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The Log-Structured Merge Tree (LSM-Tree) is widely used in key-value (KV) stores because of its excwrite performance. But LSM-Tree-based KV stores still have the overhead of write-ahead log and write stall caused by slow L 0 flush and L 0 - L 1 compaction. New byte-addressable, persistent memory (PM) devices bring an opportunity to improve the write performance of LSM-Tree. Previous studies on PM-based LSM-Tree have not fully exploited PM’s “dual role” of main memory and external storage. In this article, we analyze two strategies of memtables based on PM and the reasons write stall problems occur in the first place. Inspired by the analysis result, we propose FlatLSM, a specially designed flat LSM-Tree for non-volatile memory based KV stores. First, we propose PMTable with separated index and data. The PM Log utilizes the Buffer Log to store KVs of size less than 256B. Second, to solve the write stall problem, FlatLSM merges the volatile memtables and the persistent L 0 into large PMTables, which can reduce the depth of LSM-Tree and concentrate I/O bandwidth on L 0 - L 1 compaction. To mitigate write stall caused by flushing large PMTables to SSD, we propose a parallel flush/compaction algorithm based on KV separation. We implemented FlatLSM based on RocksDB and evaluated its performance on Intel’s latest PM device, the Intel Optane DC PMM with the state-of-the-art PM-based LSM-Tree KV stores, FlatLSM improves the throughput 5.2× on random write workload and 2.55× on YCSB-A.

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non–small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells—such as M2 tumor-associated macrophages (TAM)—thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti–PD-1–resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mechanism of action showed reduced M2 macrophage tumor infiltration, enhanced TH1 polarization, improved T-cell and macrophage function, and decreased TGFβ levels. The addition of anti–PD-1 further enhanced systemic antitumor responses. These results provide a preclinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC.

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Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non–small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells—such as M2 tumor-associated macrophages (TAM)—thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti–PD-1–resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mechanism of action showed reduced M2 macrophage tumor infiltration, enhanced TH1 polarization, improved T-cell and macrophage function, and decreased TGFβ levels. The addition of anti–PD-1 further enhanced systemic antitumor responses. These results provide a preclinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC.

Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. Although NLRP3 is typically observed for its role in exacerbating XRT-induced tissue damage, the NLRP3 inflammasome can also be protective and augment the effect of XRT when used in proper dosing and sequencing. However, whether NLRP3 agonist boosts radiation-induced immune priming and promote abscopal responses in anti-PD1 resistant model is still unknown. Therefore, in this study, we paired intratumoral injection of an NLRP3 agonist with XRT to stimulate the immune system in both wild type (344SQ-P) and anti-PD1 resistant (344SQ-R) murine-implanted lung adenocarcinoma models. We found that the combination of XRT + NLPR3 agonist enhanced control of implanted lung adenocarcinoma primary as well as secondary tumors in a radiological dose-dependent manner, in which 12Gy x 3 fractions of stereotactic XRT was better than 5Gy x 3, while 1Gy x 2 did not improve the NLRP3 effect. Survival and tumor growth data also showed significant abscopal response with the triple therapy (12Gyx3 + NLRP3 agonist + α-PD1) in both 344SQ-P and 344SQ-R aggressively growing models. Multiple pro-inflammatory cytokines (IL-1b, IL-4, IL-12, IL-17, IFN-γ and GM-CSF) were elevated in the serum of mice treated with XRT + NLRP3 or triple therapy. The Nanostring results showed that NLRP3 agonist is capable of increasing antigen presentation, innate function, and T-cell priming. This study can be of particular importance to treat patients with immunologically-cold solid tumors whom are also refractory to prior checkpoint treatments.

To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.

Neoadjuvant long-course concurrent chemoradiation plus surgery, followed by optional adjuvant chemotherapy, is a standard of care for locally advanced rectal cancer (LARC). However, this traditional approach has several limitations, including low pathological complete response (pCR) (10–25%), high metastasis rate (30–35%), and highly inconsistent compliance with adjuvant chemotherapy (25–75%). Treatment modalities for LARC have dramatically evolved in recent years. Multiple clinical trials have focused on optimizing strategies to achieve a win-win situation for oncologic outcomes and functions. Here, we review the latest studies into optimizing neoadjuvant treatment for LARC.

