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The use of double-faced, metallized, perforated PCB planes, segmented into strips for the anodic read-out of ionization signals in liquid argon TPCs, is emerging as a promising technology for charge readout in liquid argon TPCs used in large volume detectors.As a proof of concept, a prototype liquid Argon TPC hosting this new anode configuration based on single side perforated PCB planes has been constructed and exposed to cosmic rays at LNL in Italy. Tests were performed with both the metallized and insulating sides of the anode facing the drift volume, providing the first evidence of the focusing effect on drift electron trajectories through the PCB holes due to charge accumulation on the insulator surface.

A novel liquid argon purity monitor based on a 207 Bi radioactive source, emitting monochromatic internal-conversion electrons, is presented. This new monitor allows for a very precise and fast measurement of the electronegative impurities concentration in liquid argon. It can be operated continuously in liquid argon TPC experiments without interfering with the main detector operation. Different drift lengths can be assembled for the proposed device, to assess a large range of liquid argon purities while minimizing systematic uncertainties. Two prototypes have been built and successfully operated in dedicated test stands. The results and performance are reported.

We present a search for long-lived particles (LLPs) produced from kaon decay that decay to two muons inside the ICARUS neutrino detector. This channel would be a signal of hidden sector models that can address outstanding issues in particle physics such as the strong CP problem and the microphysical origin of dark matter. The search is performed with data collected in the Neutrinos at the Main Injector (NuMI) beam at Fermilab corresponding to \\(2.41\\times 10^{20}\\) protons-on-target. No new physics signal is observed, and we set world-leading limits on heavy QCD axions, as well as for the Higgs portal scalar among dedicated searches. Limits are also presented in a model-independent way applicable to any new physics model predicting the process \\(K\\to \\pi+S(\\to\\mu\\mu)\\), for a long-lived particle S. This result is the first search for new physics performed with the ICARUS detector at Fermilab. It paves the way for the future program of long-lived particle searches at ICARUS.

This paper reports on a measurement of electron-ion recombination in liquid argon in the ICARUS liquid argon time projection chamber (LArTPC). A clear dependence of recombination on the angle of the ionizing particle track relative to the drift electric field is observed. An ellipsoid modified box (EMB) model of recombination describes the data across all measured angles. These measurements are used for the calorimetric energy scale calibration of the ICARUS TPC, which is also presented. The impact of the EMB model is studied on calorimetric particle identification, as well as muon and proton energy measurements. Accounting for the angular dependence in EMB recombination improves the accuracy and precision of these measurements.

The ICARUS liquid argon time projection chamber (LArTPC) neutrino detector has been taking physics data since 2022 as part of the Short-Baseline Neutrino (SBN) Program. This paper details the equalization of the response to charge in the ICARUS time projection chamber (TPC), as well as data-driven tuning of the simulation of ionization charge signals and electronics noise. The equalization procedure removes non-uniformities in the ICARUS TPC response to charge in space and time. This work leverages the copious number of cosmic ray muons available to ICARUS at the surface. The ionization signal shape simulation applies a novel procedure that tunes the simulation to match what is measured in data. The end result of the equalization procedure and simulation tuning allows for a comparison of charge measurements in ICARUS between Monte Carlo simulation and data, showing good performance with minimal residual bias between the two.

