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Abstract Though several anti-PD-1/PD-L1 antibodies approved for monotherapy in microsatellite instability-high or mismatch repair-deficient unresectable/metastatic solid tumors, novel immunotherapy with better anti-tumor activity is needed in clinic. In this single-arm, multicenter, pivotal, phase II study, patients received iparomlimab (a novel humanized anti-PD-1 mAb, 200 mg or 3 mg/kg for patients with body weight

Zinc finger CCCH containing 11A (ZC3H11A) is a stress-induced protein that is upregulated in various conditions such as heat shock and virus infection. It has also been reported to be upregulated in certain cancers. The aim of this study was to evaluate the feasibility of targeting ZC3H11A as a therapeutic approach for cancer treatment, using nuclease-resistant, affinity-enhanced antisense oligonucleotide (ASO). An ASO targeting ZC3H11A was validated and evaluated in vitro and in the B16 melanoma model in vivo. Antigen presentation, interferon response, cell proliferation, and apoptosis were transcriptionally affected. These findings were validated on the protein level by the upregulation of major histocompatibility complex class I (MHC class I), an increased secretion of interferon-β (IFN-β), and induction of apoptosis observed as upregulation of caspases and annexin V. Immunogenic features of the induced apoptosis were evidenced by the surface exposure of calreticulin (CRT) and the secretion of ATP leading to enhanced dendritic cell (DC) phagocytosis, maturation, and activation. Treatment with the ZC3H11A-targeted ASO had limited efficacy in vivo, while constitutive lentiviral shRNA knockdown of ZC3H11A in murine B16 melanoma cells and human HeLa cells led to reduced tumor growth with prolonged survival of mice, validating ZC3H11A as a relevant target for cancer therapy.

Abstract HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2–76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9–87.5%) and 75.4% (95% CI: 68.9–82.6%)( HR: 0.75, 95% CI 0.47–1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4–84.6%) and 73.0% (95% CI: 66.3–80.3%) (HR: 0.84, 95% CI 0.54–1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

In this study, the effects of variations in the height (h) and bottom radius (r) of black silicon microstructures on their absorptance and photoelectric response efficiency were analyzed. By using the relation cot⁡θ2=hr to combine the parameters, it was found that changes in morphology affected the absorptance of black silicon microstructures, with h being directly proportional to the absorptance, while r was inversely proportional. A positive correlation was observed between cot⁡θ2 and absorptance. However, the correlation between cot⁡θ2 and photoelectric response efficiency was not significant. Through Raman spectroscopy analysis of the samples, it was concluded that as the laser ablation energy density increased, more lattice defects were introduced, weakening the charge carrier transport efficiency. This study further elucidated the mechanism by which microstructural changes impacted the absorptance and energy density of black silicon, providing valuable insights for optimizing its energy density.

Overlay accuracy, one of the three fundamental indicators of lithography, is directly influenced by alignment precision. During the alignment process based on the Moiré fringe method, a slight angular misalignment between the mask and wafer will cause the Moiré fringes to tilt, thereby affecting the alignment accuracy. This paper proposes a leveling strategy based on the DQN (Deep Q-Network) algorithm. This strategy involves using four consecutive frames of wafer tilt images as the input values for a convolutional neural network (CNN), which serves as the environment model. The environment model is divided into two groups: the horizontal plane tilt environment model and the vertical plane tilt environment model. After convolution through the CNN and training with the pooling operation, the Q-value consisting of n discrete actions is output. In the DQN algorithm, the main contributions of this paper lie in three points: the adaptive application of environmental model input, parameter optimization of the loss function, and the possibility of application in the actual environment to provide some ideas. The environment model input interface can be applied to different tilt models and more complex scenes. The optimization of the loss function can match the leveling of different tilt models. Considering the application of this strategy in actual scenarios, motion calibration and detection between the mask and the wafer provide some ideas. To verify the reliability of the algorithm, simulations were conducted to generate tilted Moiré fringes resulting from tilt angles of the wafer plate, and the phase of the tilted Moiré fringes was subsequently calculated. The angle of the wafer was automatically adjusted using the DQN algorithm, and then various angles were measured. Repeated measurements were also conducted at the same angle. The angle deviation accuracy of the horizontal plane tilt environment model reached 0.0011 degrees, and the accuracy of repeated measurements reached 0.00025 degrees. The angle deviation accuracy of the vertical plane tilt environment model reached 0.0043 degrees, and repeated measurements achieved a precision of 0.00027 degrees. Moreover, in practical applications, it also provides corresponding ideas to ensure the determination of the relative position between the mask and wafer and the detection of movement, offering the potential for its application in the industry.

In order to correct the integrated nonuniformity of a lithographic illumination field, a high-precision uniformity correction method for an advanced lithographic illumination system is proposed. The method adopts the opaque finger array structure and improves correction ability and accuracy by optimizing the arrangement and structure of the unit without changing the width of each unit. The correction accuracy is expressed as the percentage of the corrected integrated nonuniformity. Through theoretical analysis and simulation, it can be seen that the correction accuracy of a staggered finger array is better than 0.22%. When staggered and layered, the correction accuracy of a finger array is better than 0.14%, which is better than that of a non-layered finger array. When staggered, layered, and chamfered of each unit, the correction accuracy of the finger array structure is better than 0.12%.

