scholarly journals Interleukin 2-Based Fusion Proteins for the Treatment of Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Alana MacDonald ◽  
T.-C. Wu ◽  
Chien-Fu Hung
Keyword(s):  
Cd8 T Cells ◽  
Tumor Regression ◽  
Interleukin 2 ◽  
Clinical Settings ◽  
Vascular Leak Syndrome ◽  
The Past ◽  
Fda Approval ◽  
Pharmacokinetic Properties ◽  
Fusion Methods ◽  
Life Threatening

Interleukin 2 (IL-2) plays a fundamental role in both immune activation and tolerance and has revolutionized the field of cancer immunotherapy since its discovery. The ability of IL-2 to mediate tumor regression in preclinical and clinical settings led to FDA approval for its use in the treatment of metastatic renal cell carcinoma and metastatic melanoma in the 1990s. Although modest success is observed in the clinic, cancer patients receiving IL-2 therapy experience a wide array of side effects ranging from flu-like symptoms to life-threatening conditions such as vascular leak syndrome. Over the past three decades, efforts have focused on circumventing IL-2-related toxicities by engineering methods to localize IL-2 to the tumor or secondary lymphoid tissue, preferentially activate CD8+ T cells and NK cells, and alter pharmacokinetic properties to increase bioavailability. This review summarizes the various IL-2-based strategies that have emerged, with a focus on chimeric fusion methods.

Quiescent phenotype of tumor-specific CD8+ T cells following immunization

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 1970-1978 ◽  
Author(s):  
Vladia Monsurrò ◽  
Ena Wang ◽  
Yoshisha Yamano ◽  
Stephen A. Migueles ◽  
Monica C. Panelli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Proliferative Potential

Abstract In a human melanoma model of tumor antigen (TA)–based immunization, we tested the functional status of TA-specific CD8+ cytotoxic T lymphocytes. A “quiescent” phenotype lacking direct ex vivo cytotoxic and proliferative potential was identified that was further characterized by comparing its transcriptional profile to that of TA-specific T cells sensitized in vitro by exposure to the same TA and the T-cell growth factor interleukin 2 (IL-2). Quiescent circulating tumor-specific CD8+ T cells were deficient in expression of genes associated with T-cell activation, proliferation, and effector function. This quiescent status may explain the observed lack of correlation between the presence of circulating immunization-induced lymphocytes and tumor regression. In addition, the activation of TA-specific T cells by in vitro antigen recall and IL-2 suggests that a complete effector phenotype might be reinstated in vivo to fulfill the potential of anticancer vaccine protocols.

The Evolution of Lead Extraction

2009 ◽  
Vol 5 (1) ◽  
pp. 32
Author(s):  
Melanie Maytin ◽  
Laurence M Epstein ◽  
◽  
Keyword(s):  
Natural Selection ◽  
Lead Extraction ◽  
Significant Morbidity ◽  
Extraction Techniques ◽  
Extraction Technology ◽  
Device Management ◽  
Future Developments ◽  
The Past ◽  
New Methods ◽  
Life Threatening

Prior to the introduction of successful intravascular countertraction techniques, options for lead extraction were limited and dedicated tools were non-existent. The significant morbidity and mortality associated with these early extraction techniques limited their application to life-threatening situations such as infection and sepsis. The past 30 years have witnessed significant advances in lead extraction technology, resulting in safer and more efficacious techniques and tools. This evolution occurred out of necessity, similar to the pressure of natural selection weeding out the ineffective and highly morbid techniques while fostering the development of safe, successful and more simple methods. Future developments in lead extraction are likely to focus on new tools that will allow us to provide comprehensive device management and the design of new leads conceived to facilitate future extraction. With the development of these new methods and novel tools, the technique of lead extraction will continue to require operators that are well versed in several methods of extraction. Garnering new skills while remembering the lessons of the past will enable extraction technologies to advance without repeating previous mistakes.

