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Genetically Modified T-Cell-Based Adoptive Immunotherapy in Hematological Malignancies.

A significant proportion of hematological malignancies remain limited in treatment options. Immune system modulation serves as a promising therapeutic approach to eliminate malignant cells. Cytotoxic T lymphocytes (CTLs) play a central role in antitumor immunity; unfortunately, nonspecific approaches for targeted recognition of tumor cells by CTLs to mediate tumor immune evasion in hematological malignancies imply multiple mechanisms, which may or may not be clinically relevant. Recently, genetically modified T-cell-based adoptive immunotherapy approaches, including chimeric antigen receptor (

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… Subsequently, CTLs kill tumor cells by releasing perforin and granzyme B or by expressing Fas ligand (FasL) on the surface, inducing cytolysis or apoptosis. …

Killing me softly--future challenges in apoptosis research.

The induction of apoptosis, a highly regulated and clearly defined mode of cell dying, is a vital tenet of modern cancer therapy. In this review we focus on three aspects of apoptosis research which we believe are the most crucial and most exciting areas currently investigated and that will need to be better understood in order to enhance the efficacy of therapeutic measures. First, we discuss which target to select for cancer therapy and argue that not the cancer cell as such, but its interaction with the microenvironment is a more promising and genetically stable site of attack. Second, the

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… function as a ROS scavenger, gets released from the mitochondria and triggers chromatin condensation and DNA fragmentation; ( C ) CTL (Cytotoxic T lymphocytes), or NK (natural killer) cell-mediated apoptosis: A specialized form of apoptosis whereby the immune system triggers apoptosis by inserting a perforin …

Emerging insights into the immunosuppressive tumor microenvironment and its implications for glioblastoma immunotherapy.

Glioblastoma is considered the most common and lethal form of brain cancer. Despite tremendous progress in glioblastoma therapeutics, the profound intra- and inter-tumoral heterogeneity of glioblastoma tumors, the difficulty of agents to cross the blood-brain barrier (BBB), the development of drug resistance as well as the immunosuppressive tumor microenvironment (TME) predominantly account for the failure of existing conventional and targeted therapies. Therefore, there is a growing necessity to decipher the complexity of the TME that promotes immunosuppression and to discover innovative stra

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… (DC, Dendritic cell; EphA2, Ephrin type-A receptor 2; CMV, Cytomegalovirus; MTA, Mutated-derived tumour antigen; NeoAg, Neoantigen; fl, full length; LPs, lipid particles; TERT, telomerase reverse transcriptase; PTPRZ1, Protein tyrosine phosphatase receptor type Z1; WT1, Wilms; tumour 1; PFN, Perforin … TNFα and IFNγ), (b) perforin (PFN) & granzyme (GzmB) and FasL & TRAILR mediated target cell apoptosis, (c) antibody-dependent cell-mediated cytotoxicity, and (d) antigen processing and presentation. They can also have indirect anti-tumor effects through interaction with immune cells (e.g. …

BCMA-targeted immunotherapy for multiple myeloma.

B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as

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… In addition, the cytotoxicity of NK cell is mediated via the release of perforin and granzyme as well as the expression of apoptosis-inducing ligands including FasL and TRAIL. So there is much less concern about the CRS seen in many CAR-T cell therapies [ 159 , 160 ]. … The activated T cells secrete interferon-γ, granzyme B, and perforin and exert profound T cell cytotoxicity against tumor cells without requiring antigen-presenting cells, MHC-I/peptide complex, and co-stimulatory molecules [ 163 ]. …

From induced pluripotent stem cell (iPSC) to universal immune cells: literature review of advances in a new generation of tumor therapies.

Background and objectiveTumor therapy is still a tough clinical challenge, and cancer immunotherapy has drawn increasing attention. T cells and natural killer (NK) cells play crucial roles in the immune response. Induced pluripotent stem cell (iPSC) technology opens up a new way to produce functionally improved universal iPSC-derived chimeric antigen receptor (CAR) T (CAR-iT) and iPSC-derived CAR-NK (CAR-iNK) cells. This study aims to comprehensively review the generation and clinical applications of iPSC-derived universal CAR-iT and CAR-iNK cells to explore their potential and future directio

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… Then, exerting cytotoxic effects, NK cells activate the release of cytotoxic particles (e.g., perforin and granzymes) and/or express death receptor ligands [e.g., Fas ligand (FAS) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), etc.] to kill the target cells in an apoptosis-inducing …

Review of cancer therapies for the perioperative physician.