The six-degree-of-freedom (6-DOF) micromotion mechanism is a key component in extreme ultraviolet (EUV) projection lithography objectives to compensate for wavefront aberration and ensure performance stability. It is required to have high precision and high reliability. A 6-DOF mirror micromotion mechanism of an EUV lithography objective lens with Stewart configuration is proposed, and based on the RPY (Roll-Pitch-Yaw) angular rotation method and the second-type Lagrange method, the kinematic and dynamic models of the mechanism are constructed to realize the decoupling of the mechanism’s kinematics and the solution of the driving force. Comparative verification with finite element transient analysis shows that the response value of the dynamic model and the finite element method (FEM) differs by 4.8% in a specific posture. A hybrid optimization method, combining genetic algorithms and particle-swarm optimization (GA-PSO), was proposed to optimize the structural parameters of the initial design of the motion outriggers in a micromotion mechanism. The results demonstrate a 15.1% reduction in maximum driving force, significantly enhancing outrigger driving smoothness.

Abstract Background QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. Methods In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. Results Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. Conclusions QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Adaptive characteristics of plants, such as those associated with photosynthesis and resource use efficiency, are usually affected by synthesis costs and resource availability. The impact of extreme climate events such as long-term drought on plant physiological functions needs to be examined, particularly as it concerns the internal management of water and nitrogen (N) resources. In this study, we evaluated the resource management strategies for water and N by xerophytic shrubs, Artemisia ordosica and Salix psammophila, under extreme summer drought. This was carried out by comparing the plants’ physiological status during periods of wet and dry summer conditions in 2019 and 2021. Compared with the wet period, A. ordosica and S. psammophila both decreased their light-saturated net carbon (C) assimilation rate (Asat), stomatal conductance (gs), transpiration rate (E), leaf N content per leaf area (Narea), and photosynthetic N use efficiency (PNUE) during the summer drought. Whether in wet or dry summers, the gas-exchange parameters and PNUE of A. ordosica were generally greater than those associated with S. psammophila. The instantaneous water use efficiency (IWUE) response to drought varied with species. As a drought-tolerant species, the A. ordosica shrubs increased their IWUE during drought, whereas the S. psammophila shrubs (less drought-tolerant) decreased theirs. The divergent responses to drought by the two species were largely related to differences in the sensitivity of gs, and as a result, E. Compared with A. ordosica, S. psammophila’s inferior plasticity regarding gs response affected its ability to conserve water during drought. Our research illustrates the need for assessing plasticity in gs when addressing plant adaptation to long-term drought. A high dry-season IWUE in xerophytic shrubs can benefit the plants by augmenting their C gain.

Inverse lithography technologies (ILTs) are critical for improving the imaging performance of lithography in advanced technology nodes. Pixel-based source optimization (SO), as an efficient part of ILTs, can be implemented via heuristic approaches to achieve high-performance lithographic imaging. In this paper, a SO approach based on a combination of the particle-swarm optimization and genetic algorithms (PSO–GA) is proposed to determine the optimal intensity distribution of the source via iterations. The pixelated source can be decoded into the optimized variables of the merit functions in the SO model. The proposed PSO–GA algorithm, as a high-efficiency hybrid algorithm, can transform the discrete SO problem into the optimal search solution for the merit function, thereby inversely enhancing the lithographic-imaging performance. In the forward-imaging model in the lithography, the extraction of the mask's effective diffraction spectrum is implemented to calculate the layout of resist patterns. The simulation results highlight the superior performance of the proposed approach in achieving pixelated SO over the traditional GA and PSO algorithm in terms of convergence capacity.

As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic α4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNγ+ CD8+ T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (TRM) CD8+ T cells (CD103+CD49a+CD69+). The combination treatment also led to increased infiltration of CD39+CD103+ tumor-specific CD8+ T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.

Alignment precision is a crucial factor that directly impacts overlay accuracy, which is one of three fundamental indicators of lithography. The alignment method based on the Moiré fringe has the advantages of a simple measurement optical path and high measurement accuracy. However, it requires strict control of the distance between the mask and wafer to ensure imaging quality. This limitation restricts its application scenarios. A depth–DOF (depth of focus) Moiré fringe alignment by broad–spectrum modulation is presented to enhance the range of the alignment signals. This method establishes a broad–spectrum Moiré fringe model based on the Talbot effect principle, and it effectively covers the width of dark field (WDF) between different wavelength imaging ranges, thereby extending the DOF range of the alignment process, and employs a hybrid of genetic algorithms and the particle-swarm optimization (GA–PSO) algorithm to combine various spectral components in a white spectrum. By calculating the optimal ratio of each wavelength and using white light incoherent illumination in combination with this ratio, it achieves the optimal DOF range of a broad–spectrum Moiré fringe imaging model. The simulation results demonstrate that the available DOF range of the alignment system has been expanded from 400 μm to 800 μm. Additionally, the alignment precision of the system was analyzed, under the same conditions, and the accuracy analysis of the noise resistance, translation amount, and tilt amount was conducted for the Moiré fringe and broad–spectrum Moiré fringe. Compared to a single wavelength, the alignment precision of the broad–spectrum Moiré fringe decreased by an average of 0.0495 nm, equivalent to a 1.5% reduction in the original alignment precision, when using a 4 μm mask and a 4.4 μm wafer. However, the alignment precision can still reach 3.795 nm, effectively enhancing the available depth of focus range and reducing the loss of alignment precision.

Source mask optimization (SMO), a primary resolution enhancement technology, is one of the most pivotal technologies for enhancing lithography imaging quality. Due to the high computation complexity of SMO, patterns should be selected by a selection algorithm before optimization. However, the limitations of existing selection methods are twofold: they are computationally intensive and they produce biased selection results. The representative method having the former limitation is the diffraction signature method. And IBM’s method utilizing the rigid transfer function tends to cause biased selection results. To address this problem, this study proposes a novel pattern cluster and selection algorithm architecture based on a convolutional neural network (CNN). The proposed method provides a paradigm for solving the critical pattern selection problem by CNN to transfer patterns from the source image domain to unified embeddings in a K-dimensional feature space, exhibiting higher efficiency and maintaining high accuracy.