Vibration of the elevated urban rail transit (URT) severely affects the health of nearby residents, threatens the integrity of adjacent historic buildings, and aggravates the performance of vibration-sensitive instruments in buildings, and the accompanied annoying structure-borne noise always arouses public complaint. Vibration and noise mitigation measures through track structures and/or noise barriers are increasingly favored to deal with these challenging issues. This paper presents systematic field measurements on noise and vibrations of elevated URT. The vibration experiment covers vibration of track structures, bridge girders and piers, and ground soil under three different track structures, i.e., embedded sleeper track, ladder sleeper track, and floating slab track (FST) with rubber mats. Noise measurements were also conducted considered the effect of track structures and with or without fully enclosed noise barriers. It is shown that ladder sleeper track and FST were more effective in control bridge vibration than ground vibration. The overall vibration level of the bridge is 8~10 dB greater than the ground vibrations. The noise reduction effect through track structure was limited for far-field ground. Furthermore, it is found that the noise barrier was more effective to reduce near-field wheel/rail rolling noise rather than far-field noise. Good correlation between structure-borne noise and vibration was observed for both the embedded sleeper track and FST at the bottom slab of the box girder bridge.

Background: Locally advanced rectal cancers (LARC) are treated with neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision (TME), and adjuvant chemotherapy, and identifying reliable prognostic/predictive biomarkers is currently warranted for LARC. Methods: Comprehensive genomic profiling was performed in 76 LARC patients who received nCRT plus TME. All 76 patients had baseline tissue biopsies, 72 had paired baseline tissue biopsies and surgical tumor samples, and 55 had paired surgical tumor and margin samples. Post-nCRT tumor regression grade (TRG) and post-surgical disease-free survival (DFS) were used to assess treatment outcomes. Results: Baseline KRAS mutation (P=0.022) and MYC amplification (P=0.047) appeared to be independent prognostic factors for nCRT, with KRAS/MYC-mutated patients having higher tumor regression grade (TRG) and lower immune infiltration. Intriguingly, high radiation doses during nCRT were correlated with improved nCRT response in KRAS/MYC-positive patients. Additionally, aberrations in multiple signaling pathways, especially JAK-STAT (P=0.022), were enriched in TRG3 patients after nCRT, implying that they might be resistance mechanisms that impair nCRT efficacy. The post-surgical FBXW7 mutation was significantly associated with shorter disease-free survival (P=0.01), while treatment-induced branched tumor evolutionary pattern and the molecular level of residual tumor at the surgical margin were significantly correlated with both poorer nCRT response and higher post-surgical recurrence risk. Conclusions: Comprehensive genomic profiling helps identify multiple molecular prognostic and/or predictive biomarkers that could predict patients’ clinical outcomes to nCRT and TME and direct nCRT treatment regimen, thus facilitating more accurate prognostic estimation, a better balance between treatment efficacy and quality of life, and timely adjusted treatment decisions. Citation Format: Li Li, Kewen He, Aijie Li, Yang Xu, Jiaohui Pang, Dianbin Mu, Jie Ma, Hong Ge, Aurian Maleki, Xueting Qin, Xian Zhang, Qiuxiang Ou, HaiMeng Tang, Yang Shao, Jinming Yu, Shuanghu Yuan. Genomic features, evolutionary patterns, and minimal residual disease at surgical margins as novel prognostic/predictive biomarkers in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3309.

