Showing papers by "Anja Feldmann published in 2022"

Deep dive into the IoT backend ecosystem

Abstract: Internet of Things (IoT) devices are becoming increasingly ubiquitous, e.g., at home, in enterprise environments, and in production lines. To support the advanced functionalities of IoT devices, IoT vendors as well as service and cloud companies operate IoT backends---the focus of this paper. We propose a methodology to identify and locate them by (a) compiling a list of domains used exclusively by major IoT backend providers and (b) then identifying their server IP addresses. We rely on multiple sources, including IoT backend provider documentation, passive DNS data, and active scanning. For analyzing IoT traffic patterns, we rely on passive network flows from a major European ISP. Our analysis focuses on the top IoT backends and unveils diverse operational strategies---from operating their own infrastructure to utilizing the public cloud. We find that the majority of the top IoT backend providers are located in multiple locations and countries. Still, a handful are located only in one country, which could raise regulatory scrutiny as the client IoT devices are located in other regions. Indeed, our analysis shows that up to 35% of IoT traffic is exchanged with IoT backend servers located in other continents. We also find that at least six of the top IoT backends rely on other IoT backend providers. We also evaluate if cascading effects among the IoT backend providers are possible in the event of an outage, a misconfiguration, or an attack.

Validation of CD98hc as a Therapeutic Target for a Combination of Radiation and Immunotherapies in Head and Neck Squamous Cell Carcinoma

Abstract: Simple Summary The outcome of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) has not changed for the past decade despite advances in treatment strategies. SLC3A2, which encodes CD98hc, was identified as a putative biomarker for HNSCC radioresistance. Chimeric antigen receptor (CAR) T cell therapy presents a promising immunotherapy approach for the treatment of different cancer types. Due to the limitations of this system, including a lack of self-control mechanisms, the adapter UniCAR system with a switchable mechanism was developed. This study demonstrated a synergistic effect of the combination of fractionated irradiation and immune targeting of CD98hc. The sequential combination of fractionated radiotherapy and UniCAR-based immunotherapy revealed itself to be a promising approach for the treatment of high-risk HNSCC patients. Abstract Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e.g., the use of chimeric antigen receptor (CAR) T cells. This study aimed to define the potential clinical value of new treatment approaches combining conventional radiotherapy with CD98hc-targeted immunotherapy. To address this question, we analyzed the antitumor activity of the combination of fractionated irradiation and switchable universal CAR (UniCAR) system against radioresistant HNSCC cells in 3D culture. CD98hc-redirected UniCAR T cells showed the ability to destroy radioresistant HNSCC spheroids. Also, the infiltration rate of the UniCAR T cells was enhanced in the presence of the CD98hc target module. Furthermore, sequential treatment with fractionated irradiation followed by CD98hc-redirected UniCAR T treatment showed a synergistic effect. Taken together, our obtained data underline the improved antitumor effect of the combination of radiotherapy with CD98hc-targeted immunotherapy. Such a combination presents an attractive approach for the treatment of high-risk HNSCC patients.

Development and Functional Characterization of a Versatile Radio-/Immunotheranostic Tool for Prostate Cancer Management