The projection objective lens holds a pivotal role in lithography, directly influencing imaging system quality and, consequently, the lithography machine’s feature dimensions. Optical inspection methods for this lens require advancements in calibrating systematic error and enhancing alignment precision of auxiliary devices, given their impact on calibration accuracy. In the random averaging method, random ball can give rise to additional wavefront aberrations due to misalignment and numerical aperture mismatch. To mitigate these aberrations and enhance the accuracy of systematic error calibration, this paper introduces a random ball residual compensation (RBRC) model. Additionally, when combined with the random averaging technique, it elevates the calibration accuracy of the measured lens’s wavefront aberrations. The experimental results underscore the method’s effectiveness, accurately determining optical component eccentricities and numerical aperture errors. After eliminating these errors, more accurate values of lens wavefront aberrations are achieved. This research significantly contributes to enhancing error calibration of lithography objective lens systems.

In this study, we propose a spatial consistency calibration method for slightly off-axis digital holographic microscopy (SO-DHM). The acquisition of relative position errors is summarized into a solution of a nonlinear optimization problem in which the root mean squared error of phase aberration of holograms is minimized. The particle swarm optimization algorithm is chosen to solve this optimization problem due to its simple structure, high convergence efficiency, and robust global search ability. Phase-only wavefronts based on phase aberration, which remove the influence of noise, are used for calibration. The simulation result indicates that the proposed method has subpixel-level precision, and the experiment demonstrates the effectiveness of the proposed method in the SO-DHM system.

Pulse-amplitude modulated chlorophyll fluorescence (ChlF) is widely used to measure environmental stress in plants. Yet, its continuous, long-term usage in situ is challenged due to the lack of appropriate daytime indicators. We investigated the prospect of creating new daytime indicators based on an application of linear regression on daily measurements of photochemical efficiency (ФPSII) and photosynthetically active radiation acquired in situ at 30-minute intervals. Daily regression parameters, thus generated, were subsequently used in a broader context of desert-plant response to environmental change. Here, we compared parametric and non-parametric methods to test the feasibility of daytime-based regression parameters, i.e., maximal quantum yield of photosystem II photochemistry (Fv/Fm) and daily mean ФPSII, in gauging physiological response in three shrub and two herb species as influenced by eight environmental variables. Results demonstrated that: (i) Random Forest (RF; a non-parametric method) provided the best assessment of interaction between ChlF-based parameters and environmental variables, compared with multiple linear regression (MLR; a conventional parametric method); (ii) variable importance and partial dependence plots indicated that the daily regression parameters of the ФPSII-to- photosynthetic photon flux density relationship (y-intercept and slope) were superior to those of ФPSII and Fv/Fm; and (iii) compared with Fv/Fm, the y-intercept and slope improved discrimination of interspecific differences (p

Immune checkpoint inhibitors (ICIs) have revolutionized the oncology field. However, a significant number of patients do not respond, at least partly due to the lack of preexisting anti-tumor T-cell immunity. Therefore, it is emergent to add an immune-priming step to improve efficacy. Here, we report a combined approach consisting of intratumoral administration of pro-inflammatory allogeneic dendritic cells (AlloDCs) and systemic treatment with αCTLA-4 that can drastically improve the anti-tumor efficacy compared to αCTLA-4 monotherapy. When evaluated in mice with large established CT-26 tumors, monotherapy with αCTLA-4 neither delayed tumor progression nor improved mice survival. However, combination treatment of AlloDCs and αCTLA-4 drastically improved the effectiveness, with 70% of mice being cured. This effect was T cell-dependent, and all survived mice rejected a subsequent tumor re-challenge. Further investigation revealed an immune-inflamed tumor microenvironment (TME) in the combination treatment group characterized by enhanced infiltration of activated antigen-presenting endogenous DCs and CD8+ T cells with a tissue-resident memory (TRM) phenotype (CD49a+CD103+). This correlated with elevated levels of tumor-specific CD39+CD103+CD8+ T cells in the tumor and “tumor-matching” NKG2D+CD39+CX3CR1+CD8+ T cells in peripheral blood. Moreover, splenocytes from mice in the combination treatment group secreted significantly higher IFN-γ upon stimulation with the peptide from the endogenous CT-26 retroviral gp70 (model neoantigen), confirming the induction of a tumor-specific CD8+ T-cell response. Taken together, these data indicate a strong anti-tumor synergy between AlloDCs and αCTLA-4 that warrant further clinical investigation with the corresponding human AlloDC product (ilixadencel) for patients receiving αCTLA-4 therapy.

ZC3H11A is a cellular protein associated with the transcription export (TREX) complex that is induced during heat-shock. Several nuclear-replicating viruses exploit the mRNA export mechanism of ZC3H11A protein for their efficient replication. Here we show that ZC3H11A protein plays a role in regulation of NF-κB signal transduction. Depletion of ZC3H11A resulted in enhanced NF-κB mediated signaling, with upregulation of numerous innate immune related mRNAs, including IL-6 and a large group of interferon-stimulated genes. IL-6 upregulation in the absence of the ZC3H11A protein correlated with an increased NF-κB transcription factor binding to the IL-6 promoter and decreased IL-6 mRNA decay. The enhanced NF-κB signaling pathway in ZC3H11A deficient cells correlated with a defect in IκBα inhibitory mRNA and protein accumulation. Upon ZC3H11A depletion The IκBα mRNA was retained in the cell nucleus resulting in failure to maintain normal levels of the cytoplasmic IκBα mRNA and protein that is essential for its inhibitory feedback loop on NF-κB activity. These findings indicate towards a previously unknown mechanism of ZC3H11A in regulating the NF-κB pathway at the level of IkBα mRNA export.

