, and risks of on-target, off-tumor toxicity.MethodsWe outline recent advances in CAR engineering, including co-stimulatory optimization, dual- and multi-antigen targeting, armored CARs, an

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… The primary cytotoxic effects of activated CAR-T-cells are mediated by the release of granule proteins, such as perforin and granzymes, which induce apoptosis in target cancer cells. … This interaction triggers T-cell activation, cytokine production (e.g., IFN-γ, IL-2), and release of cytotoxic granules (perforin, granzyme B) to mediate tumor cell lysis [ 42 , 43 ]. …

The progress of novel strategies on immune-based therapy in relapsed or refractory diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) can be cured with standard front-line immunochemotherapy, whereas nearly 30-40% of patients experience refractory or relapse. For several decades, the standard treatment strategy for fit relapsed/refractory (R/R) DLBCL patients has been high-dose chemotherapy followed by autologous hematopoietic stem cell transplant (auto-SCT). However, the patients who failed in salvage treatment or those ineligible for subsequent auto-SCT have dismal outcomes. Several immune-based therapies have been developed, including monoclonal antibodies, antibody-drug conjugates, b

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… BsAbs function by bringing targeted tumor cells close to T-cells to allow killing via perforin and granzyme release ( b ). … CAR NK cells will release perforin and granzymes to kill tumor cells ( c ). …

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response.

Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatm

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… binding of the T-cell surface receptor (TCR) to the antigenic peptide-major histocompatibility complex (MHC). 11 , 12 The second signal is mediated by the communication of T cells with costimulatory molecules (CMs) on the surface of antigen-presenting cells (APCs). 13 These “primed” T cells can produce perforin … Mechanistically, NK cells play a key role in the first line of defense against cancer, mediating antitumor effects through two pathways: direct cytotoxicity through the release of post-perforin and granzyme or death receptors and the regulatory effect by secreting cytokines and chemokines that activate …

Therapeutic Antibodies for Myeloid Neoplasms-Current Developments and Future Directions.

Therapeutic monoclonal antibodies (mAbs) such as antibody-drug conjugates, ligand-receptor antagonists, immune checkpoint inhibitors and bispecific T cell engagers have shown impressive efficacy in the treatment of multiple human cancers. Numerous therapeutic mAbs that have been developed for myeloid neoplasms, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are currently investigated in clinical trials. Because AML and MDS originate from malignantly transformed hematopoietic stem/progenitor cells-the so-called leukemic stem cells (LSCs) that are highly resistant to

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… Anti-PD-1 and anti-PD-L1/2 mAbs (nivolumab, pembrolizumab, atezolizumab, durvalumab, PDR001, etc.) and anti-TIM-3 mAbs (MBG453) prevent the exhaustion of AML-specific CTLs and improve AML cell killing via perforin/granzyme. … Upon activation, NK cells secrete immunostimulatory cytokines, such as IFN-γ, and can directly kill target cells via perforin/granzyme B. NK cell activity is tightly regulated by the integration of stimulatory and inhibitory signals expressed on potential target cells (Figure 3 E) ( 268 ). …

Combination Immunotherapy as a Promising Strategy to Overcome Immunotherapy Resistance: From Emergence to Next-Generation Approaches.

Advances in immunotherapy, particularly with immune checkpoint inhibitors, have improved clinical outcomes in various cancer subtypes; however, resistance often occurs because these treatments rely on single agents and show limited translational success when combined. Therefore, it is necessary to develop immune checkpoint inhibitor-based combination strategies by integrating next-generation immunotherapies and innovative biomarkers. This review highlights the emerging combinatorial approaches that can be tailored to the distinct tumor microenvironment types to overcome resistance to immune ch

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… In the TME, IFNγ has dual roles: it can promote tumor destruction by acting as a cytotoxic cytokine with granzyme B and perforin, but it can also support immune suppression by stimulating production of checkpoint molecules like PD‐L1, IDO, PD–L2, CTLA4, and Foxp3 [ 31 ], which reduce the tumor‐killing … In response, cytotoxic T lymphocytes (CTLs) are primed and activated, followed by effector T cells killing of tumor cells in the presence of IFNγ, TNFα, granzyme B, and perforin, which generates effector memory T cells. …

Translational strategy to support the first-in-human study of a TCR-like T cell bispecific with an in vitro-based safety approach.