Abstract: Simple Summary In previous studies, we described a modular Chimeric Antigen Receptor (CAR) T cell platform which we termed UniCAR. In contrast to conventional CARs, the interaction of UniCAR T cells does not occur directly between the CAR T cell and the tumor cell but is mediated via bispecific adaptor molecules so-called target modules (TMs). Here we present the development and functional characterization of a novel IgG4-based TM, directed to the tumor-associated antigen (TAA) prostate stem cell antigen (PSCA), which is overexpressed in prostate cancer (PCa). We show that this anti-PSCA IgG4-TM cannot only be used for (i) redirection of UniCAR T cells to PCa cells but also for (ii) positron emission tomography (PET) imaging, and (iii) alpha particle-based endoradiotherapy. For radiolabeling, the anti-PSCA IgG4-TM was conjugated with the chelator DOTAGA. PET imaging was performed using the 64Cu-labeled anti-PSCA IgG4-TM. According to PET imaging, the anti-PSCA IgG4-TM accumulates with high contrast in the PSCA-positive tumors of experimental mice without visible uptake in other organs. For endoradiotherapy the anti-PSCA IgG4-TM-DOTAGA conjugate was labeled with 225Ac3+. Targeted alpha therapy resulted in tumor control over 60 days after a single injection of the 225Ac-labeled TM. The favorable pharmacological profile of the anti-PSCA IgG4-TM, and its usage for (i) imaging, (ii) targeted alpha therapy, and (iii) UniCAR T cell immunotherapy underlines the promising radio-/immunotheranostic capabilities for the diagnostic imaging and treatment of PCa. Abstract Due to its overexpression on the surface of prostate cancer (PCa) cells, the prostate stem cell antigen (PSCA) is a potential target for PCa diagnosis and therapy. Here we describe the development and functional characterization of a novel IgG4-based anti-PSCA antibody (Ab) derivative (anti-PSCA IgG4-TM) that is conjugated with the chelator DOTAGA. The anti-PSCA IgG4-TM represents a multimodal immunotheranostic compound that can be used (i) as a target module (TM) for UniCAR T cell-based immunotherapy, (ii) for diagnostic positron emission tomography (PET) imaging, and (iii) targeted alpha therapy. Cross-linkage of UniCAR T cells and PSCA-positive tumor cells via the anti-PSCA IgG4-TM results in efficient tumor cell lysis both in vitro and in vivo. After radiolabeling with 64Cu2+, the anti-PSCA IgG4-TM was successfully applied for high contrast PET imaging. In a PCa mouse model, it showed specific accumulation in PSCA-expressing tumors, while no uptake in other organs was observed. Additionally, the DOTAGA-conjugated anti-PSCA IgG4-TM was radiolabeled with 225Ac3+ and applied for targeted alpha therapy. A single injection of the 225Ac-labeled anti-PSCA IgG4-TM was able to significantly control tumor growth in experimental mice. Overall, the novel anti-PSCA IgG4-TM represents an attractive first member of a novel group of radio-/immunotheranostics that allows diagnostic imaging, endoradiotherapy, and CAR T cell immunotherapy.

FlowDNS: correlating netflow and DNS streams at scale

Abstract: Knowing customer's interests, e.g. which Video-On-Demand (VoD) or Social Network services they are using, helps telecommunication companies with better network planning to enhance the performance exactly where the customer's interests lie, and also offer the customers relevant commercial packages. However, with the increasing deployment of CDNs by different services, identification, and attribution of the traffic on network-layer information alone becomes a challenge: If multiple services are using the same CDN provider, they cannot be easily distinguished based on IP prefixes alone. Therefore, it is crucial to go beyond pure network-layer information for traffic attribution. In this work, we leverage real-time DNS responses gathered by the clients' default DNS resolvers. Having these DNS responses and correlating them with network-layer headers, we are able to translate CDN-hosted domains to the actual services they belong to. We design a correlation system for this purpose and deploy it at a large European ISP. With our system, we can correlate an average of 81.7% of the traffic with the corresponding services, without any loss on our live data streams. Our correlation results also show that 0.5% of the daily traffic contains malformatted, spamming, or phishing domain names. Moreover, ISPs can correlate the results with their BGP information to find more details about the origin and destination of the traffic. We plan to publish our correlation software for other researchers or network operators to use.

FlowDNS

Abstract: Knowing customer's interests, e.g. which Video-On-Demand (VoD) or Social Network services they are using, helps telecommunication companies with better network planning to enhance the performance exactly where the customer's interests lie, and also offer the customers relevant commercial packages. However, with the increasing deployment of CDNs by different services, identification, and attribution of the traffic on network-layer information alone becomes a challenge: If multiple services are using the same CDN provider, they cannot be easily distinguished based on IP prefixes alone. Therefore, it is crucial to go beyond pure network-layer information for traffic attribution.