Acclimation strategies in xerophytic plants to stressed environmental conditions vary with temporal scales. Our understanding of environmentally-induced variation in photosystem II (PSII) processes as a function of temporal scales is limited, as most studies have thus far been based on short-term, laboratory-controlled experiments. In a study of PSII processes, we acquired near-continuous, field-based measurements of PSII-energy partitioning in a dominant desert-shrub species, namely Artemisia ordosica, over a six-year period from 2012–2017. Continuous-wavelet transformation (CWT) and wavelet coherence analyses (WTC) were employed to examine the role of environmental variables in controlling the variation in the three main PSII-energy allocation pathways, i.e., photochemical efficiency and regulated and non-regulated thermal dissipation, i.e., ΦPSII, ΦNPQ, and ΦNO, respectively, across a time-frequency domain from hours to years. Convergent cross mapping (CCM) was subsequently used to isolate cause-and-effect interactions in PSII-energy partitioning response. The CWT method revealed that the three PSII-energy allocation pathways all had distinct daily periodicities, oscillating abruptly at intermediate timescales from days to weeks. On a diurnal scale, WTC revealed that all three pathways were influenced by photosynthetically active radiation (PAR), air temperature (Ta), and vapor pressure deficit (VPD). By comparing associated time lags for the three forms of energy partitioning at diurnal scales, revealed that the sensitivity of response was more acutely influenced by PAR, declining thereafter with the other environmental variables, such that the order of influence was greatest for Ta, followed by VPD, and then soil water content (SWC). PSII-energy partitioning on a seasonal scale, in contrast, displayed greater variability among the different environmental variables, e.g., ΦPSII and ΦNO being more predisposed to changes in Ta, and ΦNPQ to changes in VPD. CCM confirmed the causal relationship between pairings of PSII-energy allocation pathways, according to shrub phenology. A. ordosica is shown to have an innate ability to (i) repair damaged PSII-photochemical apparatus (maximum quantum yield of PSII photochemistry, with Fv/Fm > 0.78), and (ii) acclimatize to excessive PAR, dry-air conditions, and prolonged drought. A. ordosica is relatively sensitive to extreme temperature and exhibits photoinhibition.

A plant’s photosynthetic capacity is typically reflected by its maximum carboxylation rate (Vcmax), which varies with time and plant functional type. In what way Vcmax in a xerophytic-shrub species changes in response to variation in its desert habitat remains poorly understood. In this study, Vcmax was continuously monitored in a common desert-shrub species, Artemisia ordosica, with a portable photosynthetic system over seven growing seasons from 2013 to 2019. Vcmax’s annual and interannual variations were subsequently assessed in conjunction with a meta-analysis carried out as a separate study. Vcmax in the species did not show a distinct seasonal pattern over the seven growing seasons. It rather displayed extensive year-to-year variations in the seasonal peak and its associated timing, exhibiting greater plasticity as compared with other plant functional types. Seasonal variation in Vcmax was primarily controlled by leaf nitrogen content per area (Narea) in a positive, linear manner, with the relationship’s sensitivity varying as a function of soil volumetric water content (VWC). Interannual variation in Vcmax was regulated by annual mean VWC, also in a positive, linear manner. The effect of Narea on Vcmax was amplified during the leaf-expanding stage of the shrub. Given severe drought anticipated under continued climate change, xerophytic shrubs are believed sufficiently malleable to acclimatize to ongoing environmental change in deserts.

Source mask optimization (SMO) is an effective method for improving the image quality of high-node lithography. Reasonable algorithm optimization is the critical issue in SMO. A GA-APSO hybrid algorithm, combining genetic algorithm (GA) and adaptive particle swarm optimization (APSO), was proposed to inversely obtain the global optimal distribution of the pixelated source and mask in the lithographic imaging process. The computational efficiency was improved by combining the GA and PSO algorithms. Additionally, the global search and local search were balanced through adaptive strategies, leading to a closer result to the global optimal solution. To verify the performance of GA-APSO, simple symmetric patterns and complex patterns were optimized and compared with GA and APSO, respectively. The results show that the pattern errors (PEs) of the resist image optimized by GA-APSO were reduced by 40.13–52.94% and 10.28–33.31% compared to GA and APSO, respectively. The time cost of GA-APSO was reduced by 75.91–87.00% and 48.43–58.66% compared to GA and APSO, respectively. Moreover, repeated calculation showed that the GA-APSO results were relatively stable. The results demonstrate the superior performance of GA-APSO in efficiency, accuracy, and repeatability for source and mask optimization.

Oncolytic viruses (OVs) represent promising therapeutic agents for cancer therapy by selective oncolysis and induction of anti-tumor immunity. OVs can be engineered to express tumor-associated antigens and immune-modulating agents to provoke stronger antitumor immunity. Here, we engineered vaccinia virus (VV) and Semliki Forest virus (SFV) to express neuroblastoma-associated antigen disialoganglioside (GD2) and the immune modulator Helicobacter pylori neutrophil-activating protein (NAP) and compared their therapeutic potency. Oncolytic VV did not exhibit any antitumor benefits, whereas SFV was able to delay subcutaneous neuroblastoma (NXS2) tumor growth. Additional expression of the GD2 mimotope (GD2m) by VV-GD2m or SFV-GD2m did not improve their anti-tumor capacity compared to the parent viruses. Further arming these OVs with NAP resulted in contrasting anti-tumor efficacy. VV (VV-GD2m-NAP) significantly improved therapeutic efficacy compared to VV-GD2m, which was also associated with a significantly elevated anti-GD2 antibody, whereas there was no additive antitumor efficacy for SFV-GD2m-NAP compared to SFV-GD2m, nor was the anti-GD2 antibody response improved. Instead, NAP induced higher neutralizing antibodies against SFV. These observations suggest that distinct immune stimulation profiles are elicited when the same immunostimulatory factor is expressed by different OVs. Therefore, careful consideration and detailed characterization are needed when engineering OVs with immune-modulators.