Background: While improvements in radioimmunotherapy have made significant headway in improving outcomes for cancer patients, this treatment approach has nevertheless proven ineffective at controlling the majority of malignancies. One of the mechanisms of resistance to radioimmunotherapy is that immune cells may be suppressed via the myriad of different immune checkpoint receptors. Therefore, simultaneous blockade of multiple immune checkpoint receptors may enhance the treatment efficacy of radioimmunotherapy.Methods: We combined NBTXR3-enhanced localized radiation with the simultaneous blockade of three different checkpoint receptors: PD1, LAG3, and TIGIT and tested the treatment efficacy in an anti-PD1 resistant lung cancer model in mice. 129Sv/Ev mice were inoculated with fifty thousand αPD1-resistant 344SQR cells in the right leg on day 0 to establish primary tumors and with the same number of cells in the left leg on day 4 to establish the secondary tumors. NBTXR3 was intratumorally injected to the primary tumors on day 7, which were irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1 (200 mg), αLAG3 (200 mg), and αTIGIT (200 mg) were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42. Results: This nanoparticle-mediated combination therapy is effective at controlling growth of treated and distant untreated tumors, enhancing animal survival and is the only one that led to complete destruction of both tumors in approximately 30% of treated mice. Corresponding with this improved response is a robust activation of the immune response, as manifested by increased numbers of immune cells along with a transcriptional signature of both innate and adaptive immunity within the tumor. Furthermore, mice treated with this combinatorial therapy display immunological memory response when rechallenged by the same cancer cells, preventing tumor engraftment.Conclusions: Our results strongly attest to the efficacy and validity of combining nanoparticle-enhanced radiotherapy and simultaneous blockade of multiple immune check point receptors and provide pre-clinical rationale for investigation into its translation into human patients.

Aim: We aimed to evaluate the prognostic values of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and systemic immune-inflammation index (SII) in patients with brain metastases from non-small-cell lung cancer (NSCLC). Materials & methods: We conducted Kaplan–Meier analysis and multivariable Cox analysis to evaluate the prognostic values of NLR, PLR, LMR and SII. Results: Kaplan–Meier analysis showed that the patients in low LMR, high NLR, PLR and SII groups were associated with shorter overall survival. Multivariable Cox analysis revealed LMR and SII were independent prognostic factors for overall survival (p = 0.002 and p = 0.004, respectively). Conclusion: LMR and SII are of significant values in clinical prognostic evaluation for patients with brain metastases from NSCLC.

This study combines a novel strategy of radiotherapy that utilizes high- and low- dose radiation with immune oncology agents (anti-TIGIT and anti-PD1 monoclonal antibodies) in order to overcome the inhibitory tumor stroma and battle tumors systemically. The findings from this work will impact how checkpoint inhibitors are delivered to maximize their efficacy. Tumors deploy various immune-evasion mechanisms that create a suppressive environment and render effector T-cells exhausted and inactive. Therefore, a rational utilization of checkpoint inhibitors may alleviate exhaustion and may partially restore antitumor functions. However, in high-tumor-burden models, the checkpoint blockade fails to maintain optimal efficacy, and other interventions are necessary to overcome the inhibitory tumor stroma. One such strategy is the use of radiotherapy to reset the tumor microenvironment and maximize systemic antitumor outcomes. In this study, we propose the use of anti-PD1 and anti-TIGIT checkpoint inhibitors in conjunction with our novel RadScopal technique to battle highly metastatic lung adenocarcinoma tumors, bilaterally established in 129Sv/Ev mice, to mimic high-tumor-burden settings. The RadScopal approach is comprised of high-dose radiation directed at primary tumors with low-dose radiation delivered to secondary tumors to improve the outcomes of systemic immunotherapy. Indeed, the triple therapy with RadScopal + anti-TIGIT + anti-PD1 was able to prolong the survival of treated mice and halted the growth of both primary and secondary tumors. Lung metastasis counts were also significantly reduced. In addition, the low-dose radiation component reduced TIGIT receptor (PVR) expression by tumor-associated macrophages and dendritic cells in secondary tumors. Finally, low-dose radiation within triple therapy decreased the percentages of TIGIT(+) exhausted T-cells and TIGIT(+) regulatory T-cells. Together, our translational approach provides a new treatment alternative for cases refractory to other checkpoints and may bring immunotherapy into a new realm of systemic disease control., United States Department of Health and Human Services; National Institutes of Health (NIH); NIH National Cancer Institute (NCI)

The analysis of electromagnetic scattering by open-ended metallic waveguide cavities is important in the prediction and reduction of the radar cross section (RCS) of a target. Various diffraction problems involving two- and three-dimensional (2-D and 3-D) cavities have been analyzed thus far based on high-frequency techniques and numerical methods. However, the solutions obtained by these methods may not be uniformly valid for arbitrary dimensions of the cavities. In this paper, we shall consider a semi-infinite parallel-plate waveguide with five-layer material loading as a geometry that can form cavities, and analyze rigorously the E-polarized plane wave diffraction by means of the Wiener-Hopf technique [1] , [2] .

