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Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects.

Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time. Given that MM is the second most common blood cancer with a characteristic and unavoidable relapse/refractory state during the course of the disease, the development of new therapeutic modalities is crucial. Belantamab mafodotin (belamaf, GSK2857916) is a first-in-class therapeutic, indicated for patients who have

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… The binding of CD3 ε leads to activation of cytotoxic T-cells which release perforin and granzymes to lyse the targeted tumor cells, and interferon-γ which activates macrophages and immune cells [ 75 , 76 ]. Several anti-BCMA BiAbs are in ongoing clinical trials for patients with MM. …

Ancient genes establish stress-induced mutation as a hallmark of cancer.

Cancer is sometimes depicted as a reversion to single cell behavior in cells adapted to live in a multicellular assembly. If this is the case, one would expect that mutation in cancer disrupts functional mechanisms that suppress cell-level traits detrimental to multicellularity. Such mechanisms should have evolved with or after the emergence of multicellularity. This leads to two related, but distinct hypotheses: 1) Somatic mutations in cancer will occur in genes that are younger than the emergence of multicellularity (1000 million years [MY]); and 2) genes that are frequently mutated in cance

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… cancer co-localized with genes that are enriched for extracellular glycoproteins, G-protein coupled receptors especially olfactory receptors, cell-cell adhesion, molecular species intrinsic to the plasma membrane, Ig- and EGF-like domains, ligand gated ion channels, membrane attack complex component/perforin …

Nanoparticle-based strategy in CAR-T cell immunotherapy: challenges, implications, and perspectives.

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable progress in treating hematologic malignancies, yet its broader application faces challenges such as manufacturing complexity, solid tumor microenvironment barriers, and immune toxicity. Nanoparticles (NPs), leveraging their precise delivery, immunomodulation, and multifunctional integration capabilities, offer innovative strategies to optimize CAR-T cell therapy. This review provides a comprehensive elucidation of the fundamental framework of CAR-T cell therapy and the challenges in oncological applications. Subsequently, w

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… After recognizing tumor antigens, these engineered CAR-T cells eliminate tumor cells through three mechanisms: (1) Through the perforin and granzyme pathway, perforin released by CD8 + T cells forms pores on the tumor cell membrane, allowing granzymes to enter and induce cell death [ 6 ]; (2) Through … Notably, during CAR-T cell-mediated attack on target cells, granzyme B enters the tumor cell cytoplasm through perforin-formed pores in the plasma membrane, directly activating caspase-3. …

Всеобъемлющая оценка неблагоприятных профилей, связанных с биконкретными антителами в множестве миеломы.

Биотечные антитела (BSAbs) сулили большие надежды в борьбе с повторной/охлажденной множественной миеломой (MM). Несмотря на свою эффективность, этот класс наркотиков связан со значительными токсичными свойствами. В этом исследовании мы провели совместный анализ имеющихся клинических испытаний БСАБ для лечения ММ, включая полные публикации и резюме до апреля 2025. BsAb были отнесены к категории two группы: антигены созревания клеток B (BCMA) и GPRC5D/FcRH5 BsAbs. Тест Welch был проведен для сравнения характеристик безопасности каждого агента. Для кластеризации мы использовали анализ основных ко

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… This interaction results in an immunological synapse, leading to T cell degranulation and destruction of target cells via perforin and granzyme B, while also promoting T cell activation and memory cell differentiation [ 2 , 3 ] BsAbs are increasingly being used in penta-refractory MM resistant to two …

Эволюция антиCD20 Лечения множественных склерозов: оптимизация характеристик и функций антител.

Истощение клеток B с помощью целевых агентов CD20 обычно используется для лечения множественных склерозов (MS), других аутоиммунных заболеваний и некоторых гематологов. Первоначальный очевидный успех с ритуксимабом в использовании MS и нейромиелитной оптики стимулировал развитие антиCD20 моноклональной антителной (mAb) терапии oprelizumab, atumumab и ublituximab, а также антиCD19 mAb inebilizumab. Хотя каждая из них является эффективной в плане целеопределения и истощения элементов В, структурные различия превращаются в различные механизмы действий, влияющие на поддержание истощения и безопасн

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… This interaction initiates a series of signaling pathways in NK cells, including release of cytolytic compounds such as granzyme B and perforin, leading to B-cell lysis [ 53 , 87 , 88 , 91 ]. …

Enhancing CAR T cells function: role of immunomodulators in cancer immunotherapy.