Advances in cancer treatments over the past decades combining chemotherapy with novel technologies in immunotherapies, radiation therapies, and interventional radiology have prolonged life expectancy. Patients have more options for treatments of their primary or metastatic diseases. Increased procedural techniques amid an aging population with multiple comorbidities present risks and challenges in the perioperative period.Chemotherapy remains the mainstay of cancer treatment, can be given intraoperatively, and is combined with other treatment modalities. Immunotherapy is particular to cancer c

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… Antibody-dependent cell‐mediated cytotoxicity Cancer | Name | Trade name | Target cell receptor | Mechanism of action Multiple myeloma | Elotuzumab Daratumumab | Empliciti Darzalex | SLAMF7 CD38 | NK, ADCC Apoptosis, ADCC Acute lymphocytic leukemia | Blinatumomab | Blincyto | CD19/CD3 | Granzyme and perforin …

NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma.

CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the antitumor activity of activated and expanded NK cells (NKAE) and CD45RA- T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells

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… However, CAR-T cells exhibited higher production of IFN-γ ( p = 0.001), TNF-α ( p = 0.015), granzyme A ( p = 0.009), granzyme B ( p = 0.013), perforin ( p = 0.0176), granulysin ( p = 0.0132), sFas ( p = 0.0401), and sFasL ( p = 0.022) than untransduced T cells (Fig. 5A ). …

Advancement of NF-κB Signaling Pathway: A Novel Target in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is the third highest among cancer related deaths. Despite modest success with therapy such as gemcitabine, pancreatic cancer incidence remains virtually unchanged in the past 25 years. Among the several driver mutations for PDAC, Kras mutation contributes a central role for its development, progression and therapeutic resistance. In addition, inflammation is implicated in the development of most human cancer, including pancreatic cancer. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is recogniz

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… NF-κB modulates the anti-tumorigenic potential of NK cells, by upregulating the expression of perforins and granzyme B, which inhibit lytic potentials of NK cells [ 15 ]. 3.2. Proliferation of Cancer NF-κB plays a major role in tumor initiation, tumor promotion and tumor progression ( Figure 1 ). …

Biological and clinical basis for molecular studies of interferons.

The cytokine family of interferons (IFNs) has multiple functions, including antiviral, anti-tumor, and immunomodulatory effects and regulation of cell differentiation. The multiple functions of the IFN system are thought to be an innate defense against microbes and foreign substances. The IFN system consists first of cells that produce IFNs in response to viral infection or other foreign stimuli and second of cells that establish the antiviral state in response to IFNs. This process of innate immunity involves multiple signaling mechanisms and activation of various host genes. Viruses have evo

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… IFNs amplify T-cell and NK-cell cytotoxicity by increasing cell surface expression of TRAIL ( 61 ) or Fas ligands and release of perforin from NK cells. …

Challenges and strategies associated with CAR-T cell therapy in blood malignancies.

Cellular immunotherapy, particularly CAR-T cells, has shown potential in the improvement of outcomes in patients with refractory and recurrent malignancies of the blood. However, achieving sustainable long-term complete remission for blood cancer remains a challenge, with resistance and relapse being expected outcomes for many patients. Although many studies have attempted to clarify the mechanisms of CAR-T cell therapy failure, the mechanism remains unclear. In this article, we discuss and describe the current state of knowledge regarding these factors, which include elements that influence t

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… T cell subsets affect the quality of CART Cell products CD4 + CAR-T cells are not as effective in killing tumor cells relative to CD8 + cells due to decreased levels of intracellular perforin and granzyme [ 113 ]. … For instance, activated cytotoxic CD8 + T cells and NK cells inhibit tumor growth by the release of effectors such as granzyme B and perforin. These cell types express a major chemokine receptor, and its ligands CXCL9 and CXCL10 recruit these cells into the tumor tissue [ 143 ]. …

Cancer immunotherapies: A hope for the uncurable?

