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Background: Although significant progress has been made in immune checkpoint inhibitor (ICI) treatment of advanced squamous cell carcinoma (SqCC), most patients still experience acquired drug resistance. Methods: We used a dendritic cell-based neoantigen vaccine combined with ICIs to treat advanced SqCC in a PD-1 blockade-resistant patient. Results: The follow-up of this patient after 12 months revealed significant tumor regression. We also identified a new JAK1 ICI-resistant mutation that could become a potential universal neoantigen target for tumor vaccines. Conclusion: Individualized management of advanced SqCC through a combined neoantigen vaccine and ICI administration could yield beneficial clinical outcomes. Vaccines targeting anti-PD-1-resistant JAK1 mutations might be of particular benefit to a specific group of solid tumor patients.

Heteroatom doped porous carbon materials have great application prospects in supercapacitors. In the present study, an approach of preparing N-doped porous carbon (NPC) was proposed from porous poly(resorcinol-formaldehyde-melamine) monoliths which were prepared by high internal phase emulsion (HIPE) template. Melamine was dissolved in the external phase and copolymerized, acting as the N source and porous structure regulator to provide micropore-dominant NPCs. The structure, morphology, specific surface area (SSA), and chemical composition of the samples were systematically studied. With melamine content increasing, N-doping content in NPC increased while the SSA of NPC increased at first and then decreased. When the content of N is 8.42 ​wt%, the obtained NPC showed the highest SSA of about 1670 ​m2 ​g−1. Furthermore, high N doping content could improve the electronic conductivity and provide additional pseudocapacitance of NPC. Under the combined influences of proper N content and high porosity, the prepared NPC electrodes revealed excellent specific capacitance (228.0 ​F ​g−1 at 1.0 ​A ​g−1), favorable circling stability, and prominent rate capability in a three-electrode system with 6 ​M KOH solution as the electrolyte.

Background: Malignant pleural/peritoneal mesothelioma (MPM) is a rare, aggressive cancer with poor prognosis and high mortality of 65%-70% for pleural and 30% for peritoneal MPM. Patients who fail the standard therapy often survive less than 1 year, so it is urgent to develop new effective therapies for MPM patients. Chimeric antigen receptor (CAR)-T cells have been applied in MPM, but the efficacy was still limited due to immunosuppressive tumor microenvironment (TME). To overcome these obstacles, we developed armored CAR-T cells with nanobody targeting mesothelin (MSLN) and IFN-γ-activated secretion of PD-1 nanobody in a non-viral transposon system, named as BZDS1901. Preclinical studies have demonstrated cytotoxicity of the BZDS1901 in NCI-H226 lung/mesothelioma xenograft mouse model. To verify the safety and efficacy of BZDS1901, we conducted a single-arm, open label, dose-escalating clinical trials (NCT04503980, 05089266, 03615313) in solid tumors. Methods: Eligible patients were those who failed prior standard therapies with MSLN expression (≥50%) and PD-L1 positive in tumor specimen and voluntarily signed the informed consent. After apheresis and lymphodepletion with cyclophosphamide and fludarabine. BZDS1901 was administered intravenously in dose cohorts (1 × 106-2 × 107/kg) and the second infusion was given if no disease progression. After infusion, safety was evaluated during 28 days by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, efficacy was assessed by RECIST 1.1 or mRECIST with CT scan. Blood CAR copies were measured by qPCR, PD-1 nanobodies and cytokines by Meso Scale Discovery method, and T cell subtypes by flow cytometry. Patients’ progression-free survival (PFS) and overall survival (OS) were measured from the day of infusion to progression or death. Results: From July 20, 2020 to December 31, 2022, 11 MPM patients were enrolled and completed the assessment, while most patients received two infusions. BZDS1901 was safe, demonstrated by 54% grade 3 and 15% grade adverse events (AEs) that were hematological side effects due to lymphodepletion and reversible with supportive care. No on-target, off-tumor toxicity and dose-limiting toxicity were observed. All patients showed expansion of CAR-T cells and increased PD-1 nanobodies in circulation. CAR-T Cmax (cp/μg) copies number was 20062, and continually detectable in blood over 4 months. PD-1 Cmax (pg/ml) was 82841, and continually detectable in blood for up to 9 months. IFN- γ and IL-6 also increased at day 4 or Day 7. All patients obtained objective tumor response, one with complete response, six with partial response, and four with stable disease. The total objective response rate was 63.64%. All enrolled patients are still alive, and mPFS and mOS are not reached. The longest PFS was up to 26 months. Median follow-up was four months. Conclusions: PD-1 nanobody secreted and MSLN targeting CAR-T cells have demonstrated promising efficacy on MPM patients. Besides CAR-T direct tumor killing activity, secreted PD-1 nanobodies may provide additional clinical benefit by invigorating CAR-T from PD-L1 inhibition, activating TILs and relieving local immunosuppression. Citation Format: Zhuqing Liu, Yong Xia, Linlin Li, Yan Sun, Zhicai Lin, Lijie Rong, Zhongzheng Zhu, Zongchang Song, Hui Xue, Jianchun Duan, Shujing Shen, Jing Wang, Linjie Lv, Yaping Yang, Xue Tan, Liping Han, Wei Zhao, Jie Wang, Wenfeng Xu, Weimin Zhu, Zhong Li, Xingya Li, Jinxing Lou, Qing Xu, Qijun Qian. Non-viral mesothelin-targeted CAR-T cells armored with IFNg-induced secretion of PD-1 nanobody in treatment of malignant mesothelioma in phase I clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT134.