CAR T-cell therapy is a promising immunotherapy, providing successful results for cancer patients who are unresponsive to standard and traditional therapeutic approaches. However, there are limiting factors which create a hurdle in the therapy performing its role optimally. CAR T cells get exhausted, produce active antitumor responses, and might even produce toxic reactions. Specifically, in the case of solid tumors, chimeric antigen receptor T (CAR-T) cells fail to produce the desired outcomes. Then, the need to use supplementary agents such as immune system modifying immunomodulatory agents

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… Research reported that control group SFN-treated CAR T-cell group produced higher levels of IFN-gamma, perforin, and granzyme B which result in increased cytotoxicity by CAR T cells. PI3K/AKT signaling pathway engages in differentiation and survival of T cells, so SFN manipulates PI3/AKT axis. …

T-cell redirecting bispecific antibodies in multiple myeloma: Current landscape and future directions.

T-cell engaging bispecific antibodies (BsAbs) have substantial activity in heavily pretreated patients with multiple myeloma (MM). The overall response rate obtained with B-cell maturation antigen (BCMA)-targeting BsAbs is approximately 60%-70%, including a high proportion of patients achieving very good partial response or complete response. Comparable efficacy is seen with BsAbs targeting GPRC5D or FcRH5. Cytokine release syndrome is frequently observed with BsAb treatment, but mostly during the step-up doses and the first full dose. Early intervention with IL-6 receptor blocking antibodies

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… The cyotoxic granzyme B/perforin pathway is used by the T‐cell to induce MM cell death. BsAbs come in many different formats but can generally be classified into two groups; IgG‐like BsAbs containing a fragment crystallizable (Fc) domain and those without an Fc domain (e.g. …

Magic year for multiple myeloma therapeutics: Key takeaways from the ASH 2015 annual meeting.

Despite the availability of various anticancer agents, Multiple Myeloma (MM) remains incurable in most cases, along with high relapse rate in the patients treated with these agents. The year 2015 saw major advancements in our battle against multiple myeloma. In 2015, the U.S. Food and Drug Administration (FDA) approved three new therapies for multiple myeloma, namely Ixazomib (an oral proteasome inhibitor), Daratumumab and Elotuzumab (monoclonal antibodies against CD38 and SLAMF7 respectively). The purpose of this review is to provide a detailed analysis of these aforementioned breakthrough th

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… Subsequent cytotoxicity is mediated through ≥2 different mechanisms; one involving the release of perforin and granzymes from effector cells and the other involving death ligands FasL and tumor necrosis factor–related apoptosis-inducing ligand. …

In vitro расширила человека CD4+CD25+ регуляционные T клетки, подавляющие распространение Т клеток.

Регулирующие Т клетки (Tregs) оказались критически важными в балансе между автоиммунизацией и терпимостью и были связаны с несколькими аутоиммунными заболеваниями человека. Однако небольшое число трегов в периферии крови ограничивает их терапевтический потенциал. Поэтому мы разработали протокол, который позволит расширить "Трегз" при сохранении их подавляющей активности. Мы изолировали клетки CD4+CD25 hi от человеческой периферической крови и расширили их in vitro в присутствии anti-CD3 и anti-CD28 Магнитные кситы и высокие концентрации внешнего интерлейкина (IL) -2. Траги были эффективно расш

Engineering Immunity: Current Progress and Future Directions of CAR-T Cell Therapy.

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative form of immunotherapy, enabling the precise engineering of T cells to recognize and eliminate pathogenic cells. In hematologic malignancies, CAR-T cells targeting CD19 or B cell maturation antigens have achieved remarkable remission rates and durable responses in patients with otherwise refractory disease. Despite these successes, extending CAR-T cell therapy to solid tumors remains challenging due to antigen heterogeneity, poor T cell infiltration, and the immunosuppressive tumor microenvironment (TME). Beyond onco

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… When the CAR engages this second antigen, the T cell becomes fully activated and releases perforin and granzymes to kill the tumor cell. … Autoreactive B cells often display their self-reactive IgM on their surface as B cell receptors (BCRs), which can then bind to the autoantigen and trigger the activation of CAAR-T cells and killing of B cells mainly via the perforin/granzyme pathway. …

Prospects and Advances in Adoptive Natural Killer Cell Therapy for Unmet Therapeutic Needs in Pediatric Bone Sarcomas.