BackgroundNearly all anti-PD-1 antibodies are of the IgG4 isotype, and thus possess residual FcR effector functions. Such anti-PD-1 antibodies are also associated with immune tolerance and escape due to instability of the CH3 domain and Fc-Fc interaction. In this trial, we examined the efficacy and safety of penpulimab, a novel IgG1 anti-PD-1 antibody that does not bind to the Fc receptor, in patients with refractory or relapsed classical Hodgkin lymphoma (R/R cHL).MethodsAdult patients (≥18 years of age) with R/R cHL received 200 mg penpulimab once biweekly until disease progression or unacceptable toxicities for a maximum of 24 months. The primary endpoint was objective response rate (ORR) based on the Independent Radiology Review Committee per Lugano 2014 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs).ResultsA total of 94 patients were enrolled. The median follow-up was 15.8 months. The ORR was 89.4% (95% CI 80.8%, 95.0%) in the full analysis set (85 patients). Forty (47.1%) patients achieved complete remission, 36 (42.4%) patients achieved partial remission. The 12-month PFS rate was 72.1% (95% CI 60.5%, 80.8%) and the 18-month OS rate was 100%. Totally 97.9% (92/94) of patients experienced at least one TRAE. The rate of grade 3 and above TRAEs was 26.6% (25/94). In addition, 51 (54.3%) patients experienced an irAE, and 4 (4.3%) patients developed grade 3 or above irAEs. No irAE-related death occurred.ConclusionsPenpulimab was effective and safe in patients with R/R cHL.

Fire remains a pressing issue that requires urgent attention. Due to its uncontrollable and unpredictable nature, it can easily trigger chain reactions and increase the difficulty of extinguishing, posing a significant threat to people’s lives and property. The effectiveness of traditional photoelectric- or ionization-based detectors is inhibited when detecting fire smoke due to the variable shape, characteristics, and scale of the detected objects and the small size of the fire source in the early stages. Additionally, the uneven distribution of fire and smoke and the complexity and variety of the surroundings in which they occur contribute to inconspicuous pixel-level-based feature information, making identification difficult. We propose a real-time fire smoke detection algorithm based on multi-scale feature information and an attention mechanism. Firstly, the feature information layers extracted from the network are fused into a radial connection to enhance the semantic and location information of the features. Secondly, to address the challenge of recognizing harsh fire sources, we designed a permutation self-attention mechanism to concentrate on features in channel and spatial directions to gather contextual information as accurately as possible. Thirdly, we constructed a new feature extraction module to increase the detection efficiency of the network while retaining feature information. Finally, we propose a cross-grid sample matching approach and a weighted decay loss function to handle the issue of imbalanced samples. Our model achieves the best detection results compared to standard detection methods using a handcrafted fire smoke detection dataset, with APval reaching 62.5%, APSval reaching 58.5%, and FPS reaching 113.6.

Abstract Background Peripheral T cell lymphoma (PTCL) is a rare disease and recent approved drugs for relapsed/refractory (r/r) PTCL provided limited clinical benefit. We conducted this study to evaluate the efficacy and safety of geptanolimab (GB226), an anti-PD-1 antibody, in r/r PTCL patients. Methods We did this single-arm, multicenter phase 2 study across 41 sites in China. Eligible patients with r/r PTCL received geptanolimab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. All patients who received at least one dose of geptanolimab and histological confirmed PTCL entered full analysis set (FAS). The primary endpoint was objective response rate (ORR) in FAS assessed by the independent radiological review committee (IRRC) per Lugano 2014 criteria. Results Between July 12, 2018, and August 15, 2019, 102 patients were enrolled and received at least one dose of geptanolimab. At the data cutoff date (August 15, 2020), the median follow-up was 4.06 (range 0.30–22.9) months. For 89 patients in FAS, 36 achieved objective response (40.4%, 95% CI 30.2–51.4), of which 13 (14.6%) were complete response and 23 (25.8%) had partial response assessed by IRRC. The median duration of response (DOR) was 11.4 (95% CI 4.8 to not reached) months per IRRC. Patients with PD-L1 expression ≥ 50% derived more benefit from geptanolimab treatment compared to

Source optimisation (SO) is an approved approach to improve the imaging quality in inverse lithography techniques. It is critical to apply an optimisation approach with high convergence efficiency and minimum errors in pixel-based SO. To improve the convergence efficiency of the pixel-based SO, a route of particle swarm optimiser (PSO) combined with the adaptive nonlinear control strategy (ANCS) is proposed in this study. As a global optimisation algorithm, ANCS-PSO has the attributes of breaking away from the local optimum by adjusting the particle learning factor adaptively. In addition, the nonlinear control approach can broaden the search range and speed up the convergence of the iteration operation. The proposed approach also is compared with the linear decreasing inertia weight strategy and the simulated annealing strategy. The performance verification simulation displays the validity of PSO-ANCS and its potentials in SO with high convergence efficiency and optimisation capacity, by comparing the linear decreasing inertia weight strategy and the simulated annealing strategy.

