A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients ...with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.
Identifying T cell epitopes on pancreatic ductal adenocarcinoma (PDAC) associated antigens or neoantigens has been a challenge. In this study, we attempted to identify PDAC T cell epitopes by mass ...spectrometry (MS).
We isolated HLA class I (HLA-I) and HLA class II (HLA-II)-restricted peptides, respectively, from tissues of human PDAC by using the pan-HLA-I or pan-HLA-II affinity purification column and identified T cell epitopes by peptidome analysis with MS.
Through peptidome analysis, we identified T cell epitopes shared by multiple patients with different HLA types and those containing sequences of both anti-HLA-I and HLA-II antibodies-affinity purified peptides. The identified epitopes bound non-matched HLA molecules and induced T cell response in peripheral T cells from both HLA-type matched and non-matched patients. Peptides containing both HLA class I and class II epitopes were able to induce polyfunctional cytokine responses in peripheral T cells.
T cell epitopes in PDAC can be discovered by the MS approach and can be designed into vaccine and TCR-T cell therapies for both HLA-type matched and non-matched patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In this work we study joint pricing and power allocation for Dynamic Spectrum Access (DSA) networks with Stackelberg game. In our model, Primary User (PU) is the game leader and jointly determines ...its power allocation (to guarantee its QoS requirement) and the interference price charged to Secondary User (SU) (to reap revenue). Meanwhile, SU is the game follower and determines its power demand in response to PU's decisions. We quantify PU's and SU's benefit from the channel sharing model by deriving the Stackelberg equilibrium. Our results show that PU's equilibrium profit is asymptotically upper bounded with its marginal power cost and rate requirement. A distributed algorithm is proposed to find the equilibrium. We also propose an incentive-compatible mechanism for PU and SU to keep the social welfare optimum cooperatively. We extend our Stackelberg game to the multiple SUs scenario, where the interference among SUs results in a noncooperative power demand subgame. We propose a low-complexity heuristic algorithm for PU to maximize its profit. Our results show that PU can benefit by selecting multiple SUs to share its channel if SUs' mutual interference is limited.
As an enabling mechanism for the implementation of cognitive radio networks (CRNs), cooperative sensing provides an effective approach for exploiting spectrum opportunities. Although extensive ...research has been carried out, the fundamental question in the context of cooperative sensing is still not well understood, which can be stated as follows: Given a set of sensors and a set of primary user (PU) channels for opportunistic usage, how are the sensors appropriately assigned to sense the PU channels? We refer to this problem as the cooperative sensing scheduling (CSS) problem. Specifically, the CRN's expected throughput achieved and the overhead incurred in the sensing procedure, i.e, the energy efficiency of the CRN, are jointly considered when we make scheduling decisions. We first study a homogeneous network scenario with the objective of maximizing the expected throughput of the CRN. The energy consumption of the CRN is subsequently taken into consideration. A theoretical framework is established to analyze the structures of the two cases, and algorithms guaranteeing the optimal solutions to be found are developed. With the insights gained, we extend the study to the heterogeneous case. Low-complexity algorithms are then presented, and their computation time and performance are compared with the optimal and existing approaches.
Due to the problem of spectrum scarcity and large energy consumption in wireless communications, designing energy-efficient Cognitive Radio Networks (CRNs) becomes important and necessary. In this ...paper, we consider the problem of optimal Cooperative Sensing Scheduling (CSS) and parameter design to achieve energy efficiency in CRNs using the framework of Partially Observable Markov Decision Process (POMDP). In particular, we consider the CSS problem for a CRN with M Secondary Users (SUs) and N primary channels to determine how many SUs should be assigned to sense each channel in order to maximize the objective function that is related to energy efficiency. By assigning more SUs to sense one channel, higher sensing accuracy can be gained; however, by spreading out the SUs to sense more channels, spectrum opportunities can be better exploited. The CSS problem is formulated as a combinatorial optimization problem. While such problem is generally hard and can only be solved by numerical methods with high computation complexity, in this paper we provide a detailed analysis and the analytical results provide useful and interesting insights. The optimality of the myopic CSS is proved for the case of two channels, and it is also conjectured for the general case. We also study the tradeoff between the sensing and transmission durations. In addition, the structure of the optimal sensing time that maximizes the energy efficiency objective is also analyzed, the condition for the optimality of the myopic sensing time is obtained, and the performance upper bound of the myopic policy is derived. Based on the numerical results, we show that by carefully tuning a punishment parameter, better energy efficiency can be achieved.
In cognitive radio (CR) networks, secondary users can be coordinated to perform spectrum sensing so as to detect primary user activities more accurately. However, more sensing cooperations for a ...channel may decrease the transmission time of the secondary users, or lose opportunities for exploiting other channels. In this paper, we study this tradeoff by using the theory of oartially observable Markov decision process (POMDP). This formulation leads to an optimal sensing scheduling policy that determines which secondary users sense which channels with what miss detection probability and false alarm probability. A myopic policy with lower complexity yet comparable performance is also proposed. We further analytically study the properties and the solution structure for the myopic and the optimal policies under a simplified system model. Theoretical results reveal that under certain conditions, some simple but robust structures of the value function exist, which lead to an easy way to obtain the solution of POMDP. Moreover, the cooperative sensing scheduling problem embedded in our POMDP, which is generally a hard combinatorial problem, can be analyzed in an efficient way. Numerical and simulation results are provided to illustrate that our design can utilize the spectrum more efficiently for CR users.