Delay-Resistant Geo-Distributed Analytics

Abstract: Big data analytics platforms have played a critical role in the unprecedented success of data-driven applications. However, real-time and streaming data applications, and recent legislation, e.g., GDPR in Europe, have posed constraints on exchanging and analyzing data, especially personal data, across geographic regions. To address such constraints data has to be processed and analyzed in-situ and aggregated results have to be exchanged among the different sites for further processing. This introduces additional network delays due to the geographic distribution of the sites and potentially affecting the performance of analytics platforms that are designed to operate in datacenters with low network delays. In this paper, we show that the three most popular big data analytics systems (Apache Storm, Apache Spark, and Apache Flink) fail to tolerate round-trip times more than 30 milliseconds even when the input data rate is low. The execution time of distributed big data analytics tasks degrades substantially after this threshold, and some of the systems are more sensitive than others. A closer examination and understanding of the design of these systems show that there is no winner in all wide-area settings. However, we show that it is possible to improve the performance of all these popular big data analytics systems significantly amid even transcontinental delays (where inter-node delay is more than 30 milliseconds) and achieve performance comparable to this within a datacenter for the same load.

Combining Radiation- with Immunotherapy in Prostate Cancer: Influence of Radiation on T Cells

Abstract: Radiation of tumor cells can lead to the selection and outgrowth of tumor escape variants. As radioresistant tumor cells are still sensitive to retargeting of T cells, it appears promising to combine radio- with immunotherapy keeping in mind that the radiation of tumors favors the local conditions for immunotherapy. However, radiation of solid tumors will not only hit the tumor cells but also the infiltrated immune cells. Therefore, we wanted to learn how radiation influences the functionality of T cells with respect to retargeting to tumor cells via a conventional bispecific T cell engager (BiTE) and our previously described modular BiTE format UNImAb. T cells were irradiated between 2 and 50 Gy. Low dose radiation of T cells up to about 20 Gy caused an increased release of the cytokines IL-2, TNF and interferon-γ and an improved capability to kill target cells. Although radiation with 50 Gy strongly reduced the function of the T cells, it did not completely abrogate the functionality of the T cells.

45P The RevCAR T cell platform: A switchable and combinatorial therapeutic strategy for glioblastoma

Abstract: Glioblastoma (GBM) is a very aggressive brain tumor, associated with poor prognosis and survival. So far, the efficiency of available therapies is limited. After proving their effectiveness in targeting hematological malignancies, chimeric antigen receptor (CAR) T cells might provide a promising therapeutic approach for GBM. Here, we present our switchable Reverse CAR technology (RevCAR). Unlike conventional CAR T cells, RevCAR T cells contain an epitope in their extracellular receptor domain, and can only be activated via bispecific target modules (RevTM) which recognize the RevCAR T cells on one side and tumor cells on the other side.

SRv6: Is There Anybody Out There?

Abstract: Segment routing is a modern form of source-based routing, i.e., a routing technique where all or part of the routing decision is predetermined by the source or a hop on the path. Since initial standardization efforts in 2013, segment routing seems to have garnered substantial industry and operator support. Especially segment routing over IPv6 (SRv6) is advertised as having several advantages for easy deployment and flexibility in operations in networks. Many people, however, argue that the deployment of segment routing and SRv6 in particular poses a significant security threat if not done with the utmost care. In this paper we conduct a first empirical analysis of SRv6 deployment in the Internet. First, we analyze SRv6 behavior in an emulation environment and find that different SRv6 implementations have the potential to leak information to the outside. Second, we search for signs of SRv6 deployment in publicly available route collector data, but could not find any traces. Third, we run large-scale traceroute campaigns to investigate possible SRv6 deployments. In this first empirical study on SRv6 we are unable to find traces of SRv6 deployment even for companies that claim to have it deployed in their networks. This lack of leakage might be an indication of good security practices being followed by network operators when deploying SRv6.

Targeting CD10 on B-Cell Leukemia Using the Universal CAR T-Cell Platform (UniCAR)

Abstract: Chimeric antigen receptor (CAR)-expressing T-cells are without a doubt a breakthrough therapy for hematological malignancies. Despite their success, clinical experience has revealed several challenges, which include relapse after targeting single antigens such as CD19 in the case of B-cell acute lymphoblastic leukemia (B-ALL), and the occurrence of side effects that could be severe in some cases. Therefore, it became clear that improved safety approaches, and targeting multiple antigens, should be considered to further improve CAR T-cell therapy for B-ALL. In this paper, we address both issues by investigating the use of CD10 as a therapeutic target for B-ALL with our switchable UniCAR system. The UniCAR platform is a modular platform that depends on the presence of two elements to function. These include UniCAR T-cells and the target modules (TMs), which cross-link the T-cells to their respective targets on tumor cells. The TMs function as keys that control the switchability of UniCAR T-cells. Here, we demonstrate that UniCAR T-cells, armed with anti-CD10 TM, can efficiently kill B-ALL cell lines, as well as patient-derived B-ALL blasts, thereby highlighting the exciting possibility for using CD10 as an emerging therapeutic target for B-cell malignancies.

