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Monoclonal Antibodies: Leading Actors in the Relapsed/Refractory Multiple Myeloma Treatment.

Multiple myeloma is a complex hematologic malignancy, and despite a survival improvement related to the growing number of available therapeutic options since 2000s, it remains an incurable disease with most patients experiencing relapse. However, therapeutic options for this disease are constantly evolving and immunotherapy is becoming the mainstay of the therapeutic armamentarium of Multiple Myeloma (MM), starting with monoclonal antibodies (MoAbs) as elotuzumab, daratumumab and isatuximab. Elotuzumab, the first in class targeting SLAMF7, in combination with lenalidomide and dexamethasone and

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… Eighty-nine percent of patients developed infusion reaction (consisting on pyrexia, nausea, chills, flushing, rash, chest discomfort) during the first infusion of elotuzumab, mainly of grade 1–2 and resolving within 24 h. …

Translating IL-6 biology into effective treatments.

In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and

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… CRS leads to headache, fever, chills, severe nausea, vomiting, diarrhoea, musculoskeletal pain, dyspnoea, hypotension and tachycardia and in severe cases can be fatal. …

Pemphigus vulgaris.

Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. It is the most frequent and most severe form of pemphigus, occurring universally, usually between 40 and 60 years of age. It usually begins with blisters and erosions on the oral mucosa, followed by lesions on other mucous membranes and flaccid blisters on the skin, which can be disseminated. There is a clinical variant, pemphigus vegetans, which is characterized by the presence of vegetating lesions in the large folds of the skin. Clinical suspicion can

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… Infusion reactions, which may be reduced with previous administration of analgesics, antihistamines, and corticosteroids, include anaphylaxis, fever, hypotension, chills, headache, nausea, pruritus, and skin rash. …

The Pharmacology of T Cell Therapies.

Adoptive cellular therapy using T cells with tumor specificity derived from either natural T cell receptors (TCRs) or an artificial chimeric antigen receptor (CAR) has reached late phase clinical testing, with two CAR T cell therapies achieving regulatory approval within the United States in 2017. The effective use of these therapies depends upon an understanding of their pharmacology, which is quite divergent from traditional small molecule or biologic drugs. We review the different types of T cell therapy under clinical development, the factors affecting cellular kinetics following infusion,

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… CRS, which occurs in the majority of patients with ALL, is characterized in its mild form by a limited, influenza-like syndrome that includes fever, chills, and myalgia. …

BCMA/CD19 CAR T cell therapy for refractory myasthenia gravis: Proteomic signatures and single-cell transcriptomics of disease flares.

Myasthenia gravis (MG) is an autoimmune disorder characterized by B cell dysfunction. Here, we designed B cell maturation antigen (BCMA)/CD19 chimeric antigen receptor T cell (CAR T cell) therapy for six refractory MGs, demonstrating favorable safety with grade 1 cytokine release syndrome observed. CAR T cell expansion induced profound B cell depletion, a sustained reduction in acetylcholine receptor (AChR) antibody titers, and symptom improvement. Five patients achieved drug-free remission with minimal manifestations by month 6, persisting through the 12-month follow-up despite B cell reconst

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… − | − | − | − | − | − | − | − Headache (grade) | − | − | − | + (1) | − | + (1) | − | − | − | − | − | Hand numbness (grade) | + (1) | + | − | + (1) | − | + (1) | − | + (1) | − | − | − | + (1) Muscle soreness (grade) | + (1) | + (1) | + (1) | + (1) | − | + (1) | − | + (1) | + (1) | − | + (1) | + (1) Chills …

Stem Cells Collection and Mobilization in Adult Autologous/Allogeneic Transplantation: Critical Points and Future Challenges.

Achieving successful hematopoietic stem cell transplantation (HSCT) relies on two fundamental pillars: effective mobilization and efficient collection through apheresis to attain the optimal graft dose. These cornerstones pave the way for enhanced patient outcomes. The primary challenges encountered by the clinical unit and collection facility within a transplant program encompass augmenting mobilization efficiency to optimize the harvest of target cell populations, implementing robust monitoring and predictive strategies for mobilization, streamlining the apheresis procedure to minimize colle

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… Severe AEs were 0.1% (syncope/hypotension 25.4%, urticaria 25.4%, arrhythmia/asystole 4.8%, nausea/vomiting 3.2%, chills/fever 1.6%) [ 101 ]. Considering the above, PBSC collection by apheresis can be performed safely in an outpatient setting. …

Updates on Therapeutic Strategies in the Treatment of Relapsed/Refractory Multiple Myeloma.

Multiple myeloma is a heterogeneous condition characterized by the proliferation of monoclonal B-cells, for which there is currently no curative treatment available. Relapses are, unfortunately, common after first-line treatment. While the prognosis for relapsed refractory multiple myeloma is generally poor, advances in the treatment of relapsed or refractory multiple myeloma offer hope. However, the expansion of effective options in targeted treatment offers renewed optimism and hope that patients who fail on older therapies may respond to newer modalities, which are often used in combination

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… With intravenous administration, typical side effects include infusion reactions (especially at initial infusion), generalized symptoms like fever and chills, and gastrointestinal disturbances; adverse effects can also occur if the targeted antigen is found on normal cells that affect specific functions …

CAR-T: What Is Next?