Although definitive chemoradiation therapy (dCRT) remains the most effective treatment modality in limited stage small cell lung cancer (SCLC), some patients progress quickly or develop serious radiation-induced thoracic toxicity (RITT). Molecular correlates of response to dCRT remain to be explored.Genomic profiling was performed retrospectively on 231 patients with limited-stage SCLC treated with dCRT between 2015 and 2019 using a customized panel covering cancer and radiation therapy response-related genes. Exploratory associations of progression-free survival, overall survival, and RITT with clinical features, tumor genetics, genomic and molecular pathway alterations, and single nucleotide polymorphisms were conducted.In addition to the common SCLC genes, such as TP53, RB1, and NOTCH1/2, potentially actionable mutations in EGFR, KRAS, and BRCA1/2 were among the top alterations in the cohort. At the single-gene level, CDK4 and GATA6 alterations were independent predictors of poor survival by multivariate analysis. At the genomic level, high tumor mutational burden was strongly associated with favorable survival outcome. Pathway-level analysis showed that activating mutations in the MAPK/ERK pathway genes, particularly those in EGFR/ERBB2, correlated with poor survival. Combined analysis enabled optimized risk stratification of post-dCRT survival. On the other hand, our study also confirmed that single nucleotide polymorphisms in MTHFR, CYP2B6, NQO1, and LIG4 were risk alleles of high-grade RITT. Remarkably, somatic loss-of-function mutations in the DNA damage repair pathway genes were associated with increased risk of high-grade RITT, particularly pneumonitis, which likely reflect a complex interplay between the tumor and its immune microenvironment.Taken together, by examining the mutational landscape of a large cohort of limited-stage SCLC, we identified novel molecular predictors of survival and RITT. Our findings also implicate several key molecular pathways, including the MAPK/ERK and DNA damage repair pathways, in the regulation of dCRT response.

Metastatic cancer is inherently heterogeneous, and patients with metastatic disease can experience vastly different oncologic outcomes depending on several patient- and disease-specific characteristics. Designing trials for such a diverse population is challenging yet necessary to improve treatment outcomes for metastatic-previously thought to be incurable-disease. Here we review core considerations for designing and conducting clinical trials involving radiation therapy and immunotherapy for patients with metastatic cancer.

Background: The high recurrence rate of stage pIIIA-N2 NSCLC patients may reflect inadequate removal of all residual tumor cells despite conventional histologic negative surgery margin. The NGS-detected BRM status was possible to serve as a more accurate examination to identify those patients with a high-risk of postoperative recurrence. Methods: We retrospectively studied 119 stage IIIA-N2 NSCLC patients who received curative-intent surgery plus adjuvant chemotherapy/chemoradiotherapy, and all of the patients were classified with negative resection margin by the conventional histologic method. Each patient had paired tumor and bronchial resection margin (BRM) samples, which were analyzed using next-generation sequencing (NGS) of 474 cancer-related genes, and we explored the prognostic values of various clinical and molecular features. Results: Among the 119 stage IIIA-N2 NSCLC patients with histologic negative resection margins, the BRM samples from 56 patients (47.1%) were positive for tumor mutations, including multiple lung cancer driver mutations. The number and the variant allele frequency of genetic alterations in BRM samples were generally lower than that of the paired tumor samples. Notably, patients who were positive for NGS-detected BRM mutations had significantly shorter disease-free survival (DFS) than the negative patients (p=0.001, HR 2.18, 95%CI 1.37~3.47). Several other clinical/molecular features were also found to be significantly associated with DFS, including the metastatic lymph node ratio (MLNR), smoking history, and KRAS mutation status, and NGS-assessed BRM status remained to be statistically significant in multivariable analysis by including all of these prognostic factors (p =0.020, HR 1.82, 95%CI 1.10~3.02). Conclusions: We demonstrated that the molecular positive margin of surgical resections was a strong and independent biomarker for disease recurrence in pIIIA-N2 NSCLC patients. Our results emphasized the clinical utility of molecular diagnostic approaches to detect minimal residual disease after surgical resection, which could potentially facilitate the stratification of high-risk patients for personalized and appropriate treatments. Citation Format: Li Li, Kewen He, Jiaohui Pang, Yang Xu, Yang Shao, Shuanghu Yuan, Jinming Yu. Molecular positive margin of surgical resections is a strong biomarker for tumor recurrence in pIIIA-N2 NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5781.