The use of cancer immunotherapies is not novel but has been used over the decades in the clinic. Only recently have we found the true potential of stimulating an anti-tumor response after the breakthrough of checkpoint inhibitors. Cancer immunotherapies have become the first line treatment for many malignancies at various stages. Nevertheless, the clinical results in terms of overall survival and progression free survival were not as anticipated. Majority of cancer patients do not respond to immunotherapies and the reasons differ. Hence, further improvements for cancer immunotherapies are cruc

Bispecific and multispecific T-cell engagers: advancing the future of immunotherapy.

T-cell engagers (TCEs) represent an emerging class of immunotherapies that harness T cells' cytotoxic power to eliminate diseased cells-a transformative future therapeutic strategy. TCEs form immunological synapses to trigger potent immune responses, with proven efficacy in blood cancers; research expands their use to solid tumors via innovative molecular design and improved safety profiles. Beyond oncology, TCEs hold promise in autoimmune disorders by eliminating autoreactive cells, offering novel avenues for diseases like lupus. However, achieving optimal outcomes without disrupting immune h

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… Upon synapse formation, T cells release perforins and granzymes, inducing necrosis in target cells, while also secreting cytokines (e.g. Interferon γ (IFN-γ), Tumor Necrosis Factor α (TNF-α)) that amplify the immune response [ 4 ]. …

Landscape of T-cell engagers in solid tumors.

T-cell engagers (TCEs) are a diverse class of bispecific and multispecific molecules that co-bind CD3 on T cells and tumor-associated antigens to form an immune synapse and induce targeted T-cell-mediated cytotoxicity. While TCEs have demonstrated remarkable efficacy in hematologic malignancies, translation into solid tumors has been more challenging. Recent advances seen with tebentafusp in metastatic uveal melanoma and tarlatamab in small-cell lung cancer have validated the approach and driven a rapidly expanding pipeline targeting other tumor associated antigens such as STEAP1, MUC16, and P

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… Once CD3 is engaged, T cells are activated to release perforin and granzymes, leading to tumor cell lysis. …

Research Progress of NK Cells in Glioblastoma Treatment.

NK cells are a type of antitumor immune cell with promising clinical application, following T cells. The activity of NK cells is primarily regulated by their surface receptors and immune microenvironment. In gliomas, the tumor microenvironment exerts a strong immunosuppressive effect, which significantly reduces the clinical efficacy of NK cell immunotherapy. Therefore, this review aims to discuss the latest research on the role of NK cells in glioma immunotherapy, focusing on aspects such as NK cell development, function, and localization. It summarizes information on the compounds, monoclona

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… NK Cell Development, Functions, and Localizations In mice and humans, NK cells undergo distinct stages of development ( Figure 4 ). 6 – 9 Many NK cells are not only cytotoxic but also produce various molecules, including perforin and granzyme, which can lead to stress-induced cell death. …

Cytokine-Induced Killer Cells: A Unique Platform for Adoptive Cell Immunotherapy after Allogeneic Hematopoietic Stem Cell Transplantation.

BackgroundImmunotherapies in general, and cellular immunotherapies, in particular are becoming increasingly integrated into current personalized cancer treatment, though still facing some obstacles in the allogeneic hematopoietic stem cell transplantation (HSCT) setting.SummaryThe concept of isolating immune effector cells, expanding their numbers, enhancing their anticancer capabilities by modifying them without increasing their alloreactive potential is the mainstay of adoptive cellular immunotherapy after allogeneic HSCT. In this context, cytokine-induced killer (CIK) cells, a polyfunctiona

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… Application of IL-21 increased the expression of IFNγ, tumor necrosis factor (TNF)-α, perforin, and granzyme B, thereby enhancing cell cytotoxicity [ 13 ]. Furthermore, thymoglobulin was compared with αCD3 (OKT3) monoclonal antibody (mAb) in clinical-grade culture protocols [ 14 ]. …

Gene and Cell Therapy for Sarcomas: A Review.