Biomass carbon materials which have the merits of green, low cost and renewability, can be obtained from sodium alginate (SA) beads crosslinked by polyvalent metal ions. SA beads are possible to be obtained using diammoniums as the crosslinking agents. In this work, N-O codoped porous carbon (NO-PC) was prepared from SA beads crosslinked by diammoniums through the electrostatic interaction between ammonium cations and carboxylate groups of SA chains. The using of diammoniums as the crosslinkers achieved N doping into NO-PC. Scanning and transmission electron microscope observations revealed that NO-PC possessed hierarchically porous characteristic. X-ray photoelectron spectroscopy identified the successful N-O codoping. Both the species and concentration of diammoniums strongly affected the porous structure, surface area and electrochemical performance of NO-PC. N2 adsorption-desorption results of NO-PC indicated that the highest surface area was up to 3794 m2/g. The NO-PC based supercapacitors showed high specific capacities up to 269.0 F/g at 1 A/g and excellent cycling stability (92.09% after 5000 cycles at 5 A/g). The energy density of the symmetric supercapacitor was up to 18.9 Wh/kg at a power density of 1380 W/kg with a voltage window of −1.4–0 V.

IntroductionAnlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and suppressing tumor growth. Modulation of tumor suppressive immune microenvironment via the inhibition of vascular endothelial growth factor may augment the activity of immune checkpoint inhibitors. Here we described the results of safety, and clinical efficacy of anlotinib combined with immunotherapy in patients with advanced solid tumors, the serum cytokine levels, and peripheral blood T lymphocyte populations were detected simultaneously.MethodsTwenty six cases with advanced late-stage cancers including lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or intolerable toxicity. Imaging was performed every 6 weeks for the first year of therapy. Blood samples were collected from patients prospectively. Serum interleukin (IL)-2, IL-4, IL-6, IL-10, Tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and circulating immune cell subsets were measured at baseline and after two cycles of treatment via flow cytometry.ResultsThere were ten tumor types enrolled with lung, gallbladder, cholangiocarcinoma and soft tissue sarcoma being the most common. Most patients had received front line treatments for metastatic disease (80.8%). The objective response rate (ORR) was 23.1%, including one complete response (CR) (3.8%) and five partial responses (PR) (19.2%) and a disease control rate (DCR=CR+PR+SD) of 80.8% (21 of 26). The median PFS was 4.77 months (95% CI: 4.10-5.44 months). Three patients (11.5%) had grade 3 treatment-related adverse events. There were no grade 4 or 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n=2) and hypertension (n=1). Higher serum IL-2, IL-4, IL-10, TNF-α, IFN-γ levels and lower ratios of CD4/CD8 T cells were found in the responders compared with non-responders.ConclusionsThe preliminary data showed that the combination of anlotinib and anti-PD-1 antibodies demonstrated promising durable antitumor efficacy with acceptable toxicity in patients with various advance tumors, and promoted favorable changes in serum IL-2, IL-4, IL-10, TNF-α, IFN-γ levels and circulating immune cell subsets in clinical responders. It is worth to further validate the efficacy in a randomized prospective trial.