The nonclinical development of T-cell receptor (TCR)-based therapeutics is uniquely challenged by the human-exclusive specificity of the peptide-HLA target, rendering conventional animal models unsuitable for safety assessment. To support first-in-human (FIH) studies in patients with solid tumors with the novel TCR-like T Cell Bispecific (TCB) antibody MAGE-A4-TCB, targeting the MAGE-A4 peptide presented by HLA-A*02:01 and engaging T-cells via the CD3ϵ chain, we implemented a comprehensive, prediction-independent safety strategy relying on New Approach Methodologies (NAMs). This approach utili

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… This connects the tumor cell to a T cell, resulting in T-cell activation, release of cytokines like IL-2, interferon-gamma, and tumor necrosis factor-alpha, and secretion of granzymes and perforin. …

CAR-T cell therapy: A new dawn in the treatment of autoimmune disease.

Autoimmune diseases (AIDs) are a class of diseases caused by autoimmune intolerance, which can be divided into systemic and organ-specific diseases. AIDs affect approximately 10% of the global population and rank among the leading causes of disability and mortality. At present, immunosuppressive agents are the first choice for the treatment of AIDs. B-cell-targeted therapies-particularly CD20 monoclonal antibodies-have brought new hope for systemic AIDs, yet a subset of patients still respond poorly. As a rapidly developing cellular immunotherapy technology, Chimeric antigen receptor T cell (C

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… (a) After specifically recognizing the surface antigens of B cells, such as CD19 or B cell mature antigen (BCMA), chimeric antigen receptor T cell (CAR-T) can directly induce apoptosis of B cells by secreting perforin and granase and can also secrete cytokines to recruit immune cells and kill B cells …

Advances in cancer immunotherapy and future directions in personalized medicine.

Cancer immunotherapy has revolutionized oncologic treatment by harnessing and reprogramming the immune system to target malignant cells. This review provides a comprehensive picture of modern approaches to immunotherapy-based treatment strategies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor T cells, mRNA vaccines, and biomaterials-based platforms, with a focus on their translational value and application to precision medicine. Emerging insights into the tumor microenvironment, immune resistance mechanisms, and T-cell subpopulation dynamics (e.g., γδ T cells, exhauste

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… Cytotoxic T cells then induce the apoptosis of cancer cells through such actions as granzyme and perforin-mediated activities. …

Circadian clocks and adaptive immune function: from mechanisms to therapeutic applications.

The circadian clock exerts profound regulatory control over adaptive immunity, particularly affecting T and B lymphocyte development, trafficking, activation, and effector function. These immune cells possess autonomous molecular clocks governed by core genes such as Bmal1, Clock, Per1/2, and Cry1/2, which influence transcriptional programs related to receptor expression, cytokine signaling, and metabolism. Circadian regulation shapes the daily oscillation of lymphocyte recirculation through lymphoid organs, modulates antigen responsiveness, and fine-tunes subset differentiation-most notably s

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… during the day when T cells are most immunoreactive-by regulating the rhythmic expression of surface receptors (e.g., TCR, Interleukin-2 Receptor (IL-2R), CD28, CXCR4), signaling kinases (Zeta-chain-associated protein kinase 70 (ZAP70), Akt, mTOR), and effector molecules (e.g., Interferon-γ (IFN-γ), perforin …

T-клеток, перенаправляющих терапию на рецидив миеломы.

В последние годы использование иммуномодуляционных препаратов, протеиозных ингибиторов и CD38, направленных против моноклонных антител, привело к значительному улучшению общих результатов пациентов с множественной миеломой. Несмотря на эти достижения, рецидивы остаются обычным явлением, и до недавнего времени прогнозы таких пациентов охранялись. Одобрение T-клеток химерика антигенного рецептора (CAR) и Т-комплексов (TCE) значительно повысило выживаемость этих пациентов с тройной и пента-классовой рефракторной болезнью. В настоящем документе рассматриваются клинические результаты, связанные с э

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… TCE binding redirects T-cells into the tumor microenvironment and initiates T-cell activation and downstream T-cell mediated tumor cell killing by the release of granzymes, perforins and pro-inflammatory cytokines [ 2 ]. …

Acute Generalized Exanthematous Pustulosis: Clinical Features, Differential Diagnosis, and Management.

