Covert Ephemeral Communication in Named Data Networking

In the last decade, there has been a growing realization that the current Internet Protocol is reaching the limits of its senescence. This has prompted several research efforts that aim to design potential next-generation Internet architectures. Named Data Networking (NDN), an instantiation of the content-centric approach to networking, is one such effort. In contrast with IP, NDN routers maintain a significant amount of user-driven state. In this paper we investigate how to use this state for covert ephemeral communication (CEC). CEC allows two or more parties to covertly exchange ephemeral messages, i.e., messages that become unavailable after a certain amount of time. Our techniques rely only on network-layer, rather than application-layer, services. This makes our protocols robust, and communication difficult to uncover. We show that users can build high-bandwidth CECs exploiting features unique to NDN: in-network caches, routers' forwarding state and name matching rules. We assess feasibility and performance of proposed cover channels using a local setup and the official NDN testbed

Meeting Report: Fourth International Congress of the Society for Melanoma Research

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73384/1/j.1755-148X.2007.00437.x.pd

Improved Endpoints for Cancer Immunotherapy Trials

Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation

Potentiating vascular-targeted photodynamic therapy through CSF-1R modulation of myeloid cells in a preclinical model of prostate cancer

Vascular-targeted photodynamic therapy (VTP) induces rapid destruction of targeted tissues and is a promising therapy for prostate cancer. However, the resulting immune response, which may play an important role in either potentiating or blunting the effects of VTP, is still incompletely understood. Myeloid cells such as myeloid-derived suppressor cells (MDSCs) and macrophages are often found in tumors and are widely reported to be associated with cancer angiogenesis, tissue remodeling, and immunosuppression. These cells are also known to play a critical role in wound-healing, which is induced by rapid tissue destruction. In this study, we investigated the effects of VTP on the recruitment of tumor-infiltrating myeloid cells, specifically MDSCs and tumor-associated macrophages (TAMs), in the Myc-Cap and TRAMP C2 murine prostate cancer models. We report that VTP increased the infiltration of myeloid cells into the tumors, as well as their expression of CSF1R, a receptor required for myeloid differentiation, proliferation, and tumor migration. As anti-CSF1R treatment has previously been used to deplete these cells types in other murine models of prostate cancer, we hypothesized that combining anti-CSF1R with VTP therapy would lead to decreased tumor regrowth and improved survival. Importantly, we found that targeting myeloid cells using anti-CSF1R in combination with VTP therapy decreased the number of tumor MDSCs and TAMs, especially M2 macrophages, as well as increased CD8 T cell infiltration, decreased tumor growth and improved overall survival. These results suggest that targeting myeloid cells via CSF1R targeting is a promising strategy to potentiate the anti-tumor effects of VTP

Authentication with Weaker Trust Assumptions for Voting Systems

Some voting systems are reliant on external authentication services. Others use cryptography to implement their own. We combine digital signatures and non-interactive proofs to derive a generic construction for voting systems with their own authentication mechanisms, from systems that rely on external authentication services. We prove that our construction produces systems satisfying ballot secrecy and election verifiability, assuming the underlying voting system does. Moreover, we observe that works based on similar ideas provide neither ballot secrecy nor election verifiability. Finally, we demonstrate applicability of our results by applying our construction to the Helios voting system

Immunologic responses to xenogeneic tyrosinase DNA vaccine administered by electroporation in patients with malignant melanoma

BACKGROUND: Prior studies show that intramuscular injection and particle-mediated epidermal delivery of xenogeneic melanosomal antigens (tyrosinase or Tyr, gp100) induce CD8(+) T cell responses to the syngeneic protein. To further define the optimal vaccination strategy, we conducted a phase I study of in vivo electroporation (EP) of a murine Tyr DNA vaccine (pINGmuTyr) in malignant melanoma patients. METHODS: Human leukocyte antigen (HLA)-A1, A2, A24 or B35 stage IIb-IV melanoma patients received up to five doses of the mouse tyrosinase DNA vaccine by EP every three weeks at dose levels of 0.2 mg, 0.5 mg, or 1.5 mg per injection. Peripheral blood mononuclear cells (PBMC) were collected, cultured with a peptide pool containing eight HLA class I-restricted Tyr-specific T-cell epitopes, and analyzed by HLA-A*0101-restricted tetramers and intracellular cytokine staining (ICS). RESULTS: Twenty-four patients received ≥1 dose of the pINGmuTyr vaccine; PBMCs from 21 patients who completed all five doses were available for Tyr immune assays. The only common toxicity was grade 1 injection site reaction. Six of 15 patients (40%) in the 1.5 mg dose cohort developed Tyr-reactive CD8(+) T cell responses following stimulation, defined as a ≥3 standard deviation increase in baseline reactivity by tetramer or ICS assays. No Tyr-reactive CD8(+) T cell response was detected in the 0.2 mg and 0.5 mg dose cohort patients. Epitope spreading of CD8(+) T cell response to NY-ESO-1 was observed in one patient with vitiligo. One patient subsequently received ipilimumab and developed an enhanced Tyr-reactive response with polyfunctional cytokine profile. After a median follow-up of 40.9 months, median survival has not been reached. CONCLUSIONS: A regimen of five immunizations with pINGmuTyr administered by EP was found to be safe and resulted in Tyr-reactive immune responses in six of 15 patients at 1.5 mg dose cohort. TRIAL REGISTRATION: ClinicalTrials.gov NCT0047113

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Two Distinct Categories of Focal Deletions in Cancer Genomes

One of the key questions about genomic alterations in cancer is whether they are functional in the sense of contributing to the selective advantage of tumor cells. The frequency with which an alteration occurs might reflect its ability to increase cancer cell growth, or alternatively, enhanced instability of a locus may increase the frequency with which it is found to be aberrant in tumors, regardless of oncogenic impact. Here we've addressed this on a genome-wide scale for cancer-associated focal deletions, which are known to pinpoint both tumor suppressor genes (tumor suppressors) and unstable loci. Based on DNA copy number analysis of over one-thousand human cancers representing ten different tumor types, we observed five loci with focal deletion frequencies above 5%, including the A2BP1 gene at 16p13.3 and the MACROD2 gene at 20p12.1. However, neither RNA expression nor functional studies support a tumor suppressor role for either gene. Further analyses suggest instead that these are sites of increased genomic instability and that they resemble common fragile sites (CFS). Genome-wide analysis revealed properties of CFS-like recurrent deletions that distinguish them from deletions affecting tumor suppressor genes, including their isolation at specific loci away from other genomic deletion sites, a considerably smaller deletion size, and dispersal throughout the affected locus rather than assembly at a common site of overlap. Additionally, CFS-like deletions have less impact on gene expression and are enriched in cell lines compared to primary tumors. We show that loci affected by CFS-like deletions are often distinct from known common fragile sites. Indeed, we find that each tumor tissue type has its own spectrum of CFS-like deletions, and that colon cancers have many more CFS-like deletions than other tumor types. We present simple rules that can pinpoint focal deletions that are not CFS-like and more likely to affect functional tumor suppressors