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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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… mechanisms are medicated by the interaction of the Fc region of the antibody with the neonatal Fc receptors present on effector immune cells. 34 In ADCC, the Fc region's interaction with the Fc Ɣ receptor activates immune cells like natural killer (NK) cells, which release cytotoxic molecules (e.g., perforins …

Tumour Immunotherapy and Applications of Immunological Products: A Review of Literature.

Malignant tumors, characterized by uncontrolled cell proliferation, are a leading global health challenge, responsible for over 9.7 million deaths in 2022, with new cases expected to rise to 35 million annually by 2050. Immunotherapy is preferred to other cancer therapies, offering precise targeting of malignant cells while simultaneously strengthening the immune system's complex responses. Advances in this novel field of science have been closely linked to a deeper knowledge of tumor biology, particularly the intricate interplay between tumor cells, the immune system, and the tumor microenvir

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… Upon recognition of TAAs presented by major histocompatibility complex class I (MHC-I) molecules on the tumor cell surface, CTLs are activated and exert their cytotoxic effects by releasing perforin and granzymes, which induce apoptosis in the target tumor cells [ 33 ]. …

Cytokine release syndrome and cancer immunotherapies - historical challenges and promising futures.

Cancer is the leading cause of death worldwide. Cancer immunotherapy involves reinvigorating the patient's own immune system to fight against cancer. While novel approaches like Chimeric Antigen Receptor (CAR) T cells, bispecific T cell engagers, and immune checkpoint inhibitors have shown promising efficacy, Cytokine Release Syndrome (CRS) is a serious adverse effect and remains a major concern. CRS is a phenomenon of immune hyperactivation that results in excessive cytokine secretion, and if left unchecked, it may lead to multi-organ failure and death. Here we review the pathophysiology of C

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… It is also suggested that the concurrent binding of BiTE with the tumor associated antigen and CD3 in the TCR complex forms a cytolytic synapse between the T cells and the tumor cells that mediate perforin and granzyme mediated killing of the tumor cells via caspase activation ( 84 , 101 , 102 ). …

A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments.

Tumors are composed of a plethora of extracellular matrix, tumor and non-tumor cells that form a tumor microenvironment (TME) that nurtures the tumor cells and creates a favorable environment where tumor cells grow and proliferate. In multiple myeloma (MM), the TME is the bone marrow (BM). Non-tumor cells can belong either to the non-hematological compartment that secretes soluble mediators to create a favorable environment for MM cells to grow, or to the immune cell compartment that perform an anti-MM activity in healthy conditions. Indeed, marrow-infiltrating lymphocytes (MILs) are associate

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… NK Cells NK cells are anti-tumor and anti-microbial cells of the innate immune system equipped with a wide array of activating and inhibitory receptors that activate or inhibit their activity through different mechanisms such as granzyme and perforin release, death receptor pathways, and release of …

Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most s

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… Natural killer (NK) cell function is impaired in higher-risk MDS, with some patients exhibiting a quantitative deficiency in NK cell numbers, and other patients having normal cell numbers but deficiencies in levels of perforin and granzyme B and ineffective cell killing [ 45 , 46 ]. …

Critical considerations for targeting colorectal liver metastases with nanotechnology.

Colorectal cancer remains a significant cause of morbidity and mortality worldwide. Half of all patients develop liver metastases, presenting unique challenges for their treatment. The shortcomings of conventional chemotherapy has encouraged the use of nanomedicines; the application of nanotechnology in the diagnosis and treatment of disease. In spite of technological improvements in nanotechnology, the complexity of biological systems hinders the prospect of nanomedicines being applied in cancer therapy at the present time. This review highlights current biological barriers and discusses aspe

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… Other antitumor responses include KC‐mediated phagocytosis and NK cell‐induced apoptosis, that is, through the release of cytotoxic granules containing perforin and granzymes (Lorenzo‐Herrero et al., 2018 ). …

Switching Homes: How Cancer Moves to Bone.