Cell Counting in Silicon Nanosensor for CAR T-Cell Therapy Monitoring

Abstract: Silicon nanowire sensors have demonstrated outstanding utility in biosensing, especially for small biomolecules at extremely low concentrations. However, the sensor is less commonly applied in whole-cell monitoring, such as CAR T-cell counting during cancer treatment. The patient’s T-cells are modified to express chimeric antigen receptors (CAR), targeting specific tumor cells in CAR T-cell treatment. Therefore, the CAR T-cell level in blood is an essential parameter when it comes to determining the immune system’s reactivity to fight cancer cells. Although nanosensors are typically beneficial for early cancer diagnosis and detection, we want to expand their application and explore their usage in cancer treatment monitoring and development. Our previous works showed promising results of using nanosensors to find the most effective immunotherapy. In this work, we study the response of silicon nanowire field-effect transistors (SiNW FET) to the binding of CAR T-cells and discuss the benefits and limitations of the sensors in cell monitoring. The SiNW FETs fabricated in a top-down manner showed superior sensitivity to IgG antibodies sensing in our previous study. A peptide with a high affinity to the designed CAR T-cells immobilized on SiNW FETs to detect the cell binding. We observed distinguished signals following the number of cells binding to the sensing area. The results pave the way for using nanosensors in monitoring cancer treatment, yet they suggest some room for improvement.

P4IX: a concept for P4 programmable data planes at IXPs

Abstract: Internet Exchange Points (IXPs) are a crucial part of the Internet's infrastructure. Large IXPs can potentially interconnect thousands of ASes and facilitate the exchange of more than 10 Tbps of traffic during peaks. However, their specific technical requirements (e.g., large Layer-2 domains, complex traffic filtering) are not well addressed by today's networking hardware, as vendors optimize for the ISP market due revenues that are orders of magnitude higher. Software Defined internet eXchanges (SDXes) are a promising solution since they enable tailored hardware and software stacks to satisfy the specific IXP requirements. They combine a high degree of automation with the flexibility to implement value-added services and, thus, may reduce IXP's costs. Since previous work is based on the OpenFlow standard, which was last updated in 2017, we revisit the idea by leveraging the flexibility of P4 networking hardware. We present the P4IX, a technical concept for a generic P4 packet processing pipeline for IXPs. The P4IX concept is built upon a comprehensive requirements analysis: we characterize the IXP landscape and provide first-hand insights of a large IXP operator (more than 1000 well distributed ports). Moreover, we use our insights to critically discuss the P4IX from an operational, technical, and organizational perspective.

P4ix

Abstract: Internet Exchange Points (IXPs) are a crucial part of the Internet's infrastructure. Large IXPs can potentially interconnect thousands of ASes and facilitate the exchange of more than 10 Tbps of traffic during peaks. However, their specific technical requirements (e.g., large Layer-2 domains, complex traffic filtering) are not well addressed by today's networking hardware, as vendors optimize for the ISP market due revenues that are orders of magnitude higher. Software Defined internet eXchanges (SDXes) are a promising solution since they enable tailored hardware and software stacks to satisfy the specific IXP requirements. They combine a high degree of automation with the flexibility to implement value-added services and, thus, may reduce IXP's costs. Since previous work is based on the OpenFlow standard, which was last updated in 2017, we revisit the idea by leveraging the flexibility of P4 networking hardware. We present the P4IX, a technical concept for a generic P4 packet processing pipeline for IXPs. The P4IX concept is built upon a comprehensive requirements analysis: we characterize the IXP landscape and provide first-hand insights of a large IXP operator (more than 1000 well distributed ports). Moreover, we use our insights to critically discuss the P4IX from an operational, technical, and organizational perspective.