Findings Overall, 148 patients were included in the pooled analysis, 76 of whom had been assigned pembrolizumab and 72 who had been assigned pembrolizumab plus radiotherapy. Median follow-up for all patients was 33 months (IQR 32?4?33?6). 124 (84%) of 148 patients had non-squamous histological features and 111 (75%) had previously received chemotherapy. Baseline variables did not differ between treatment groups, including PD-L1 status and metastatic disease volume. The most frequently irradiated sites were lung metastases (28 of 72 [39%]), intrathoracic lymph nodes (15 of 72 [21%]), and lung primary disease (12 of 72 [17%]). Best ARR was 19?7% (15 of 76) with pembrolizumab versus 41?7% (30 of 72) with pembrolizumab plus radiotherapy (odds ratio [OR] 2?96, 95% CI 1?42?6?20; p=0?0039), and best ACR was 43?4% (33 of 76) with pembrolizumab versus 65?3% (47 of 72) with pembrolizumab plus radiotherapy (2?51, 1?28?4?91; p=0?0071). Median progression-free survival was 4?4 months (IQR 2?9?5?9) with pembrolizumab alone versus 9?0 months (6?8?11?2) with pembrolizumab plus radiotherapy (hazard ratio [HR] 0?67, 95% CI 0?45?0?99; p=0?045), and median overall survival was 8?7 months (6?4?11?0) with pembrolizumab versus 19?2 months (14?6?23?8) with pembrolizumab plus radiotherapy (0?67, 0?54?0?84; p=0?0004).Methods Inclusion criteria for the PEMBRO-RT and MDACC trials were patients (aged ?18 years) with metastatic nonsmall-cell lung cancer and at least one unirradiated lesion to monitor for out-of-field response. In the PEMBRO-RT trial, patients had previously received chemotherapy, whereas in the MDACC trial, patients could be either previously treated or newly diagnosed. Patients in both trials were immunotherapy-naive. In the PEMBRO-RT trial, patients were randomly assigned (1:1) and stratified by smoking status (

Purpose/Objective(s) Despite advances in radiotherapy (RT) and immunotherapy, their antitumor activity remains suboptimal in metastatic non-small cell lung cancer (NSCLC). The tumor microenvironment after hypofractionated RT (hRT) is largely immunosuppressive and replete with M2 tumor-associated macrophages. STAT6 is a highly activated transcription factor that contributes to M2 macrophage polarization but has been difficult to target therapeutically. We selectively targeted STAT6 with antisense nucleotides (ASOs), hypothesizing that using ASOs to inhibit STAT6 in combination with hRT and anti-PD1 would inhibit M2 polarization and improve systemic antitumor effects in NSCLC. Materials/Methods We tested three bilaterally established lung cancer murine models: Lewis lung carcinoma in B6.Foxp3EGFP mice, and 344SQ-parental or 344SQ anti-PD1-resistant adenocarcinomas in 129Sv/Ev mice. The primary tumor was treated with hRT (3 fractions of 12 Gy each) and secondary tumors were observed for evidence of abscopal effects. STAT6 knockdown was determined by Western blotting and qRT-PCR. Tumor-infiltrating leukocytes were characterized by immunohistochemical tissue microarray-based immunofluorescence, flow cytometry, and 770 gene-Immune NanoString analyses. Also, serum TGF-β was measured by ELISA. Results The combination of hRT and STAT6 ASOs reduced the volumes of both primary and secondary tumors and extended survival (vs. either treatment alone). The addition of anti-PD1 enhanced the systemic antitumor effect (vs. STAT6 ASOs + hRT or hRT+anti-PD1) and led to decreased STAT6, increased M1 genes (IL1R, iNOS, CD80, CD86), and lowered M2 genes (Arg-1, Fizz-1, CD163, CCR2) in tumor-infiltrating leukocytes by qRT-PCR. Treatment with hRT+STAT6 ASOs ± anti-PD1 also enhanced tumor infiltration by macrophages and Th1 cells, improved T-cell and macrophage function, and slowed cancer progression. Flow cytometry and tissue microarray confirmed the hRT (vs. control) led to higher STAT6 and lower M1/M2 ratio, but hRT+ STAT6 ASOs ± anti-PD1 led to decreased STAT6, reduced Tregs, increased M1/M2 ratio, and lowered TGF-β levels. Depletion of macrophages by anti-F4/80 abrogated the observed antitumor effect. Conclusion The combination of STAT6 ASOs and hRT reduces immunosuppressive M2 macrophage infiltration into tumors and enhances the systemic antitumor effect of hRT; this radio-immunotherapy combination may provide an alternative therapeutic approach for NSCLC patients with PD1-resistance.

