Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

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Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.

The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.

The Ubiquitin System

The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

/pdf/the-role-of-pattern-recognition-receptors-in-innate-immunity-39y77tlxza.pdf

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.

Immunobiology of Dendritic Cells

Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.

https://science.sciencemag.org/content/sci/early/2015/03/11/science.aaa1348.full.pdf

Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Purpose: To determine the immunogenicity and antitumor activity of a vaccine consisting of autologous, tumor-derived heat shock protein gp96-peptide complexes (HSPPC-96, Oncophage; Antigenics, Inc, Woburn, MA) in metastatic (American Joint Committee on Cancer stage IV) melanoma patients. Patients and Methods: Sixty-four patients had surgical resection of metastatic tissue required for vaccine production, 42 patients were able to receive the vaccine, and 39 were assessable after one cycle of vaccination (four weekly injections). In 21 patients, a second cycle (four biweekly injections) was given because no progression occurred. Antigen-specific antimelanoma T-cell response was assessed by enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Immunohistochemical analyses of tumor tissues were also performed. Results: No treatment-related toxicity was observed. Of 28 patients with measurable disease, two had a complete response (CR) and three had stable disease (SD) at the end of follow-up. Duration of CR was 559 and 703 days, whereas SD lasted for 153, 191, and 272 days, respectively. ELISPOT assay with PBMCs of 23 subjects showed a significantly increased number of postvaccination melanoma-specific T-cell spots in 11 patients, with clinical responders displaying a high frequency of increased T-cell activity. Immunohistochemical staining of melanoma tissues from which vaccine was produced revealed high expression of both HLA class I and melanoma antigens in seven of eight clinical responders (two with CR, three with SD, and the three with long-term disease-free survival) and in four of 12 nonresponders. Conclusion: Vaccination of metastatic melanoma patients with autologous HSPPC-96 is feasible and devoid of significant toxicity. This vaccine induced clinical and tumor-specific T-cell responses in a significant minority of patients. J Clin Oncol 20:4169-4180. © 2002 by American Society of Clinical Oncology.

V a c c ination o f M etastatic M elanoma P atients W ith Autologous T umor-Derived H eat S hock P rotein g p96- Peptide C omplexes: C linical a nd I mmunologic F indings

Synthesis of N-aryl-N'-2-naphthiazolylguanidines

That inbred rodents can be immunized against their own tumors or against other syngeneic tumors was convincingly demonstrated between 1943 and 1962 (Gross 1943; Prehn and Main 1957; Klein et al 1960; Old et al1962; for a review, see Srivastava and Old 1988) This provided the basis for the idea of immunogenicity of cancers and by deduction, of the existence of tumor-specific antigens In essence, these studies showed that mice vaccinated with inactivated cancer cells are immune to subsequent challenges of live cancer cells The phenomenon was shown to be individually tumor-specific, in that mice were immune specifically to the tumors that were used to immunize them and not to other tumors (Basombrio 1970; Globerson and Feldman 1964), hence the nomenclature individually distinct tumor rejection antigens

Heat-Shock-Protein-Based Vaccines against Cancers and Intracellular Infections

The protection of wireless sensor networks (WSN) against malware attacks is crucial. The paper discusses the issue of malware attacks in WSN, which are commonly used for monitoring and surveillance in various applications. Due to resource constraints, sensor nodes in WSN are vulnerable to malware attacks, which can spread rapidly and paralyze the network. The development of new technologies such as IoT, Industry 4.0 has increased the importance of WSN, and it has become essential to address the challenges posed by the resource-constrained nature of sensor nodes and security concerns. In this paper, a model is considered with two exposed states to investigate the behaviour of malware spreading in WSN, and a SE1E2IR (Susceptible—Exposed State 1 - Exposed State 2 - Infectious—Recovered) model is proposed. The model is formulated as a system of differential equations, and its equilibrium and stability are examined. The basic reproduction number (R0) is also calculated as a key parameter that characterizes the spread of malware in the network. This parameter helps to identify the conditions under which the network will remain malware-free or when it will experience an outbreak of malware. The proposed model provides a mechanism for the earlier detection of malware occurrences in WSN, and also discusses the effect of connectivity and coverages on the propagation of malware in the network. The paper also includes a comparative study of the proposed model with existing models; extensive theoretical study and computation analysis are performed to validate the proposed model. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1049/cmu2.12622

An epidemic model for the investigation of multi‐malware attack in wireless sensor network

Described herein are isolated dendritic cells, e.g., blood or bone marrow derived dendritic cells, which can be combined with a neoepitope for immunotherapy.

Pramod K. Srivastava

Papers

V a c c ination o f M etastatic M elanoma P atients W ith Autologous T umor-Derived H eat S hock P rotein g p96- Peptide C omplexes: C linical a nd I mmunologic F indings

Synthesis of N-aryl-N'-2-naphthiazolylguanidines

Heat-Shock-Protein-Based Vaccines against Cancers and Intracellular Infections

An epidemic model for the investigation of multi‐malware attack in wireless sensor network

Dendritic Cells as a Novel Delivery System for Immunotherapy