BackgroundLiver abscess is a potentially fatal disease, however identification of its causative pathogen remains challenging, which is crucial for guiding appropriate antibiotic therapy. To the best of our knowledge, the use of plasma next-generation sequencing (NGS) based pathogen analysis in patients with liver abscess has never been reported.Case presentationWe report a case with large liver abscess due toEdwardsiella tardathat was diagnosed by the plasma-based NGS assay within 24 h. After a 2-week single agent anti-infection therapy, the patient completely recovered. A second NGS assay following anti-infection therapy failed to detect the pathogenic DNA. Follow-up magnetic resonance imaging (MRI) of the abdomen on 1 month and 3 months showed a gradually decrease in size of the liver abscess, and the 6-month MRI showed that the abscess disappeared completely.ConclusionsOur data indicated that the plasma NGS test can sensitively and minimal-invasively detect pathogens within a clinically actionable timeframe, and antibiotic alone is an alternative to first-line treatment for large liver abscess with the aid of NGS for accurate detection of the pathogenic bacterial genome.

Next-generation sequencing (NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously. Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology (CSCO) and the China Actionable Genome Consortium (CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians, pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure (SOP), data analysis, report, and NGS platform certification and validation.

Early diagnosis and reasonable treatment of cancer can effectively reduce the progression and decrease the proliferation. Exosomes are considered to be an excellent biomarker due to their special role in cancer development and post-treatment evaluation. Here, a simple and effective method for constructing two-dimensional heterostructure modified films on the electrode surface is reported to realize the electrochemical detection of exosomes. Flake gold nano triangle (AuNTs) as spacer, effectively inhibits the decline of electron transport capacity caused by the van der Waals stacking effect of graphene, a layered conductive network based on GO/AuNTs heterojunction was constructed on glassy carbon electrode. Multifunctional peptides with antifouling and specific binding characteristics for target exosomes were carefully anchored onto the surface of GO/AuNTs conductive network composite through Au-S. Combined with the innovative micro nanostructure on the electrode surface and the multifunctional peptides probe, the fabricated sensor shows an excellent limit of detection of 76 particles/ml with a detection range of 102 to 106 particles ml−1. The proposed sensor provides a powerful platform for direct measurement of exosomes, opening new opportunities for highly sensitive determination of other biomarkers.

e17535 Background: Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death among women. Most of patients often have refractory or relapse. We have developed a CAR T cell secreting PD-1 nanoantibodies and targeting mesothelin (αPD-1-mesoCAR-T) and conducted a phase I clinical trial for evaluation of safety and efficacy of the αPD-1-mesoCAR-T cells in gynecologic tumors. Methods: This study is a single-arm, open, dose-increasing clinical study and two infusions (interval 14-35 days). Patients with advanced gynecological cancer were enrolled when immunohistochemical analysis for positive mesothelin over 70% and failed second-line treatment in Mengchao Cancer Hospital affiliated to Shanghai University and Shanghai Tenth People's Hospital affiliated to Tongji University. All patients underwent lymphodepletion before infusion at a dose of 1 to 15x106/kg. CAR copies, nanobody levels, cytokines, T lymphocyte subtypes were determined before and after infusion. Results: a total of 7 patients were enrolled so far and completed the first evaluation. After treatment, most symptoms of the patients were alleviated, two patients (#2, #3) had their lesions decreased. By RECIST 1.1, all 7 patients’ diseases became stable, and the disease control rate was 100%. The PFS of #3 patient with stable disease (SD) was 5.3 months, the patient #2 was 4.1 months. The frequent adverse events were fever, fatigue, nausea and pruritus. No sever adverse events above grade 3 occurred. The number of CAR-T cells in the peripheral blood increased significantly during day 4-14 after the infusion, and the PD-1 nanoantibody levels and the contents of INF-γ、IL-6、IL-2 and MCP-1 also increased at day 1-4. Conclusions: The preliminary clinical study showed that the aPD-1-mesoCAR-T cells are safe for the treatment of gynecologic cancer and stabilized the diseases. More data of the treatment is warrantied to continually follow up these patients.