BackgroundCD47 is an integral membrane protein that alters adaptive immunosurveillance when bound to the matricellular glycoprotein thrombospondin-1 (TSP1). We examined the impact of the CD47/TSP1 signaling axis on melanoma patient response to anti-PD-1 therapy due to alterations in T cell activation, proliferation, effector function, and bioenergetics.MethodsA syngeneic B16 mouse melanoma model was performed to determine if targeting CD47 as monotherapy or in combination with anti-PD-1 impacted tumor burden. Cytotoxic (CD8+) T cells from Pmel-1 transgenic mice were used for T cell activation, cytotoxic T lymphocyte, and cellular bioenergetic assays. Single-cell RNA-sequencing, ELISA, and flow cytometry was performed on peripheral blood mononuclear cells and plasma of melanoma patients receiving anti-PD-1 therapy to examine CD47/TSP1 expression.ResultsHuman malignant melanoma tissue had increased CD47 and TSP1 expression within the tumor microenvironment compared with benign tissue. Due to the negative implications CD47/TSP1 can have on antitumor immune responses, we targeted CD47 in a melanoma model and observed a decrease in tumor burden due to increased tumor oxygen saturation and granzyme B secreting CD8+ T cells compared with wild-type tumors. Additionally, Pmel-1 CD8+ T cells exposed to TSP1 had reduced activation, proliferation, and effector function against B16 melanoma cells. Targeting CD47 allowed CD8+ T cells to overcome this TSP1 interaction to sustain these functions. TSP1 exposed CD8+ T cells have a decreased rate of glycolysis; however, targeting CD47 restored glycolysis when CD8+ T cells were exposed to TSP1, suggesting CD47 mediated metabolic reprogramming of T cells. Additionally, non-responding patients to anti-PD-1 therapy had increased T cells expressing CD47 and circulating levels of TSP1 compared with responding patients. Since CD47/TSP1 signaling axis negatively impacts CD8+ T cells and non-responding patients to anti-PD-1 therapy have increased CD47/TSP1 expression, we targeted CD47 in combination with anti-PD-1 in a melanoma model. Targeting CD47 in combination with anti-PD-1 treatment further decreased tumor burden compared with monotherapy and control.ConclusionCD47/TSP1 expression could serve as a marker to predict patient response to immune checkpoint blockade treatment, and targeting this pathway may preserve T cell activation, proliferation, effector function, and bioenergetics to reduce tumor burden as a monotherapy or in combination with anti-PD-1.

Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.

Background: Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. Objectives: We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors’ knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. Methods and analysis: In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. Ethics: This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. Clinical trial registration: This study is registered on ClinicalTrials.gov: NCT04375384.

KSA (Ep-CAM) is highly expressed by colorectal cancers. The safety and immunologic effects of a vaccine consisting of recombinant baculovirus-derived KSA formulated with monophosphoryl lipid A (MPL) in liposomes and emulsified in mineral oil were evaluated, with and without co-administration of granulocyte-macrophage colony-stimulating factor (GM-CSF). Eleven patients with metastatic colorectal cancer received three subcutaneous (s.c.) injections of the vaccine at 4-week intervals. Six patients were randomized to also receive human recombinant GM-CSF (rGM-CSF) by subcutaneous injection daily for 4 days with each vaccination. Immunizations with and without rGM-CSF were well tolerated. Seven of the 11 patients developed significant KSA-specific cellular immune responses as assessed by lymphoproliferation and interferon-γ (IFN-γ) ELISPOT assays. All nine tested patients developed positive delayed type hypersensitivity reactions. Eight of the 11 patients developed KSA-specific antibody responses. The highest levels of cellular immune responses were observed in patients who received GM-CSF. Immunization with baculovirus-derived KSA formulated with monophosphoryl lipid A in liposomal emulsion is safe and can elicit KSA-specific immune responses. Co-administration of GM-CSF with this formulation is an effective method of generating KSA-specific T-helper (Th) 1-associated cellular immune responses.

The potential of adeno-associated virus (AAV)-based vectors in human gene therapy is being explored for several diseases. Although sustained transgene expression and low vector-associated cellular immunity are attractive features of recombinant (r) AAV, the wider application of rAAV vectors encapsidated in serotype 2 capsid is hampered by poor transduction efficiency in many target tissues. These include ex vivo -generated dendritic cells (DC), which have demonstrated promising immunotherapeutic activity. We report here that efficient transduction of mouse bone marrow-derived DC can be achieved with self-complementary ( sc ) rAAV encapsidated in serotype 6 capsid. Sequential exposure of DC precursor cultures to IL-4 and GM-CSF with sc rAAV6 encoding the human tumor antigen, carcinoembryonic antigen (CEA), for 7 days followed by activation with CpG oligodeoxynucleotides (ODN) and anti-mouse CD40 antibody resulted in highly efficient transduction of DC. DC surface markers as determined by flow cytometry analysis of sc rAAV6-transduced DC were comparable to nontransduced DC. Efficiency of vector transduction and transgene expression were confirmed by immunostaining and real-time PCR. Microarray analysis of RNA from CpG ODN and CD40 antibody stimulated sc AAV6-transduced DC revealed upregulation of transcription factors and cytokines involved in immune activation and downregulation of inhibitory factors, suggesting a possible role of transcriptional activation in the observed effect. The adoptive transfer into syngeneic mice of the ex vivo -transduced and activated DC resulted in the development of CEA-specific antibody and T-helper 1-associated immune responses. Immunized mice also developed antibody to AAV6 capsid protein, which did not crossreact with AAV2 capsid protein. These studies demonstrate the potential utility of sc rAAV serotype 6-based vectors in transduction of DC for genetic vaccination approaches.