Acute generalized exanthematous pustulosis (AGEP) is a rare, acute, severe cutaneous adverse reaction mainly attributed to drugs, although other triggers, including infections, vaccinations, ingestion of various substances, and spider bites, have also been described. AGEP is characterized by the development of edema and erythema followed by the eruption of multiple punctate, non-follicular, sterile pustules and subsequent desquamation. AGEP typically has a rapid onset and prompt resolution within a few weeks. The differential diagnoses for AGEP are broad and include infectious, inflammatory, a

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… Using the perforin/granzyme B and Fas ligand pathways, these drug-specific CD8+ T cells induce apoptosis of keratinocytes within the epidermis, tissue destruction and epidermal vesicle formation [ 2 ]. …

Race for the Cure: From the Oldest to the Newest Monoclonal Antibodies for Multiple Myeloma Treatment.

Multiple myeloma is characterized by a wide clinical heterogeneity due to an intricate network of interactions between bone marrow-resident clonal plasma cells and the microenvironment. Over the last years, dramatic improvement in the understanding of these pathways led to the introduction of novel drugs with immune-mediated mechanisms of action. Some of these compounds, such as the anti-cd38 daratumumab and isatuximab, the anti-slamf-7 elotuzumab, and the antibody-drug conjugate belantamab-mafodotin, have been tested in large clinical trials and have now fully entered the real-life management

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… Therefore, the compound induces the creation of a cytolytic synapsis, addressing the release of granzyme-B and perforin from the effector cell towards the aberrant plasma cell [ 14 ]. …

Role of Dietary Antioxidants in p53-Mediated Cancer Chemoprevention and Tumor Suppression.

Cancer arises through a complex interplay between genetic, behavioral, metabolic, and environmental factors that combined trigger cellular changes that over time promote malignancy. In terms of cancer prevention, behavioral interventions such as diet can promote genetic programs that may facilitate tumor suppression; and one of the key tumor suppressors responsible for initiating such programs is p53. The p53 protein is activated by various cellular events such as DNA damage, hypoxia, heat shock, and overexpression of oncogenes. Due to its role in cell fate decisions after DNA damage, regulato

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… Phytochemicals also exhibit anticancer activity through various signaling pathways, including the death receptor or extrinsic pathway, mitochondrial or intrinsic pathway, and perforin/granzyme apoptotic pathway [ 8 , 17 ]. …

BH3 Mimetics in Hematologic Malignancies.

Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapse

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… Apoptotic signaling in mammalian cells can be triggered by exogenous/extrinsic stimuli such as death/dependence receptors or cytotoxic perforin/granzymes-containing granules and by a range of intrinsic stimuli. …

Pro- and Antioxidant Effects of Vitamin C in Cancer in correspondence to Its Dietary and Pharmacological Concentrations.

Vitamin C is an antioxidant that may scavenge reactive oxygen species preventing DNA damage and other effects important in cancer transformation. Dietary vitamin C from natural sources is taken with other compounds affecting its bioavailability and biological effects. High pharmacological doses of vitamin C may induce prooxidant effects, detrimental for cancer cells. An oxidized form of vitamin C, dehydroascorbate, is transported through glucose transporters, and cancer cells switch from oxidative phosphorylation to glycolysis in energy production so an excess of vitamin C may limit glucose tr

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… These cells secreted less interferon gamma (IFN- γ ) after coculturing with cancer cells and showed a decreased expression of perforin and granzyme B. Gulo −/− mice showed a shorter survival time than control animals. …

Оптимизация реального использования BCMA-Targeted T-Cell-Enging терапии у пациентов с тройным-классным рефлекторным/отредактированным множественным Myeloma: итальянский модифицированный Delphi Консенсус.

Площадь лечения повторной/рефракторной множественной миеломы (RRMM) значительно изменилась с внедрением новых классов агентов и, в последнее время, T-директивных методов лечения, включая биконкретные антитела (BSAbs). Существенно важно укрепить и согласовать терапевтическое управление БСА в рамках клинической практики. Мы провели модифицированное исследование экспертов Дельфи на основе консенсуса по вопросу об использовании BsAbs в целях борьбы с созреванием B-Cell (BCMA) у пациентов с тройным классом (TCE) RRMM. Исследование было проведено в апреле-ноябре 2025 в соответствии с установленными

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… Often referred to as off-the-shelf alternatives to CAR-T-cell therapies [ 9 , 10 ], BsAbs simultaneously bind to CD3 on the T-cell surface and to the target antigen, thus promoting the formation of an immune synapse with the subsequent activation of T cells, which release granzymes and perforins, ultimately …