8559 Background: Malignant pleural/peritoneal mesothelioma (MPM) is an aggressive cancer characterized by poor therapeutic response and poor survival. Programmed cell death protein-1 (PD-1)-mediated immunosuppression is believed to be associated with T cell exhaustion and dysfunction in solid tumors. We generated chimeric antigen receptor (CAR-T) cells that can secret PD-1 nanobodies and target mesothelin (PD-1-mesoCAR-T). After identifying the anti-tumor activity and cytotoxicity of PD-1-mesoCAR-T cells by pharmacokinetics and pharmacodynamics, we conducted a proof-of-concept clinical trial in the Shanghai Tenth People's Hospital affiliated to Tongji University and the Mengchao Tumor Hospital affiliated to Shanghai University to evaluate the safety and efficacy of PD-1-mesoCAR-T cells in a dose-escalation study for malignant pleural/peritoneal mesothelioma. 6 patients received one or more infusions of the CAR-T cells with prior lymphodepletion and the longest survival is up to 18 months. Methods: This open-label, single-arm, multicenter, phase 1 study was enrolled patients with pathological diagnosis with malignant mesothelioma whose mesothelin expression in immunohistochemical samples was equal or greater than 50%. Immunohistochemical samples derived from surgical tissue, puncture tissue or pleural effusion. PD-1-mesoCAR-T cells were administered intravenously ranging 1×106−1.5×107/kg. Safety and efficacy were assessed in response-evaluable patients (ie, patients who received at least one dose of PD-1-mesoCAR-T and had at least one post-baseline response evaluation). Results: From July 20, 2020 to January 31, 2022, 9 patients were screened and enrolled and only 6 patients were evaluable. Mesothelin positive rate in the samples of these patients were from 50% to 100%. Three patients of them had PD-L1 positive staining in specimen. All patients underwent lymphodepletion before infusion. Two of patients (33.3%) had cytokine release syndrome, which were grade 1 and grade 3, respectively. Four patients (66.7%) developed fever. Two patients (25%) had grade 3 pulmonary infection. Stable disease was sustained for ≥3 months in 5 patients; 1 exhibited complete response and one partial response on PET or CT scan. The objective response rate (ORR) was 33.3%, but increased to 66.7% in the patients with PD-L1 positive. Only one patient of these patients appeared progression of disease after infusion. All enrolled patients are alive and observed continually. Conclusions: The clinical study of 6 patients with malignant mesothelioma shows that PD-1-mesoCAR-T cells are safe and feasible, indicating a promising curative effect. Effect of the CAR-T cells on the long term survival will be observed continually. Clinical trial information: 01722149.

Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity. Dendritic cell (DCs) vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality. Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world. Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years, their efficacy is still unsatisfactory overall. Therefore, there is an urgent unmet clinical need for lung cancer treatment. Here, we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm, 2 medical centers, pilot study initiated by the investigator (ChiCTR-ONC-16009100, NCT02956551). The patients enrolled were patients with heavily treated metastatic lung cancer. Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis. A total of 12 patients were enrolled in this study. A total of 85 vaccine treatments were administered with a median value of 5 doses/person (range: 3–14 doses/person). In total, 12–30 peptide-based neoantigens were selected for each patient. All treatment-related adverse events were grade 1–2 and there were no delays in dosing due to toxic effects. The objective effectiveness rate was 25%; the disease control rate was 75%; the median progression-free survival was 5.5 months and the median overall survival was 7.9 months. This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.

High Intensity Focused Ultrasound (HIFU) is a non-invasive tumor treatment technology with advantages such as less pain and faster recovery after surgery, and its treatment features coincide with the general trend of tumor treatment development, and is suitable for the treatment of many benign malignant solid tumors. Preoperative assessment, perioperative management and follow-up of HIFU have special features, and HIFU treatment has special real-time observation and auxiliary measures. In the treatment advanced pancreatic cancer, HIFU technology combined with arterial perfusion chemotherapy, intravenous chemotherapy and other therapeutic methods can make the effectiveness better with less side effects, which is more favorable to the comprehensive treatment of tumor, HIFU therapy is a truly non-invasive treatment, and is a very promising methods of cancer treatment.

A triple recognition voltammetric method for the determination of brain natriuretic peptide (BNP) is described. Gold nanoparticles (AuNPs) and magnetic nanoparticles (MagNPs), sized 26 and 310 nm, respectively, were synthesized and characterized by transmission electron microscopy (TEM), FT-IR, dynamic light scattering (DLS), and Z-potential measurements. Antibody-modified MagNPs and methylene blue–labeled aptamer (Apt-MB)–modified AuNPs were used as an identifier, a signal reporter, and an amplifier, respectively. In the presence of BNP, the magnetic gold nanocomposite is formed through cascade conjugation via specific interaction. It then hybridized with complementary DNA (cDNA) on the interface, thereby amplifying the current signal of Apt-MB and increasing the selectivity of the immunoassay. Results obtained demonstrate the development of a highly selective method with a detection limit of 0.56 pg mL−1 and a linear response over the concentration range 1–10,000 pg mL−1. The standard deviation of the method is