Bone metastases (BM) are a very common complication of the most prevalent human cancers. BM are extremely painful and may be life-threatening when associated with hypercalcaemia. BM can lead to kidney failure and cardiac arrhythmias and arrest, but why and how do cancer cells decide to "switch homes" and move to bone? In this review, we will present what answers science has provided so far, with focus on the molecular mechanisms and cellular aspects of well-established findings, such as the concept of "vicious cycle" and "osteolytic" vs. "osteosclerotic" bone metastases; as well as on novel co

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… This equilibrium status seems to be mainly promoted by adaptive immune cells and factors, such as CD4 + /CD8 + T-cells, perforin-mediated toxicity by NK cells, IL-12 and IFN-γ, while cancer cells respond by increasing Treg and MDSC production of TGF-β, IL-10, ROS and NO and upregulating their own programmed …

CAR T клеточная терапия в неврологических расстройствах, вызванных автоантибиозами: многообещающая стратегия.

Клеточная терапия химерного антигенного рецептора (CAR) Т становится перспективным подходом к неврологическим аутоиммунным расстройствам на базе клеток B, особенно тем, которые характеризуются патогенными автоантиорганизмами, направленными на ключевые нейронные структуры. Эти заболевания, включая расстройство спектрального спектра нейромиелита, миастения гравис, синдром Ламберта-Итона миастеника, болезнь, связанная с антителами MOG, энцефалит рецептора против NMDA, диацилглицирол губазы альфа антитела, ассоциируемый с энцефалитом, синдромом жесткого человека и множественным склерозом, могут бы

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… Upon target antigen recognition, CAR T cells become activated, leading to perforin-mediated cytotoxicity, cytokine release, and autocrine stimulation, ultimately inducing target cell apoptosis. …

Current strategies for armoring chimeric antigen receptor T-cells to overcome barriers of the solid tumor microenvironment.

Chimeric antigen receptor (CAR) T-cell therapy is a transformative immunotherapeutic approach, yet its application in solid tumors is hindered by the immunosuppressive tumor microenvironment (TME). The TME restricts T-cell trafficking, impairs effector functions, and promotes exhaustion through soluble factors, metabolic stress, and suppressive cell populations. Recent efforts to enhance CAR T-cell efficacy have focused on armoring strategies that 'reprogram' and 'boost' T-cell responses within the TME. These include engineered expression of dominant-negative receptors or cytokine-releasing co

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… The synergistic improvement in anti-tumor activity induced by Super2 and IL-33 armoring was independent of IFN-γ or perforin-mediated cytotoxicity. Instead, the combination appeared to function primarily by harnessing an endogenous immune response. …

Immunological Targets in Generalized Myasthenia Gravis Treatment: Where Are We Going Now?

BackgroundGeneralized myasthenia gravis (gMG) is a heterogeneous autoimmune disorder marked by antibody-mediated disruption of neuromuscular transmission. Despite advancements in immunosuppressive therapies and biologics, a subset of patients remains refractory, necessitating more targeted and personalized treatment strategies.ObjectiveThis review aims to synthesize current knowledge of the immunopathological mechanisms across gMG subtypes and to explore emerging therapeutic targets tailored to these diverse disease phenotypes.MethodsA narrative review was conducted, integrating recent finding

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… This dual binding promotes targeted B-cell apoptosis via perforin- and granzyme-mediated mechanisms. …

Advances and Challenges in Cervical Cancer: From Molecular Mechanisms and Global Epidemiology to Innovative Therapies and Prevention Strategies.

BackgroundIn the global scenario of public health, cervical cancer poses a major threat with high mortality rates, especially in women. New incidence cases and prevalence vary across different regions, as recently shown by GLOBOCAN data. The development of cervical cancer is primarily due to persistent infection by high-risk genotypes of human papillomavirus (HPV), which is a multifaceted process that is influenced by genetic, environmental, and lifestyle factors.PurposeThe goal of this study is to thoroughly investigate cervical cancer, including its etiology, molecular mechanisms, progressio

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… Immunotherapy with Checkpoint Inhibitors Targeting PD-1, PD-L1, and CTLA-4 Boosts CD8 + T Cells to Target Tumor Antigens and Kill Cancer Cells via Perforin and Granzyme B, Aided by Vaccines. …

CAR T cells: engineered immune cells to treat brain cancers and beyond.