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•Utilized a simple hydrothermal method to create PN junction composites.•Proved enhanced Faradaic activity via charge redistribution at interfaces.•Reduced band gap enhanced LDH ...material conductivity.•Investigated charge transfer pathways during charging/discharging.
Heterostructure materials, owing to their unique interfaces, robust structures, and synergistic effects, are increasingly garnering attention for their potential to enhance the energy/power output and lifespan of energy storage devices. Nonetheless, the intricate relationship between the band theory of heterostructures and their design strategies still demands further exploration. In this study, a binder-free NiCo2O4@NiCoAl-layered double hydroxide (LDH) PN junction cathode was constructed through a straightforward hydrothermal reaction. Extensive characterization and first-principles calculations have substantiated that the redistribution of charge within the space charge region considerably boosts the Faradaic activity and augments the conductivity of the LDH component, demonstrating an impressive specific capacitance of 1434.0 C g−1. Furthermore, the analysis focusing on the width of the space charge region has shed light on the charge transfer mechanism during charging and discharging, thereby validating the efficacy of the PN junction material design strategy. This research underscores the pivotal role of semiconductor theory in heterostructures and illuminates the potential of Faradaic PN junction composite materials in battery-type energy storage applications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cooperative spectrum sensing, which provides an effective approach to improve the sensing performance and better exploit the spectrum opportunities, is an important technology to enable the ...implementation of Cognitive Radio Networks (CRNs). The most fundamental and practical problem of cooperative spectrum sensing is: how to appropriately schedule Secondary Users (SUs) to sense multiple primary channels? In this paper, we study this Cooperative Sensing Scheduling (CSS) problem in the context of energy-aware CRNs. The CSS problem is modeled as a combinatorial optimization problem with the objective of improving energy efficiency in CRNs. Different from general approaches which employ heuristic methods to solve such combinatorial optimization problem, we propose a theoretical framework and analytically study the problem. Some interesting and important properties are obtained, while a simple but robust algorithm that guarantees to find the optimal solution efficiently is developed based on our findings. By observing that our problem shares a general form as studied in many other topics, we also discuss about the potential applications of our framework.
Tumor antigens are crucial targets for T-cell-based therapy to induce tumor-specific rejection. However, identifying pancreatic ductal adenocarcinoma (PDAC)-specific T-cell epitopes has been ...challenging. Using advanced mass spectrometry (MS) analysis, we previously identified cancer-associated, class I MHC-bound epitopes shared by multiple PDAC patients with different HLA-A types. Here, we investigated one of these epitopes, LAMC2203-211, a naturally occurring nonmutated epitope on the LAMC2 protein. Following stimulation with the LAMC2203-211 peptide, we cloned T-cell receptors (TCRs) and transduced them into the Jurkat human T-cell line using a lentiviral vector. We found that Jurkat cells expressing LAMC2203-211-specific TCRs resulted in potent, LAMC2 specific, in vitro cytotoxic effects on PDAC cells. Furthermore, in mice that harbored either subcutaneously or orthotopically implanted tumors originating from both HLA-A allele-matched and unmatched PDAC patients, tumor growth was suppressed in a LAMC2-dependent manner following the infusion of LAMC2-targeting T cells. We have therefore developed a LAMC2-specific TCR-based T-cell therapy strategy likely suitable for many PDAC patients. This is the first study to adopt MS analysis to identify natural CD8+ T-cell epitopes in PDAC that could potentially serve as targets for PDAC immunotherapy.
•Mass spectrometry analysis identified MHC-Class I epitopes shared by multiple PDAC patients with different HLA-A types.•The LAMC2203-211 epitope is a promising target for T-cell-based immunotherapy against PDAC.•LAMC2203-211-targeting TCR-T cells can suppress tumor growth in xenograft models of PDAC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teff). We prospectively collected and applied multi-omic ...analyses to paired pre- and post-treatment PDAC specimens collected in a platform neoadjuvant study of granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDAC vaccine (GVAX) vaccine ± nivolumab (anti-programmed cell death protein 1 PD-1) to uncover sensitivity and resistance mechanisms. We show that GVAX-induced tertiary lymphoid aggregates become immune-regulatory sites in response to GVAX + nivolumab. Higher densities of tumor-associated neutrophils (TANs) following GVAX + nivolumab portend poorer overall survival (OS). Increased T cells expressing CD137 associated with cytotoxic Teff signatures and correlated with increased OS. Bulk and single-cell RNA sequencing found that nivolumab alters CD4+ T cell chemotaxis signaling in association with CD11b+ neutrophil degranulation, and CD8+ T cell expression of CD137 was required for optimal T cell activation. These findings provide insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include TAN regulators and T cell activators.
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•Prospectively collected PDAC specimens from a neoadjuvant platform clinical trial•Identified sensitivity and resistance mechanisms to anti-PD-1 therapy in PDAC•Informed studies of additional immune-modulating agents in the ongoing platform trial•Generated hypotheses of reprogramed TME signals for combination immunotherapy strategies
Li et al. perform multi-omic analyses on pre- and post-treatment specimens from a pancreatic cancer neoadjuvant platform trial, and identify sensitivity and resistance mechanisms associated with anti-PD-1 combination therapy. Results associate tumor-associated neutrophils with poor outcomes but CD137+CD8+ T cells with better outcomes, suggesting treatment strategies for future interventions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