Malignant bone tumors are aggressive tumors, with a high tendency to metastasize, that are observed most frequently in adolescents during rapid growth spurts. Pediatric patients with malignant bone sarcomas, Ewing sarcoma and osteosarcoma, who present with progressive disease have dire survival rates despite aggressive therapy. These therapies can have long-term effects on bone growth, such as decreased bone mineral density and reduced longitudinal growth. New therapeutic approaches are therefore urgently needed for targeting pediatric malignant bone tumors. Harnessing the power of the immune

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… These innate effector cells are a heterogenous group of lymphocytes that both exhibit perforin/granzyme B-based cytolytic activity and secrete cytokines that activate the adaptive arm of the immune system. … The activating immunological synapse between the NK cell and its susceptible target triggers a series of downstream events that, unless counteracted by the inhibitory receptors, leads to the release of preformed cytolytic granules containing perforin and granzyme B. …

Alternative CAR Therapies: Recent Approaches in Engineering Chimeric Antigen Receptor Immune Cells to Combat Cancer.

For nearly three decades, chimeric antigen receptors (CARs) have captivated the interest of researchers seeking to find novel immunotherapies to treat cancer. CARs were first designed to work with T cells, and the first CAR T cell therapy was approved to treat B cell lymphoma in 2017. Recent advancements in CAR technology have led to the development of modified CARs, including multi-specific CARs and logic gated CARs. Other immune cell types, including natural killer (NK) cells and macrophages, have also been engineered to express CARs to treat cancer. Additionally, CAR technology has been ada

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… Mature NK cells will also participate in ADCC by the binding of CD16 to the Fc region of an antibody, causing a release of perforins and granzyme B. In addition to providing an innate cytotoxic response, NK cells produce pro-inflammatory cytokines, including TNF-α and INFγ [ 98 ]. … They use standard CD8 T cell killing mechanisms, including perforin and granzymes. ( B ) Chimeric autoantigen receptor (CAAR) T cells are a novel approach that use an epitope of an autoantigen as the binding domain of the CAAR T cell. …

FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review.

Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug

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… This induces apoptosis and lysis of the CD19 positive B cells via the release of perforin and granzymes from cytotoxic granules in the T cells. … CAR-T cells lead to cancer cell death mainly via the secretion of cytotoxic granules containing granzymes and perforin, and the release of cytokines (i.e., IFNγ and tumor necrosis factor (TNF)) ( Figure 14 ). …

Targeting cancer stem cells with CAR-based immunotherapy: biology, evidence, and future directions.

Cancer stem cells (CSCs) are pivotal in tumor initiation, progression, and relapse, underscoring the need for targeted therapies to achieve lasting responses. This review delves into CSC biology, highlighting their tumor-initiating potential demonstrated through limiting dilution assays and their role in resistance to therapies. Although successful CAR therapies, such as anti-CD19 CAR T-cells, can induce complete responses without directly targeting CSCs, CAR strategies focusing on CSCs may offer promising avenues to prevent recurrence. We assess CAR therapies targeting CSC-specific antigens,

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… Second-generation anti-NKG2D CAR T-cells have demonstrated the ability to release high levels of cytokines, such as perforin and granzyme B, to eliminate GBM cells and GSCs. … For instance, a study demonstrated that universal off-the-shelf dual CAR NK92-cells, engineered to target prostate-specific membrane antigen (PSMA) simultaneously and PSCA, effectively released cytokines such as IFN-γ, perforin, and granzyme B in response to prostate cancer in vivo. …

Natural biomolecules and derivatives as anticancer immunomodulatory agents.

Despite advancements in chemotherapy, the issue of resistance and non-responsiveness to many chemotherapeutic drugs that are currently in clinical use still remains. Recently, cancer immunotherapy has gathered attention as a novel treatment against select cancers. Immunomodulation is also emerging as an effective strategy to improve efficacy. Natural phytochemicals, with known anticancer properties, been reported to mediate their effects by modulating both traditional cancer pathways and immunity. The mechanism of phytochemical mediated-immunomodulatory activity may be attributed to the remode

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… Immune-derived granzymes enter cancer cells via perforin-formed pores to induce DNA fragmentation and caspase-3-dependent apoptosis. ACT-dependent induction of granzyme B indirectly induced apoptosis of pancreatic ( 74 ), liver ( 75 ) and breast ( 73 ) cancer cells. … proliferation and tumor burden ↓ melanoma metastasis ↓ Treg-mediated immunosuppression | ( 79 ) Ovarian | Ovarian cancer model in vivo | ↑ miR-142 in CD4+ cells → ↓ Sirt1 expression ↑ Th1 differentiation from CD4+ lymphocytes | T cells | ↑ T-cell medicated apoptosis | ( 78 ) Pancreatic | In vitro | ↑ perforin …

Emerging Mechanisms of Physical Exercise Benefits in Adjuvant and Neoadjuvant Cancer Immunotherapy.

