The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory has been involved in the development of synthetic peptide-based anti-cancer therapeutic vaccines. We first dedicated our efforts in the identification and validation of peptide epitopes for both CD8 and CD4 T cells from tumor-associated antigens (TAAs). Because of suboptimal immune responses and lack of therapeutic benefit of peptide vaccines containing these epitopes, we have focused our recent efforts in optimizing peptide vaccinations in mouse tumor models using numerous TAA epitopes. In this focused research review, we describe how after taking lessons from the immune system’s way of dealing with acute viral infections, we have designed peptide vaccination strategies capable of generating very high numbers of therapeutically effective CD8 T cells. We also discuss some of the remaining challenges to translate these findings into the clinical setting.

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On April 8, 2016 Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on the treatment of primary and metastatic liver cancers, reported that the Hacettepe University Clinic in Ankara, Turkey has been activated as a treatment center for the Delcath Hepatic CHEMOSAT Delivery System (CHEMOSAT) for the treatment of cancers of the liver (Press release, Delcath Systems, APR 8, 2016, View Source;p=RssLanding&cat=news&id=2155549 [SID:1234510558]). Hacettepe University Clinic successfully completed its first CHEMOSAT treatments in March, and the center represents the first CHEMOSAT commercial location to be activated outside of the European Union.

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"We are especially pleased to be expanding access to CHEMOSAT to benefit the thousands of patients in Turkey suffering with these life-threatening cancers of the liver for which there are limited treatment options," said Dr. Jennifer K. Simpson, Ph.D., MSN, CRNP, President and Chief Executive Office of Delcath. "With its high level of clinical expertise, we believe that Hacettepe University can serve as an important hub for CHEMOSAT treatment to patients in Turkey and throughout the region. We are selectively evaluating other markets in the wider European region in order to continue our geographic expansion and the steady growth in clinical adoption of CHEMOSAT as a treatment for patients with cancers of the liver."

p53 tumor suppressor maintains genomic stability, typically acting through cell-cycle arrest, senescence, and apoptosis. We discovered a function of p53 in preventing conflicts between transcription and replication, independent of its canonical roles. p53 deficiency sensitizes cells to Topoisomerase (Topo) II inhibitors, resulting in DNA damage arising spontaneously during replication. Topoisomerase IIα (TOP2A)-DNA complexes preferentially accumulate in isogenic p53 mutant or knockout cells, reflecting an increased recruitment of TOP2A to regulate DNA topology. We propose that p53 acts to prevent DNA topological stress originating from transcription during the S phase and, therefore, promotes normal replication fork progression. Consequently, replication fork progression is impaired in the absence of p53, which is reversed by transcription inhibition. Pharmacologic inhibition of transcription also attenuates DNA damage and decreases Topo-II-DNA complexes, restoring cell viability in p53-deficient cells. Together, our results demonstrate a function of p53 that may underlie its role in tumor suppression.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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H.P. Acthar Gel (Acthar) is a highly purified repository gel preparation of adrenocorticotropic hormone (ACTH1-39), a melanocortin peptide that can bind and activate specific receptors expressed on a range of systemic lupus erythematosus (SLE)-relevant target cells and tissues. This study was performed to evaluate the effects of Acthar in a mouse model of SLE, using an F1 hybrid of the New Zealand Black and New Zealand White strains (NZB/W F1). Twenty-eight week old NZB/W F1 mice with established autoimmune disease were treated with Acthar, Placebo Gel (Placebo), or prednisolone and monitored for 19 weeks. Outcomes assessed included disease severity (severe proteinuria, ≥ 20% body weight loss, or prostration), measurement of serial serum autoantibody titers, terminal spleen immunophenotyping, and evaluation of renal histopathology. Acthar treatment was linked with evidence of altered B cell differentiation and development, manifested by a significant reduction in splenic B cell follicular and germinal center cells, and decreased levels of circulating total and anti-double-stranded DNA (IgM, IgG, and IgG2a) autoantibodies as compared with Placebo. Additionally, Acthar treatment resulted in a significant decrease of proteinuria, reduced renal lymphocyte infiltration, and attenuation of glomerular immune complex deposition. These data suggest that Acthar diminished pathogenic autoimmune responses in the spleen, peripheral blood, and kidney of NZB/W F1 mice. This is the first preclinical evidence demonstrating Acthar’s potential immunomodulatory activity and efficacy in a murine model of systemic lupus erythematosus.
© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

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The most common congenital disorder of glycosylation, PMM2-CDG, is caused by mutations in phosphomannomutase 2 (PMM2) that limit availability of mannose precursors required for protein N-glycosylation. The disorder has no therapy and there are no models to test new treatments. We generated compound heterozygous mice with the R137H and F115L mutations inPmm2that correspond to the most prevalent alleles found in patients with PMM2-CDG. ManyPmm2(R137H/F115L)mice died prenatally, while survivors had significantly stunted growth. These animals and cells derived from them showed protein glycosylation deficiencies similar to those found in patients with PMM2-CDG. Growth-related glycoproteins insulin-like growth factor (IGF) 1, IGF binding protein-3, and acid-labile subunit, along with antithrombin III, were all deficient inPmm2(R137H/F115L)mice, but their levels in heterozygous mice were comparable to wild-type (WT) littermates. These imbalances, resulting from defective glycosylation, are likely the cause of the stunted growth seen both in our model and in PMM2-CDG patients. BothPmm2(R137H/F115L)mouse and PMM2-CDG patient-derived fibroblasts displayed reductions in PMM activity, GDP-mannose, lipid-linked oligosaccharide precursor, and total cellular protein glycosylation, along with hypoglycosylation of a new endogenous biomarker, glycoprotein 130 (gp130). Over-expression of WT-PMM2 in patient-derived fibroblasts rescued all these defects, showing that restoration of mutant PMM2 activity is a viable therapeutic strategy. This functional mouse model of PMM2-CDG,in vitroassays, and identification of the novel gp130 biomarker all shed light on the human disease, and moreover, provide the essential tools to test potential therapeutics for this untreatable disease.
© The Author 2016. Published by Oxford University Press.

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