Purpose/objective(s) Retrospective and prospective studies in patients with oligometastatic non-small-cell lung cancer (NSCLC) suggested clinical benefit after complete metastatic ablation (CMA). So far, no studies have addressed the toxicity and efficacy of CMA to oligometastatic lesions in patients that progressed during immune checkpoint inhibitors (ICIs) therapy. Here, we report results of a single arm- radiotherapy (RT) to oligometastatic lesions from our ongoing phase II trial (NCT02710253). Materials/methods This study enrolled patients that progressed within 6 months of ICI therapy and developed oligo-metastases. Treatment intervention allowed for any dose and fractions of RT per the treating physician to all metastatic sites, with irradiation for up to 6 sites. Primary endpoints of this study are time to new lesion development, and disease control rate (DCR) by RECIST 1.1. Secondary endpoints are toxicity, progression-free survival (PFS), overall survival (OS) and absolute lymphocyte counts (ALC). Results Of the 30 patients initially enrolled in this study, 26 patients (N = 21 NSCLC; N = 5 melanoma) were included in the analysis as they had completed imaging follow-up. A total of 64 lesions were irradiated with a mean of 2.5 lesions per patient. Most frequent location of irradiated was lung (n = 45), followed by adrenal (n = 7), liver (n = 4), bone (n = 4) and others (n = 4); 50% of patients received SBRT. At a median follow-up time of 23.0 months (range, 5.0-44.7 months), 12 patients had no new lesions, while 14 patients developed new lesions in lung (50%), bone (25%), brain (21%). Median time to new lesion development was 14.6 months. DCR was 77% (complete response 19%, partial response 19%, stable disease 38%); median PFS was 10.1 months and median OS was not reached. No toxicities greater than grade 2 was observed. Pre-RT ALC is an independent risk factor for time to new lesion development (P = 0.006, HR = 0.1, 95% CI, 0.02-0.51). Patients without new lesion development had significantly higher baseline ALC (P = 0.011) and more ALC after RT at 1 month (P = 0.025), 3 months (P = 0.006), 6 months (P = 0.002) and 12 months (P = 0.045) compared to patients with new lesions. Other factors including age, gender, SBRT, baseline tumor size, performance status and tumor histology did not affect the time to new lesion development. Conclusion In patients with oligometastatic lesions that progressed on ICI, CMA may be a valid treatment option that generates clinical benefits. By eradicating gross sites of disease by converting area sites into in-situ vaccines, T cells are able to access microscopic metastasis. Larger randomized trials are indicated to further define the role of CMA for ICIs resistance.