The primary factors that can be modified in one's lifestyle are the most influential determinants and significant preventable causes of various types of cancer. Exercise has demonstrated numerous advantages in preventing cancer and aiding in its treatment. However, the precise mechanisms behind these effects are still not fully understood. To contribute to our comprehension of exercise's impact on cancer immunotherapy and provide recommendations for future research in exercise oncology, we will examine the roles and underlying mechanisms of exercise on immune cells. In addition to reducing the

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… Participants engaged in light to moderate or high-intensity physical activities showed elevated levels of granzyme B and perforin in their NK cells [ 40 ]. …

Bispecific antibodies for non-Hodgkin's lymphomas and multiple myeloma.

Immunotherapy has revolutionized the treatment of cancers. There are several approaches, including naked monoclonal antibodies, antibody-drug conjugates, immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies with important success. Bispecific antibodies represent a novel immunotherapeutic approach for the treatment of several malignancies, in particular non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Early-phase studies have shown encouraging clinical activity in poor-risk B cell NHL and MM. Several constructs are currently available and in clinical development fo

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… Mosunetuzumab induced potent T cell activation against CD20 + normal and neoplastic B cells via the granzyme–perforin pathway even at low concentrations of CD20 and despite the presence of high levels of rituximab. 24 The initial clinical studies with mosunetuzumab were reported in the phase I dose-escalation …

γδ T cells: origin and fate, subsets, diseases and immunotherapy.

The intricacy of diseases, shaped by intrinsic processes like immune system exhaustion and hyperactivation, highlights the potential of immune renormalization as a promising strategy in disease treatment. In recent years, our primary focus has centered on γδ T cell-based immunotherapy, particularly pioneering the use of allogeneic Vδ2+ γδ T cells for treating late-stage solid tumors and tuberculosis patients. However, we recognize untapped potential and optimization opportunities to fully harness γδ T cell effector functions in immunotherapy. This review aims to thoroughly examine γδ T cell im

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… Specifically, NKG2D on Vδ2 T cells binds to MICA/B 285 – 287 and UL16 Binding Proteins (ULBPs) of cancer cells, 288 , 289 and the DNAX Accessory Molecule 1(DNAM1) on Vδ2 + binds to Nectin-like 5 of cancer cells, leading to perforin-granzyme axis mediated cancer cytotoxicity. 290 Like NK cells, Vδ2 T … Afterward, activated γδ T cells exhibit cytotoxic capabilities and directly eliminate infected cells by releasing cytotoxic molecules, such as perforin and granzymes, which induce apoptosis in target cells. …

The anti-inflammatory effects of mesenchymal stem cells and their research progress in hematopoietic stem cell transplantation: A comprehensive review.

Hematopoietic stem cell transplantation (HSCT) is frequently accompanied by severe inflammation-related complications, among which graft-versus-host disease (GVHD) stands out as one of the most common and life-threatening. As a systemic inflammatory disorder, GVHD arises when donor T cells recognize the recipient's alloantigens and initiate an immune attack. Currently, effective second-line treatment options remain scarce for patients with antibiotic-resistant or steroid-refractory GVHD. Mesenchymal stem cells (MSCs) are non-hematopoietic cells widely distributed in fetal and adult tissues and

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… The main mechanisms are as follows: MSCs can alleviate the inflammatory response of GVHD by inhibiting the activation of donor T cells, promoting the proliferation of regulatory T cells, regulating the cytokine balance (e.g. reducing TNF-α and increasing IL-10), and decreasing the release of perforin …

CAR-NK cell therapy for hematological malignancies.

AbstractChimeric antigen receptor (CAR)-natural killer (NK) cells represent a novel cell therapy platform distinguished from CAR T cells by their more favorable safety profile, easier off-the-shelf allogeneic manufacturing and consequent scalability, and their innate cytotoxicity without needing previous sensitization. CAR-NK cells derived from a variety of sources have been used against hematologic malignancies in several clinical trials, showing significant therapeutic responses and efficacy without severe adverse effects. Limitations that are being addressed in CAR-NK cell therapy include c

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… and kill malignant or virally infected cells without previous sensitization through a diverse array of activating and inhibitory receptors on target cells. 12 They recognize missing-self signals on major histocompatibility complex (MHC) class I–negative targets, release cytotoxic granules containing perforin …