The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Since then, extensive research activities have been ongoing globally on different hematologic and solid tumors to assess the safety and efficacy of CAR-T therapy for these diseases. Limitations to CAR

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… The key cytokine for CRS is IL-6, which is the main cause of the immune reactions of CRS such as fever, chills, headache, and malaise. …

Mathematical reconstruction of the metabolic network in an in-vitro multiple myeloma model.

It is increasingly apparent that cancer cells, in addition to remodelling their metabolism to survive and proliferate, adapt and manipulate the metabolism of other cells. This property may be a telling sign that pre-clinical tumour metabolism studies exclusively utilising in-vitro mono-culture models could prove to be limited for uncovering novel metabolic targets able to translate into clinical therapies. Although this is increasingly recognised, and work towards addressing the issue is becoming routinary much remains poorly understood. For instance, knowledge regarding the biochemical mechan

Current Trends and Challenges in the Clinical Translation of Nanoparticulate Nanomedicines: Pathways for Translational Development and Commercialization.

The use of nanotechnology in medicine has the potential to have a major impact on human health for the prevention, diagnosis, and treatment of diseases. One particular aspect of the nanomedicine field which has received a great deal of attention is the design and development of nanoparticulate nanomedicines (NNMs) for drug delivery (i.e., drug-containing nanoparticles). NNMs are intended to deliver drugs via various mechanisms: solubilization, passive targeting, active targeting, and triggered release. The NNM approach aims to increase therapeutic efficacy, decrease the therapeutically effecti

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… CARPA is an immediate, non-IgE-mediated hypersensitivity reaction that can cause symptoms, including anaphylaxis, facial swelling, facial flushing, chills, headache, and cardiopulmonary distress (Szebeni, 2005 ). …

Clinical uses of GM-CSF, a critical appraisal and update.

The role of granulocyte-macrophage-colony-stimulating factor (GM-CSF) in the supportive care of cancer patients has been evaluated with promising results. More recently, GM-CSF has been added to regimens for the mobilization of hematopoietic progenitor cells. An expanding role for GM-CSF in regulating immune responses has been recognized based upon its activity on the development and maturation of antigen presenting cells and its capability for skewing the immune system toward Th1-type responses. GM-CSF has been shown to preferentially enhance both the numbers and activity of type 1 dendritic

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… | IL-6 1, 5, or 10 μg/kg/day D 1–14 | 3 μg/kg/day D1–14 | No responses | DLT: thrombocytosis and hyperbilirubinemia De Gast et al 2000 | 18 11 RCC 7 melanoma Phase I | IL-2: 1, 4, or 8 MIU/m 2 , and INF-α: 5 MIU SQ × 12 days every 3 wks | 2.5 or 5 μg/kg/day SQ | CR: 3/11 SD: 5/11 | DLT: fever with chills …

Механизм поглощения и токсичности антителного препарата BCMA в сочетании с полезной нагрузкой MMAF неантигенными функционирующими элементами.

Belantamab mafodotin, антитело-наркомания (ADC), продемонстрировал высокую эффективность в множестве миеломы. Он состоит из гуманизированного антиклектового антигена (BCMA) IgG1 моноклонального антитела, смешанного с монометил-ауристатином F (MMAF) с помощью манимидокапроилового связующего устройства. С помощью неизвестных механизмов поступили сообщения о связанных с окультизмом неблагоприятных явлениях, в частности о роговицах, в которых содержится АКЦ, в том числе белантамб мафодотин. В ходе этого исследования изучался механизм поглощения и цитотоксичности белантамбом мафодотином, содержащим

Endothelial dysfunction and hemostatic imbalance in CAR T-cell-associated toxicities: pathophysiological insights and the role of circulating biomarkers.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory hematologic malignancies. While its clinical efficacy is well established, CAR T-cell therapy is frequently associated with severe immune-mediated toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), coagulopathy, and hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Increasing evidence suggests that endothelial dysfunction, hemostatic imbalance, and complement activation are key contributors to the pathogenesis of

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… Fever is typically the first manifestation, followed by chills, sinus tachycardia, hypotension, hypoxemia, and dyspnea ( 32 ). Reported incidence ranges from 42% to 92%, with severe cases occurring in 0-24% depending on the CAR T-cell product ( 45 – 48 ). …

Neutropenic events associated with new anticancer treatments, from pathophysiology to practice: a scoping review-NEW Group (Neutropenic Events Working Group).

INTRODUCTION: New anticancer agents are increasingly being prescribed, either in combination or as a replacement or maintenance therapy after conventional chemotherapy. Although they present certain previously unknown complications, they are also responsible for more classic hematological toxicities, such as neutropenia. Unlike conventional chemotherapy, the comprehension and management of NAN (Neutropenia Associated with Novel anticancer agent) is currently poorly codified and understood. METHODS: A literature scoping review was conducted by the NEW Group (Neutropenic Events multidisciplinar

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… Classical anti-CD20 mAb toxicities are generally manageable infusion-related side effects, such as chills, rigors, fever, dyspnea and hypotension, and are usually transient [ 85 ]. …

How can Cytokine-induced killer cells overcome CAR-T cell limits.