Oncolytic adenovirus is one of the most promising treatments against cancer and is widely evaluated clinically. During high titer production, “Wild-type-” like replication-competent adenovirus (RCA) contaminants can be generated through recombination events due to the DNA sequence similarity between oncolytic virus and host cells. These RCA contaminants raise various safety concerns in clinics. Cell culture-based methods have been developed to detect RCA contaminants in replication-deficient adenovirus vectors. These methods were based on that only RCA contaminants, but not the vectors, are able to grow in and lyse the test cell line. However, these methods are not suitable for distinguishing RCA contaminants from the oncolytic adenovirus products because both can replicate in test cell lines. Herein, we reported a qPCR-based method to quantify RCA contaminants quickly and reliably in E1B-deleted oncolytic adenovirus products. This method is based on specific detection of the E1B gene, which can be acquired during production via recombination events between viral and host cell DNA. The assay is sensitive with the limit of detection at 10 VP of the RCA contaminants and the limit of quantification at 75 VP of the RCA contaminants in each 40 µL qPCR reaction. We have also validated the method on virus batches produced in the non-GMP and GMP conditions. Our results showed that this qPCR-based method was reliable and robust for detecting and quantifying RCA contaminants in oncolytic adenovirus products. The method may also be adapted for other oncolytic adenoviruses products by switching primer sets.

The analysis of complex relationship between stand structure and soil and water conservation function (SWCF) of forests and the precise adjustment of stand structure based on an improvement in function are the key technical problems of forestry ecological engineering construction in the Loess Plateau. This study was conducted in the Caijiachuan watershed of the Loess Plateau in western Shanxi, China. Sixty standard plots (20 × 20 m2), including 20 stand densities (900 ∼ 2,800 plants·hm−2), of Robinia pseudoacacia L. were established in the watershed. The 10 factors of stand structure and four functional indices of the SWCF, including 29 sub-functional indices, were investigated and monitored each year from June to September in 2016 to 2019. The results indicated that there are differences in the SWCF under different stand structures, and the differences are concentrated in the water conservation function (FWC) and soil conservation function (FSC) of functional indices of the SWCF. In particular, they are reflected in the soil moisture and hydrological characteristics of the litter of sub-functional indices. Stand structure factors could effectively explain the differences of functional indices of the SWCF of a R. pseudoacacia forest, and a rate of 81.4% of functional indices could be explained by stand structure factors. Based on the configuration of the optimal stand structure (included a stand density of 1,800 plants·hm−2, mean diameter at breast height of 15.19 cm, mean tree height of 10.49 m, leaf area index of 2.86, canopy density of 0.85, uniform angle index of 0.50, story differentiation of 0.59, diameter dominance of 0.45, and biomass dominance of 0.46), the density of existing stands was concentrated in the range of 1,500 ∼ 1,900 plants·hm−2 and was more effective at optimizing the SWCF. The optimization strategy of the stand structure of the R. pseudoacacia forest in the study area should focus on increasing the differentiation of forest layer, enrich the vertical structure of the stand and maintain a random distribution pattern of trees. The overall growth of the stand remained uniform, avoiding the excessive dominance of individual trees and unreasonable stand density. These results will provide a more scientific and complete reference to optimize the stand structure of the R. pseudoacacia forest in the Loess Plateau.

Abstract Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18–80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

Background The clumping bamboo Bambusa oldhamii Munro, known as “green bamboo”, is famous for its edible bamboo shoots and fast-growing timber. The green and yellow striped-culm B. oldhamii variety, named B. oldhamii f. revoluta W.T. Lin & J. Y. Lin, is an attractive system for researching the culm color variation of B. oldhamii. Methods Millions of clean reads were generated and assembled into 604,900 transcripts, and 383,278 unigenes were acquired with RNA-seq technology. The quantification of ABA, IAA, JA, GA1, GA3, GA4, and GA7 was performed using HPLC–MS/MS platforms. Results Differential expression analysis showed that 449 unigenes were differentially expressed genes (DEGs), among which 190 DEGs were downregulated and 259 DEGs were upregulated in B. oldhamii f. revoluta. Phytohormone contents, especially GA1 and GA7, were higher in B. oldhamii. Approximately 21 transcription factors (TFs) were differentially expressed between the two groups: the bZIP, MYB, and NF-YA transcription factor families had the most DEGs, indicating that those TFs play important roles in B. oldhamii culm color variation. RNA-seq data were confirmed by quantitative RT-PCR analysis of the selected genes; moreover, phytohormone contents, especially those of ABA, GA1 and GA7, were differentially accumulated between the groups. Our study provides a basal gene expression and phytohormone analysis of B. oldhamii culm color variation, which could provide a solid fundamental theory for investigating bamboo culm color variation.

Due to their unprecedented ability to flexibly manipulate the parameters of light, metasurfaces offer a new approach to integrating multiple functions in a single optical element. In this paper, based on a single-celled metasurface composed of chiral umbrella-shaped metal–insulator–metal (MIM) unit cells, a strategy for simultaneous multiple polarization generation and wavefront shaping is proposed. The unit cells can function as broadband and high-performance polarization-preserving mirrors. In addition, by introducing a chiral-assisted Aharonov–Anandan (AA) geometric phase, the phase profile and phase retardation of two spin-flipped orthogonal circular polarized components can be realized simultaneously and independently with a single-celled metasurface via two irrelevant parameters. Benefiting from this flexible phase manipulation ability, a vectorial hologram generator and metalens array with spatially varying polarizations were demonstrated. This work provides an effective approach to avoid the pixel and efficiency losses caused by the intrinsic symmetry of the PB geometric phase, and it may play an important role in the miniaturization and integration of multipolarization-involved displays, real-time imaging, and spectroscopy systems.