Brain-eating Amoebae Infection: Challenges and Opportunities in Chemotherapy

2019 ◽  
Vol 19 (12) ◽  
pp. 980-987 ◽  
Author(s):  
Mohammad Ridwane Mungroo ◽  
Ayaz Anwar ◽  
Naveed Ahmed Khan ◽  
Ruqaiyyah Siddiqui
Keyword(s):  
Mortality Rate ◽  
Free Living ◽  
Outdoor Activities ◽  
The Past ◽  
Free Living Amoeba ◽  
Challenges And Opportunities ◽  
Life Threatening ◽  
The Central Nervous System ◽  
Living Nature ◽  
Treatment And Diagnosis

Pathogenic free-living amoeba are known to cause a devastating infection of the central nervous system and are often referred to as “brain-eating amoebae”. The mortality rate of more than 90% and free-living nature of these amoebae is a cause for concern. It is distressing that the mortality rate has remained the same over the past few decades, highlighting the lack of interest by the pharmaceutical industry. With the threat of global warming and increased outdoor activities of public, there is a need for renewed interest in identifying potential anti-amoebic compounds for successful prognosis. Here, we discuss the available chemotherapeutic options and opportunities for potential strategies in the treatment and diagnosis of these life-threatening infections.

scholarly journals A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katherine E. Harris ◽  
Kyle J. Lorentsen ◽  
Harbani K. Malik-Chaudhry ◽  
Kaitlyn Loughlin ◽  
Harish Medlari Basappa ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Bispecific Antibody ◽  
T Regulatory Cells ◽  
Tumor Regression ◽  
Interleukin 2 ◽  
In Vivo Studies ◽  
Preferential Binding

AbstractThe use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαβγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rβγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule’s in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.

The Role of Histones and Heparin in Sepsis: A Review

2021 ◽  
pp. 088506662199232
Author(s):  
Xiaojuan Zhang ◽  
Xin Li
Keyword(s):  
Septic Shock ◽  
Multiple Organ ◽  
Clinical Settings ◽  
The Past ◽  
Life Saving ◽  
Extracellular Histones ◽  
Sepsis And Septic Shock ◽  
Development And Management ◽  
Made In

Septic shock with multiple organ failure is a devastating situation in clinical settings. Through the past decades, much progress has been made in the management of sepsis and its underlying pathogenesis, but a highly effective therapeutic has not been developed. Recently, macromolecules such as histones have been targeted in the treatment of sepsis. Histones primarily function as chromosomal organizers to pack DNA and regulate its transcription through epigenetic mechanisms. However, a growing body of research has shown that histone family members can also exert cellular toxicity once they relocate from the nucleus into the extracellular space. Heparin, a commonly used anti-coagulant, has been shown to possess life-saving capabilities for septic patients, but the potential interplay between heparin and extracellular histones has not been investigated. In this review, we summarize the pathogenic roles of extracellular histones and the therapeutic roles of heparin in the development and management of sepsis and septic shock.

scholarly journals Trauma-Induced Coagulopathy: Overview of an Emerging Medical Problem from Pathophysiology to Outcomes

Medicines ◽  
2021 ◽  
Vol 8 (4) ◽  
pp. 16
Author(s):  
Gabriele Savioli ◽  
Iride Francesca Ceresa ◽  
Luca Caneva ◽  
Sebastiano Gerosa ◽  
Giovanni Ricevuti
Keyword(s):  
Major Trauma ◽  
Management Strategies ◽  
Medical Problem ◽  
Current Evidence ◽  
Potential Drug ◽  
The Past ◽  
Trauma Induced Coagulopathy ◽  
Threatening Condition ◽  
Life Threatening ◽  
Trauma Mortality

Coagulopathy induced by major trauma is common, affecting approximately one-third of patients after trauma. It develops independently of iatrogenic, hypothermic, and dilutive causes (such as iatrogenic cause in case of fluid administration), which instead have a pejorative aspect on coagulopathy. Notwithstanding the continuous research conducted over the past decade on Trauma-Induced Coagulopathy (TIC), it remains a life-threatening condition with a significant impact on trauma mortality. We reviewed the current evidence regarding TIC diagnosis and pathophysiological mechanisms and summarized the different iterations of optimal TIC management strategies among which product resuscitation, potential drug administrations, and hemostatis-focused approaches. We have identified areas of ongoing investigation and controversy in TIC management.

scholarly journals Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range

2020 ◽  
Vol 21 (24) ◽  
pp. 9777
Author(s):  
Camille Le Guilcher ◽  
Tomas Luyten ◽  
Jan B. Parys ◽  
Mathieu Pucheault ◽  
Olivier Dellis
Keyword(s):  
Cell Activation ◽  
Interleukin 2 ◽  
Calcium Entry ◽  
Ip3 Receptors ◽  
Excitable Cells ◽  
Cellular Targets ◽  
Entry Inhibitors ◽  
The Past ◽  
Store Operated Calcium Entry

The store-operated calcium entry, better known as SOCE, forms the main Ca2+ influx pathway in non-excitable cells, especially in leukocytes, where it is required for cell activation and the immune response. During the past decades, several inhibitors were developed, but they lack specificity or efficacy. From the non-specific SOCE inhibitor 2-aminoethyl diphenylborinate (2-APB), we synthetized 16 new analogues by replacing/modifying the phenyl groups. Among them, our compound P11 showed the best inhibitory capacity with a Ki ≈ 75 nM. Furthermore, below 1 µM, P11 was devoid of any inhibitory activity on the two other main cellular targets of 2-APB, the IP3 receptors, and the SERCA pumps. Interestingly, Jurkat T cells secrete interleukin-2 under phytohemagglutinin stimulation but undergo cell death and stop IL-2 synthesis when stimulated in the presence of increasing P11 concentrations. Thus, P11 could represent the first member of a new and potent family of immunosuppressors.

Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Michael R. Verneris ◽  
Mobin Karami ◽  
Jeanette Baker ◽  
Anishka Jayaswal ◽  
Robert S. Negrin
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Malignant Cell ◽  
Leukemic Cells ◽  
Target Cells ◽  
High Dose ◽  
Effector Cells ◽  
Nkg2d Expression

Abstract Activating and expanding T cells using T-cell receptor (TCR) cross-linking antibodies and interleukin 2 (IL-2) results in potent cytotoxic effector cells capable of recognizing a broad range of malignant cell targets, including autologous leukemic cells. The mechanism of target cell recognition has previously been unknown. Recent studies show that ligation of NKG2D on natural killer (NK) cells directly induces cytotoxicity, whereas on T cells it costimulates TCR signaling. Here we demonstrate that NKG2D expression is up-regulated upon activation and expansion of human CD8+ T cells. Antibody blocking, redirected cytolysis, and small interfering RNA (siRNA) studies using purified CD8+ T cells demonstrate that cytotoxicity against malignant target cells occurs through NKG2D-mediated recognition and signaling and not through the TCR. Activated and expanded CD8+ T cells develop cytotoxicity after 10 to 14 days of culture, coincident with the expression of the adapter protein DAP10. T cells activated and expanded in low (30 U/mL) and high (300 U/mL) concentrations of IL-2 both up-regulated NKG2D expression equally, but only cells cultured in high-dose IL-2 expressed DAP10 and were cytotoxic. Collectively these results establish that NKG2D triggering accounts for the majority of major histocompatibility complex (MHC)–unrestricted cytotoxicity of activated and expanded CD8+ T cells, likely through DAP10-mediated signaling. (Blood. 2004;103: 3065-3072)

Terminal ileum resection as a trigger for Strongyloides stercoralis hyperinfection and ensuing serial sepsis in a 37-year-old patient with complicated Crohnʼs disease: a case report

2018 ◽  
Vol 56 (04) ◽  
pp. 380-383 ◽  
Author(s):  
Mirjana Topić ◽  
Silvija Čuković-Čavka ◽  
Marko Brinar ◽  
Mirjana Kalauz ◽  
Ivica Škrlec ◽  
...  
Keyword(s):  
Terminal Ileum ◽  
Skin Penetration ◽  
Strongyloides Stercoralis ◽  
Developed Countries ◽  
Clinical Settings ◽  
Solid Organ ◽  
Transplant Patients ◽  
Skin Contact ◽  
Life Threatening ◽  
The Tropics

AbstractThe nematode Strongyloides stercoralis, outside the tropics and subtropics present in small endemic foci, can cause an infection after direct skin contact with contaminated soil containing infective filariform larvae and, rarely, after intimate interhuman contact or after transplantation of an infected solid organ. Following skin penetration, migration, and maturation through several stages, a small number of invasive filariform larvae can develop anew in the gut lumen, perpetuating new cycles of penetration, tissue migration, and reproduction, without leaving the host.In a state of immunosuppression, autoinfection can progress to life-threatening hyperinfection and/or infection disseminated through virtually any organ. In developed countries, the most frequently recognized risk for severe hyperinfection is corticosteroid therapy, but this has been also described in malnourished, alcoholic, cancer, and transplant patients. Due to the frequent need for immunosuppressive therapy, patients suffering from inflammatory bowel disease (IBD) are susceptible to develop overwhelming strongyloidiasis. Strongyloidiasis can be easily overlooked in clinical settings, and in many European regions there is poor insight into the epidemiological burden of this disease.We present a case of S. stercoralis hyperinfection that triggered 3 successive episodes of sepsis caused by pathogens of the gut flora in a young patient suffering from stenotic form of Crohn’s disease. S. stercoralis hyperinfection occurred in the corticosteroid-free period, shortly after resection of the terminal ileum, which was probably the trigger for the overwhelming course. The patient was successfully treated with 10-day albendazole therapy.

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