The successful treatment of patients affected by B-cell malignancies with Chimeric Antigen Receptor (CAR)-T cells represented a breakthrough in the field of adoptive cell therapy (ACT). However, CAR-T therapy is not an option for every patient, and several needs remain unmet. In particular, the production of CAR-T cells is expensive, labor-intensive and logistically challenging; additionally, the toxicities deriving from CAR-T cells infusion, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), have been documented extensively. Alternative

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… Clinical trials occasionally reported the incidence of only minor side effects, which include mild hypotension, fever and chills, headaches, nausea, and vomiting that do not require intensive medical interventions ( 72 ). …

Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer.

In tumor-bearing mice, cyclic fasting or fasting-mimicking diets (FMD) enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. Here we conducted a clinical trial to investigate the safety and biological effects of cyclic, five-day FMD in combination with standard antitumor therapies. In 101 patients, the FMD was safe, feasible, and resulted in a consistent decrease of blood glucose and growth factor concentration, thus recapitulating metabolic changes that mediate fasting/FMD anticancer effects in preclinical experiments. Integrated

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… 27.7) | 8 (7.9) | 1 (1.0) | 0 Nausea | 34 (33.7) | 14 (13.9) | 1 (1.0) | 0 Vomiting | 18 (17.8) | 3 (3.0) | 0 | 0 Syncope | 0 | 0 | 1 (1.0) | 0 Presyncope | 5 (5.0) | 2 (2.0) | 0 | 0 Tachycardia | 5 (5.0) | 2 (2.0) | 0 | 0 Epigastric pain | 9 (8.9) | 4 (4.0) | 0 | 0 Hot flushes | 6 (5.9) | 0 | 0 | 0 Chills …

Viral Vector-Based Melanoma Gene Therapy.

Gene therapy applications of oncolytic viruses represent an attractive alternative for cancer treatment. A broad range of oncolytic viruses, including adenoviruses, adeno-associated viruses, alphaviruses, herpes simplex viruses, retroviruses, lentiviruses, rhabdoviruses, reoviruses, measles virus, Newcastle disease virus, picornaviruses and poxviruses, have been used in diverse preclinical and clinical studies for the treatment of various diseases, including colon, head-and-neck, prostate and breast cancer as well as squamous cell carcinoma and glioma. The majority of studies have focused on i

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… The most common adverse effects upon application of TVEC were fatigue, chills, nausea and local injection symptoms. …

T-cell Immunotherapies and the Role of Nonclinical Assessment: The Balance between Efficacy and Pathology.

Gene-engineered T-cell therapies have the potential to revolutionize the treatment of cancer. These therapies have shown exceptional clinical efficacy specifically in the field of B-cell malignancies and the first products (Kymriah™ and Yescarta™) have recently been approved in the United States for specific indications. The power of these treatments is also linked with a distinct set of toxicities both predicted and unpredicted, including off-tumor activity, cytokine release syndromes, and neurotoxicity, occasionally with fatal consequences. As these therapies begin to reach more patients, it

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… Symptoms include fever, chills, hypotension, and tachycardia generally occurring days to occasionally weeks after gene-engineered T-cell therapy infusion but typically peaking around 8 days coinciding with maximal in vivo T-cell expansion. …

Management of cutaneous T cell lymphoma: new and emerging targets and treatment options.

Cutaneous T cell lymphomas (CTCL) clinically and biologically represent a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the most common subtypes. Over the last decade, new immunological and molecular pathways have been identified that not only influence CTCL phenotype and growth, but also provide targets for therapies and prognostication. This review will focus on recent advances in the development of therapeutic agents, including bortezomib, the histone deacetylase inhibitors (vorinostat and romidepsin), and pralatrexate in CTCL.

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… expressing IFN-γ that has been shown to induce a Th1 response when injected intralesionally. 96 A recent Phase II trial of repeated intralesional TG-1042 injections had a local response rate of 46% in CTCL patients and minimal adverse effects, including injection site reactions, lymphopenia, fever, and chills …

Fludarabine in the treatment of chronic lymphocytic leukemia: a review.

Fludarabine (FAMP) is the most effective and most extensively studied purine analog in indolent B-cell malignancies. Its use is indicated for first-and second-line treatment of B-cell chronic lymphocytic leukemia (B-CLL). FAMP as a single agent has produced superior response rates and progression-free survival than standard therapy with chlorambucil and alkylator-based regimen. Efficacy of FAMP may be increased by combining this purine analog with other chemotherapeutic and non-chemotherapeutic agents. FAMP and cyclophosphamide combination (FC) has shown promising results with higher overall r

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… The most common adverse events included nausea (77%), pyrexia (61%), chills (55%), neutropenia (55%), and fatigue (48%). Twenty patients (65%) experienced a Grade III or IV event. CR was achieved in 48% of patients with an OR rate of 71%. …