The enhancement of the ecological functions of forests through stand structure optimization is a key issue for high-quality forestry and its sustainable development on the Loess Plateau. In this study, fifty standard plots of Pinus tabuliformis Carr. forest were established in the Loess Plateau of western Shanxi, China. Eleven factors of the stand structure, three topographical factors, and four functional indices of the ecological function, including 20 sub-functional indices, were investigated and monitored. The study results indicated that the stand structure and topographical conditions could significantly affect the ecological functions of the Pinus tabuliformis forest, which was primarily reflected in the water-holding function, soil improvement function, and diversity function of understory plants, but had little effect on the function of reducing runoff and sediment yield on slope. We found that the stand density and uniform angle index could be used to achieve the optimal regulation of the stand structure to enhance the ecological functions of the Pinus tabuliformis forest. Overall, the optimization strategy for the stand structure of Pinus tabuliformis on the Loess Plateau should be to (1) determine the characteristics of the regulation target by understanding the stand structure and its ecological function characteristics through stand surveys on the altitude of the stand, stand density, uniform angle index of the individual trees in the sample plot, and average uniform angle index of the sample plot; (2) determine the optimization target by quantifying and analyzing the ecological functions of the stand, selecting a certain functional index as the optimization target, and specifying the degree of improvement in the functional index; and (3) substitute the optimization target and elevation of the stand into the corresponding stand structure optimization model and determine the regulation direction and regulation range of the stand density, uniform angle index, and specific stand structure regulation measures. The results of this study serve as a guide for optimizing the stand structure on the Loess Plateau.

Bambusa stenoaurita is an excellent sympodial bamboo species, which is cultivated for its shoots in some parts of China. Here, we sequenced and reported the complete chloroplast genome of B. stenoaurita for the first time. The complete chloroplast genome sequence of B. stenoaurita was generated by de novo assembly using whole-genome next-generation sequencing. The genome was 139,451 bp in total length, including a large single-copy region of 82,958 bp, a small single-copy region of 12,897 bp, a pair of invert repeats regions of 21,798 bp. The plastid genome contained 134 genes including 87 protein-coding genes, 39 tRNA genes, and 8 rRNA genes. Phylogenetic analysis based on 23 chloroplast genomes demonstrates that B. stenoaurita is closely related to B. emeiensis in Bambusoideae.

Background: Blood-based biomarker such as circulating tumor DNA (ctDNA) has emerged as a promising tool for assessment of response to immunotherapy in solid tumors; But in hematological malignances, evidences are still lacking to support its clinical utility. In current study the feasibility of ctDNA for prediction and monitoring of response to anti-PD-1 therapy in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r cHL) was assessed. Methods: A total of 192 plasma samples from 75 patients with r/r cHL were collected at baseline and upon therapeutic evaluation. ctDNA were sequenced by targeting panels capturing frequently mutated genes in cHL and other hematological malignancies and then quantified. Analysis on: 1) Gene mutation profile and association of the gene mutations with progression-free survival; 2) Association of pre- and post-treatment ctDNA variant allelic frequencies with clinical outcome; (3) Correlation of the mutated genes with treatment resistance; were performed. Findings: Somatic mutations were detected in 50 out of 61 patients by ctDNA genotyping. The mutations of CHD8 was significantly higher in patients with PFS ≥ 12 months. Baseline ctDNA was significantly higher in responders and a decrease of ctDNA ≥ 40% from baseline indicated superior clinical outcome. Strong agreement between ctDNA dynamic and radiographic response change during therapy was observed in majority of the patients. Furthermore, the mutations of B2M, TNFRSF14 and KDM2B were found to be associated with acquired resistance. Interpretation: ctDNA could be an informative biomarker for anti-PD-1 immunotherapy in r/r cHL. Funding: This work was supported by Innovent Biologics, Eli Lilly and Companyhttps://doi.org/10.13039/501100002852, China National New Drug Innovation Program (2014ZX09201041-001 and 2017ZX09304015), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001) and National Key Scientific Program Precision Medicine Research Fund of China (2017YFC0909801). The funders had no role in study design, data collection, data analysis, interpretation or writing. Keywords: Circulating tumor DNA, Immunotherapy, anti-PD-1, Biomarker, Classical hodgkin lymphoma, Sintilimab

Understanding plant resource use efficiencies (RUEs) and their tradeoffs in a desert shrub community, particularly as it concerns the usage of water, light, and nitrogen, remains an ecological imperative. Plant RUEs have been widely used as indicators to understand plant acclimation processes to unfavorable environmental conditions. This study aimed to examine seasonal dynamics in RUEs in two widely distributed plant species in a typical desert shrub community (i.e., Artemisia ordosica and Leymus secalinus) based on in-situ measurements of leaf photosynthesis, specific leaf area (SLA), leaf nitrogen concentration (i.e., Nmass + Narea), and several site-related abiotic factors. Both species exhibited significant seasonal variation in RUEs, with a coefficient of variation (CV) >30% and seasonal divergence among the various RUEs. Seasonal divergence was largely controlled by variation in stomatal conductance (Gs), which was in turn influenced by variation in soil water content (SWC) and water vapor pressure deficit (VPD). RUEs between species converged, being positively correlated, yielding: (i) r2 = 0.40 and p < 0.01 for WUE; (ii) r2 = 0.18 and p < 0.01 for LUE; and (iii) r2 = 0.25 and p < 0.01 for NUE. RUEs for A. ordosica were mostly larger than those for L. secalinus, but less reactive to drought. This suggests A. ordosica was more conservative in its usage of available resources and was, therefore, better able to adapt to arid conditions. Resource use strategies between species differed in response to drought. Desert shrubs are projected to eventually replace grasses, as drought severity and duration increase with sustained regional climate change.