Background: The heterogeneity of sarcomas and resulting distinct sub-type specific characteristics, their high recurrence rates, and tendency for distant metastasis, continue to present significant challenges to providing optimal treatments. Objective: To provide a comprehensive review of current literature and clinical trials in gene and cell therapies for sarcomas. Methods: A comprehensive literature search was conducted utilizing the following databases: PubMed, Medline, Google Scholar and clinicaltrials.gov. Search terms included "gene therapy", "cell therapy", "NK cell therapy, "CAR-T the

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… Upon cell recognition, NK cells induce apoptosis in target cells through the granzyme/perforin pathway or via the death receptor–ligand pathway (tumor necrosis factor family) [ 38 , 39 ]. …

CAR-T cells in the treatment of multiple myeloma: an encouraging cell therapy.

Multiple myeloma (MM) is a malignant disease of plasma cells that accounts for approximately 10% of all hematological malignancies and is characterized by a clonal proliferation of malignant plasma cells in the bone marrow. Numerous therapeutic strategies, including proteasome inhibitors, immunomodulators, monoclonal antibodies against CD38 and autologous stem cell transplantation, have prolonged the median survival of MM patients. Nevertheless, almost all MM patients suffer disease relapses due to drug resistance and eventually die from MM or MM-related complications. Chimeric antigen recepto

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… Chimeric antigen receptor (CAR) T cell therapy mediate tumor killing in several ways, including secretion of cytotoxic granules containing perforin and granzymes, production of pro-inflammatory cytokines such as IFN-g and TNF-a and activation of Fas/Fas ligand (Fas/FasL), elevation of circulating levels …

The roles of inflammasomes in cancer.

Inflammation is a key characteristic of all stages of tumor development, including tumor initiation, progression, malignant transformation, invasion, and metastasis. Inflammasomes are an important component of the inflammatory response and an indispensable part of the innate immune system. Inflammasomes regulate the nature of infiltrating immune cells by signaling the secretion of different cytokines and chemokines, thus regulating the anti-tumor immunity of the body. Inflammasome expression patterns vary across different tumor types and stages, playing different roles during tumor progression

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… Activated CD8 + T cells may further promote the activation of NLRP3 inflammasomes of antigen-presenting cells through perforin-dependent mechanisms and achieve anti-tumor effects through a positive feedback mechanism ( 60 ). Figure 2 Inflammasome in tumor suppression. …

Primary Bone Lymphoma: A Review of the Literature with Emphasis on Histopathology and Histogenesis.

Primary bone lymphoma (PBL) is a rare neoplasm of malignant lymphoid cells presenting with one or more bone lesions without nodal or other extranodal involvement. It accounts for approximately 1% of all lymphomas and 7% of malignant primary bone tumors. Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) represents the predominant histological type and constitutes over 80% of all cases. PBL may occur at all ages with a typical diagnosis age of 45-60 years and a slight male predominance. Local bone pain, soft tissue edema, palpable mass and pathological fracture are the most co

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… Immunoreactivity for CD45, epithelial membrane antigen (EMA), cytotoxic proteins, T-cell intracellular antigen 1 (TIA-1), perforin and granzyme B varies [ 15 , 72 , 77 , 79 ]. …

Drug Conjugated and Bispecific Antibodies for Multiple Myeloma: Improving Immunotherapies off the Shelf.

The impressive improvement of overall survival in multiple myeloma (MM) patients in the last years has been mostly related to the availability of new classes of drugs with different mechanisms of action, including proteasome inhibitors (PI), immunomodulating agents (IMiDs), and monoclonal antibodies. However, even with this increased potence of fire, MM still remains an incurable condition, due to clonal selection and evolution of neoplastic clone. This concept underlines the importance of immunotherapy as one of the most relevant tools to try to eradicate the disease. In line with this concep

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… BsAbs therapy shares several similarities with another popular type of immunotherapeutic approach like Chimeric Antigen Receptor expressing T-cell (CAR-T) like a MHC-independent T-cell activation and killing of tumor cells by release of granzyme B and perforin. …