Programmed death ligand 1 (PD-L1) is a typical immune checkpoint protein, whose up-regulation on the membrane of different tumor cells inhibits the immune response of T cells and leads to the escape of tumor cells. In this work, we designed a facile and highly specific surface plasmon resonance (SPR) biosensor to detect PD-L1 in human plasma based on magnetite nanorods containing ordered mesocages (MNOM) and silver nanoclusters (AgNCs). Magneto-optical nanocomplex MNOM@AgNCs with superior magneto-optical properties and high signal-to-noise ratio were fabricated to improve the detection sensitivity owing to the high specific surface area of MNOM and excellent localized SPR of AgNCs. The PD-L1 Antibody on the surface of gold chip and the PD-L1 aptamer on MNOM@AgNCs could realize dual selective recognition of PD-L1, providing the specificity of the sensor and reducing non-specific binding. The SPR sensor showed a good linear range of PD-L1 from 10 ng/mL to 300 ng/mL with the detection limit of 3.29 ng/mL. The practical performance of this immunosensing platform had been successfully verified by clinical samples which included healthy donors and cancer patients. Based on the analysis, the developed immunosensor provided a new strategy for point-of-care detection of PD-L1 and could be used as clinical companion diagnosis of PD-1/PD-L1 inhibitor therapy.

Programmed death ligand 1 (PD-L1) immune checkpoint has been regarded as a new target for predicting cancer immunotherapy. As a transmembrane protein, PD-L1 has very low blood concentration and is likely to deplete their native activity when separated from the membrane environment due to significant hydrophobic domains, which make it difficult to measure sensitively. The reported PD-L1 aptamers and antibodies are both extracellular region binding molecules with the overlapping binding sites, which seriously limit with the construction of biosensor. Specific intracellular binding peptide (SIBP) as a unique PD-L1 intracellular region homing probe molecule is utilized for specifically capture targets. A simple and sensitive surface plasmon resonance (SPR) sandwich assay was constructed to detect serum soluble PD-L1 (sPD-L1) based on the unique and strong binding ability of SIBP to the intracellular region of sPD-L1. The designed SPR sensor showed great selectivity and wide dynamic response range of sPD-L1 concentration from 10 ng/mL to 2000 ng/mL. The limit of detection was calculated to be 1.749 ng/mL (S/N = 3). Owing to the SIBP's strong and specific binding ability with sPD-L1, the sensitive sensor can successfully detect sPD-L1 in serum samples, paving the way for the development of efficient test tools for clinical diagnosis and analysis.

A nanoprobe was developed to achieve apoptosis detection by cell membrane-functionalized gold nanoparticles (AuNP-pep@Mem). The fluorescence of the fluorescein isothiocyanate isomer I (FITC)-labeled caspase-3 substrates was quenched by the attachment to AuNPs. The fluorescence signal was recovered via the cleavage of caspase-3 under apoptotic conditions. It exhibited a low detection limit of 1.3 pg·mL−1 with a linear range from 3.2 to 100 pg·mL−1 for caspase-3 detection with excitation wavelength of 490 nm. After wrapped by the cell membrane, the nanoprobe was effectively delivered into cells with high cell permeability. AuNP-pep@Mem nanoprobe provided signal enhancement of 1.8 times in living cells compared to non-membrane-coated nanoparticles (AuNP-pep). In combination with its excellent stability, low LOD and good specificity, the AuNP-pep@Mem probe can be an ideal probe for fluorescence imaging of apoptosis.