In this paper, a Janus metasurface is designed by breaking the structural symmetry based on the polarization selection property of subwavelength grating. The structure comprises three layers: a top layer having a metallic nanostructure, a dielectric spacer, and a bottom layer having subwavelength grating. For a forward incidence, the metal-insulator-metal (MIM) structure operates as a gap plasmonic cavity if the linearly polarized (LP) component is parallel to the grating wires. It also acts as a high-efficiency dual-layer grating polarizer for the orthogonal LP component. For the backward incidence, the high reflectance of the grating blocks the function of the gap plasmonic cavity, leading to its pure functioning as a polarizer. A bifunctional Janus metasurface for 45 degrees beam deflector and polarizer, with a transmission of 0.87 and extinction ratio of 3840, is designed at 1.55 μm and is investigated to prove the validity of the proposed strategy. Moreover, the proposed metasurface can be cascaded to achieve more flexible functions since these functions are independent in terms of operational mechanism and structural parameters. A trifunctional Janus metasurface that acts as a focusing lens, as a reflector, and as a polarizer is designed based on this strategy. The proposed metasurface and the design strategy provide convenience and flexibility in the design of multifunctional, miniaturized, and integrated optical components for polarization-related analysis and for detection systems.

Abstract Chimeric antigen receptor (CAR) T‐cell therapy is a new successful treatment for refractory B‐cell leukemia. Successful therapeutic outcome depends on long‐term expression of CAR transgene in T cells, which is achieved by delivering transgene using integrating gamma retrovirus (RV) or lentivirus (LV). However, uncontrolled RV/LV integration in host cell genomes has the potential risk of causing insertional mutagenesis. Herein, we describe a novel episomal long‐term cell engineering method using non‐integrating lentiviral (NILV) vector containing a scaffold/matrix attachment region (S/MAR) element, for either expression of transgenes or silencing of target genes. The insertional events of this vector into the genome of host cells are below detection level. CD19 CAR T cells engineered with a NILV‐S/MAR vector have similar levels of CAR expression as T cells engineered with an integrating LV vector, even after numerous rounds of cell division. NILV‐S/MAR‐engineered CD19 CAR T cells exhibited similar cytotoxic capacity upon CD19+ target cell recognition as LV‐engineered T cells and are as effective in controlling tumor growth in vivo. We propose that NILV‐S/MAR vectors are superior to current options as they enable long‐term transgene expression without the risk of insertional mutagenesis and genotoxicity.

We present an effective method for the topography characterization of large gradient micro-structure based on digital holographic microscope (DHM). Due to the limitation of numerical aperture of DHM system, high frequency information corresponding to large gradient regions of specimen is prohibited from entering the imaging system and the complete collection of specimen features cannot be implemented. To solve this problem, we use a common configuration of off-axis DHM system to capture the holograms from multiple angles of the sample, and the various object waves coming from the sample of different tilt angle is corrected and spliced into a fully topography by multi-angle stitching process. In this way, the measurement of large gradient topography of specimen can be realized. Experimental results of large gradient microlens demonstrate the practicability and precision of the presented method.

The effect of the thermal annealing on the optical and spin properties in GaAs0.44Sb0.56 epilayers grown on InP was investigated via photoreflectance, power-dependent and time-resolved photoluminescence spectroscopy as well as optical orientation measurement. The carrier’s localization and the optical spin detection efficiency increase with an increase of annealing temperature up to 600 °C. The enhancement of the spin detection efficiency is attributed to both the shortening of the electron lifetime and the prolonging of the spin lifetime as a result of the enhanced carriers’ localization induced by the annealing process. Our results provided an approach to enhance spin detection efficiency of GaAsSb with its PL emission in the 1.55 μm region.

Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are poor in migration and in fact do not directly present TAA epitopes to naïve T cells in vivo. Instead, it is proposed that bystander host DCs take up material from vaccine-DCs, migrate and subsequently initiate antitumor T-cell responses. We used mouse models to examine the possibility of using pro-inflammatory allogeneic DCs (alloDCs) to activate host DCs and enable them to promote antigen-specific T-cell immunity. We found that alloDCs were able to initiate host DC activation and migration to draining lymph node leading to T-cell activation. The pro-inflammatory milieu created by alloDCs also led to recruitment of NK cells and neutrophils at the site of injection. Vaccination with alloDCs combined with Ad5M(gp100), an infection-enhanced adenovirus encoding the human melanoma-associated antigen gp100 resulted in generation of CD8+ T cells with a T-cell receptor (TCR) specific for the gp10025-33 epitope (gp100-TCR+). Ad5M(gp100)-alloDC vaccination in combination with transfer of gp100-specific pmel-1 T cells resulted in prolonged survival of B16-F10 melanoma-bearing mice and altered the composition of the tumor microenvironment (TME). We hereby propose that alloDCs together with TAA- or neoepitope-encoding Ad5M can become an “off-the-shelf” cancer vaccine, which can reverse the TME-induced immunosuppression and induce host cellular anti-tumor immune responses in patients without the need of a time-consuming preparation step of autologous DCs.

Accumulating evidence support an important role for endogenous bystander dendritic cells (DCs) in the efficiency of autologous patient-derived DC-vaccines, as bystander DCs take up material from vaccine-DCs, migrate to draining lymph node and initiate antitumor T-cell responses. We examined the possibility of using allogeneic DCs as vaccine-DCs to activate bystander immune cells and promote antigen-specific T-cell responses. We demonstrate that human DCs matured with polyI:C, R848 and IFN-γ (denoted COMBIG) in combination with an infection-enhanced adenovirus vector (denoted Ad5M) exhibit a pro-inflammatory state. COMBIG/Ad5M-matured allogeneic DCs (alloDCs) efficiently activated T-cells and NK-cells in allogeneic co-culture experiments. The secretion of immunostimulatory factors during the co-culture promoted the maturation of bystander-DCs, which efficiently cross-presented a model-antigen to activate antigen-specific CD8+ T-cells in vitro. We propose that alloDCs, in combination with Ad5M as loading vehicle, may be a cost-effective and logistically simplified DC vaccination strategy to induce anti-tumor immune responses in cancer patients.