Purpose Radiation combined with PD1 blockade offers significant treatment benefits in several tumor types; however, anti-PD1 resistance precludes such benefits in many cases. Here we attempted to overcome anti-PD1 resistance by combining localized radiation with a radioenhancing nanoparticle (NBTXR3) and systemic anti-PD1 treatment to achieve abscopal effects in an anti-PD1–resistant mouse model of lung cancer. Methods and Materials Female 129Sv/Ev mice were inoculated with 344SQ anti-PD1–resistant (344SQR) or anti-PD1–sensitive (344SQP) metastatic lung cancer cells in the right leg on day 0 (“primary” tumor) and the left leg on day 4 (“secondary” tumor). Primary tumors were injected intratumorally with NBTXR3 on day 7 and were irradiated with 12 Gy on days 8, 9, and 10. Mice were given 6 intraperitoneal injections of anti-PD1. T cell receptor repertoire was analyzed in tumor samples with RNA sequencing, infiltration of CD8 T cells with immunohistochemical staining, and activities of various immune pathways with NanoString analysis. Results The triple combination of NBTXR3 with localized radiation and systemic anti-PD1 significantly delayed the growth of both irradiated and unirradiated tumors in both 344SQP and 344SQR tumor models. NBTXR3 remodeled the immune microenvironment of unirradiated tumors by triggering the activation of various immune pathways, increasing the number of CD8+ T cells, and modifying the T cell receptor repertoire in the 344SQR tumor model. Conclusions The ability of NBTXR3 to evoke significant abscopal effects in both anti-PD1–sensitive and anti-PD1–resistant lung cancers could open the possibility of its use for treating patients with metastatic lung cancer regardless of sensitivity (or resistance) to immunotherapies.

Data deduplication is an effective method to reduce data storage requirements. In data deduplication process, fingerprint identification may cause frequent on-disk fingerprint lookups which hurt performance seriously. Some locality-aware approaches were proposed to tackle this issue. Recently, the Persistent Memory (PM) brings low latency and high bandwidth, and has become a hotspot in data storage. Deduplication systems with fingerprints stored on PM will provide extremely fast on-disk fingerprint lookup, and therefore traditional locality-aware approaches designed for slow devices are likely no longer valid.

Radiation therapy (RT) is emerging as an interventional modality in the cancer-immunity cycle, augmenting the activation of an adaptive immune response against tumors. RT, particularly in combination with immunotherapy, can enhance immune memory effects and shape the tumor-directed T-cell populations. However, a single cycle of RT delivered to a limited number of polymetastatic lesions is rarely sufficient to achieve systemic control. We hypothesize that several rounds of RT, akin to several rounds of immunotherapeutic drugs, is likely to provide greater clinical benefit to patients with metastatic disease. We propose that the repeated exposure to tumor antigens released by ""pulsed-RT"" (i.e., treating 2-4 tumor lesions with 3 irradiation cycles given one month apart) may amplify the adaptive immune response by expanding the tumor-specific T-cell receptor repertoire, the production of high-affinity tumor antibodies, and the generation of memory lymphocytes and thereby improve immune control of systemic disease., National Cancer Institute; National Institutes of Health; Cancer Center Support (Core) Grant

Highlights • High-dose RT upregulated pDCs within the tumor microenvironment. • The administration of intratumoral TLR9 agonist (CMP-001) after stereotactic RT significantly enhanced the anti-tumor immune response both locally and at secondary tumor site. • CMP-001 Post-RT delayed the abscopal tumor growth and extended the survival rate via increasing the percentages of activated CD4+ and CD8+ T-cells within the tumor microenvironment. • The treatment proved efficacious in both lung adenocarcinoma and colon carcinoma syngeneic models used., Radiotherapy (RT) has been used to control tumors by physically damaging DNA and inducing apoptosis; it also promotes antitumor immune responses via neoantigens release and augmenting immune-oncology agents to elicit systemic response. Tumor regression after RT can recruit inflammatory cells, such as tumor-associated macrophages and CD11b+ myeloid cell populations, a major subset of which may actually be immunosuppressive. However, these inflammatory cells also express Toll-like receptors (TLRs) that can be stimulated to reverse suppressive characteristics and promote systemic antitumor outcomes. Here, we investigated the effects of adding CMP-001, a CpG-A oligodeoxynucleotide TLR9 agonist delivered in a virus-like particle (VLP), to RT in two murine models (344SQ metastatic lung adenocarcinoma and CT26 colon carcinoma). High-dose RT (12Gy x 3 fractions) significantly increased the percentages of plasmacytoid dendritic cells within the tumor islets 3- and 5-days post-RT; adding CMP-001 after RT also enhanced adaptive immunity by increasing the proportion of CD4+ and CD8+ T cells. RT plus CMP-001-mediated activation of the immune system led to significant inhibition of tumor growth at both primary and abscopal tumor sites, thereby suggesting a new combinatorial treatment strategy for systemic disease., Graphical Abstract Image, graphical abstract