Malignant brain tumors rank among the most challenging type of malignancies to manage. The current treatment protocol commonly entails surgery followed by radiotherapy and/or chemotherapy, however, the median patient survival rate is poor. Recent developments in immunotherapy for a variety of tumor types spark optimism that immunological strategies may help patients with brain cancer. Chimeric antigen receptor (CAR) T cells exploit the tumor-targeting specificity of antibodies or receptor ligands to direct the cytolytic capacity of T cells. Several molecules have been discovered as potential t

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… Granzyme and perforin, which are capable of harming tumor cells, are secreted by CAR T cells to exert cytotoxicity [ 23 ]. The other method of cytotoxicity involves inducing apoptosis in cancer cells by endorsing apoptotic signal transduction. …

Glioblastoma Treatment: State-of-the-Art and Future Perspectives.

(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve ove

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… The attack mechanisms by NKs are through the release of perforins and granzymes, inducing apoptosis through the caspases pathway by regulating death ligands, such as FAS and TRAIL [ 92 , 93 ]. NKs infiltrate approximately 90% of GBMs. …

Mechanisms of Action of the New Antibodies in Use in Multiple Myeloma.

Monoclonal antibodies (mAbs) directed against antigen-specific of multiple myeloma (MM) cells have Fc-dependent immune effector mechanisms, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), but the choice of the antigen is crucial for the development of effective immuno-therapy in MM. Recently new immunotherapeutic options in MM patients have been developed against different myeloma-related antigens as drug conjugate-antibody, bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CA

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… Once the cytolytic synapse has occurred, the T cells release perforin and granzyme B, thus inducing the apoptosis of the tumor cells. …

34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019): part 1 : National Harbor, MD, USA. 6-10 November 2019.

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Необычные хранители мозга: MAIT клетки как новые игроки в иммунитете от глиобластомы.

Глиобластома (GBM) является агрессивной формой рака мозга без лечения. Несмотря на то, что T-клеточная терапия продемонстрировала значительный успех в борьбе с раком крови, их применение для лечения твердых опухолей, включая GBM, затрудняется иммуновосприимчивой микроопухолью и нехваткой целевых показателей по борьбе с опухолью. Существует настоятельная необходимость более глубокого понимания иммунной реакции на ГБМ, с тем чтобы можно было разработать новые терапевтические подходы. Недавно было описано постоянное население мукосальных инвариантов Т (MAIT) в мозгу, которые могут выполнять крити

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… These TCRs allow recognition of lipid antigens produced by microbes, presented by the MHC class I-like molecule CD1d ( 97 ). iNKT cells display innate-like functions, rapidly producing a high level of cytotoxic molecules, including perforin and granzymes, upon antigen recognition. …

Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies.

Immune cell engagers are engineered antibodies with at least one arm binding a tumor-associated antigen and at least another one directed against an activating receptor in immune effector cells: CD3 for recruitment of T cells and CD16a for NK cells. The first T cell engager (the anti-CD19 blinatumomab) was approved by the FDA in 2014, but no other one hit the market until 2022. Now the field is gaining momentum, with three approvals in 2022 and 2023 (as of May): the anti-CD20 × anti-CD3 mosunetuzumab and epcoritamab and the anti-B cell maturation antigen (BCMA) × anti-CD3 teclistamab, and anot

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… ADCC relies on the formation of an IS and the degranulation of lytic granules containing perforin and granzymes, being the killing machinery comparable to that of effector CD8 T cells [ 111 ]. …

Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease?

Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypep

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… By contrast, the macrophages and activated NK cells were much more abundant in the mice receiving vildagliptin, which was accompanied by an increased expression of proinflammatory cytokines, perforin, FasL, and TRAIL. …

Immunotherapies for pediatric cancer: current landscape and future perspectives.

The advent of immunotherapy has revolutionized how we manage and treat cancer. While the majority of immunotherapy-related studies performed to date have focused on adult malignancies, a handful of these therapies have also recently found success within the pediatric space. In this review, we examine the immunotherapeutic agents that have achieved the approval of the US Food and Drug Administration for treating childhood cancers, highlighting their development, mechanisms of action, and the lessons learned from the seminal clinical trials that ultimately led to their approval. We also shine a

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… These NK cells secrete cytotoxic granules containing perforin and granzymes that directly kill cancer cells by inducing apoptosis through different mechanisms such as Fas and TRAIL pathways. …

Targeting Tumor Microenvironment for Cancer Therapy.

Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response

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… The immune surveillance of early stage solid tumor is mainly accomplished with NK cells and CD8+ T cells, which induce perforin- and granzyme-mediated apoptosis of the tumor cells, and consequently act in prevention of tumor development [ 23 ]. …