3605 Background: Recombinant human adenovirus serotype 5 injection (H101), obtained through genetic engineering to delete the E1B domain and part of the E3 domain and then selectively replicated in tumor cells, has been approved in 2005 for the local treatment of nasopharyngeal carcinoma and head and neck cancers. This trial aimed to evaluate the safety and the preliminary treatment efficacy of H101 combined with standard treatments in patients with liver metastases from colorectal cancer. Methods: In this phase 1, dose-escalation trial (ChiCTR1900027922), 17-75 years old colorectal cancer patients with unresectable liver metastases that failed to first-line therapy were included at The Tenth People's Hospital Affiliated to Tongji University between 2018.9 and 2020.12. All patients received H101 combined with standard therapy (bevacizumab + mFOLFOX6/FOLFIRI). Ultrasound-guided injection of H101 into the liver metastases was performed for all patients, with one of the following doses: 5×1011 vp/injection for the low, 1×1012 vp/injection for the moderate, 2×1012 vp/injection for the moderate-high, and 3×1012 vp/injection for the high dose groups. Intravenous infusion of bevacizumab (5 mg/kg) and administration of standard-dose mFOLFOX6 or FOLFIRI within 48 h after the intratumor injection was performed. The primary endpoint of the trial was the maximum tolerated dose (MTD). The secondary endpoints included safety, tumor responses, and tumor marker CEA. The adverse events (AEs) were monitored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) and evaluated within 1 week after injection. Imaging examinations were performed for all patients to evaluate the tumor responses, according to the irRECIST. Results: Finally, 8 patients were included; the numbers of patients in the 4 groups were 1, 3, 3, and 1, respectively. MTD was not observed in this study. No grade >4 AEs were observed. The major AE included fatigue (5/8), fever (4/8), shiver (3/8), abdominal pain (3/8), and night sweat (3/8). The tumor responses included partial response in one patient (moderate dose group), stable disease in 6 patients (1, 1, 3, and 1 in the low, moderate, moderate-high, and high dose groups, respectively), and progressive disease in 1 patient (moderate group). No dose-effect response was found. The tumor marker CEA was reduced in 6 of the 8 patients, including 1 (1/1), 3 (3/3), 2 (2/3), and 0 patients in the low, moderate, moderate-high, and high-dose groups, respectively. Conclusions: The safety of H101 combined with standard therapy for liver metastases from colorectal cancer is acceptable, which also shows certain preliminary efficacy. The phase 2 trial is now ongoing. Clinical trial information: ChiCTR1900027922. [Table: see text]

3082 Background: Chemotherapy-induced thrombocytopenia (CIT) contributes to treatment dose delay and/or modification, often resulting in poorer survival and disease progression. Compared with partial splenic embolization (PSE) and drugs, high-intensity focused ultrasound has the advantages as following: (1) it is a noninvasive treatment modality with potentially fewer adverse effects and complications; (2) the hospital stay and recovery time after treatment are short; (3) its cost is relatively low compared to surgery. The purpose of this work was to preliminarily investigate the efficacy and safety of high intensity focused ultrasound treatment of chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. Methods: 26 patients with chemotherapy-induced thrombocytopenia and hypersplenism (15 male and 11 female; median age, 56 years; range, 51-66 years) were treated with ultrasound guided high-intensity focused ultrasound. Complications were recorded. Laboratory examination and magnetic resonance imaging were used to evaluate the efficacy. The spleen volume and ablation volume rate of the spleen were calculated by MRI after treatment. They were followed closely for at least 6 months. Results: After high-intensity focused ultrasound treatment, the MRI showed that the ablation area had turned into a non-perfused volume, the mean percent spleen ablation volume was 18.76% ± 6.1% (range, 11.17%-32.34%). After 6 months of HIFU ablation, the ablated area shrank evidently; the sunken spleen formed a lobulated shape and the splenic volume decreased. The platelet count increased 3-7 days after treatment and remained for 1-2weeks higher than baseline (53.33 ± 15.80 × 109/L). The white blood cell count and platelet count of the patients were substantially improved during the follow-up period. No substantial difference was observed in RBC counts between baseline and after treatment. In addition, symptoms such as epistaxis and gingival bleeding were ameliorated or even eliminated, and the quality of life was improved. Follow-up imaging showed a nonperfused volume in the spleen. Conclusions: For the first time to our knowledge, high-intensity focused ultrasound ablation was used to treat Chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. High-intensity focused ultrasound ablation of the spleen may cause damage to a certain volume of the spleen parenchyma to achieve the purpose of hypersplenism treatment. High intensity focused ultrasound may be an effective and safe alternative for treatment of CIT and hypersplenism.

Tribocorrosion of Ti6Al4 V alloy has been investigated in 3.5 wt.% NaCl solution under simulated deep-sea environment. The results demonstrate tribocorrosion rate increases with hydrostatic pressure (i. e. seawater depth) at an accelerated speed of 5.9×10-6 mm3·N-1·m-1·MPa-1. Wear volume under potentiostatic tribocorrosion depends on potential and experiences a maximum at -0.2 VAg/AgCl where the volume at 20 MPa is almost tripled that at 0.1 MPa. Therefore, both hydrostatic pressure and potential have significant effect on tribocorrosion behaviour. At higher hydrostatic pressure, tribocorrosion is dominated by delamination wear and the increment in wear volume results from mechanical wear and synergism.

BACKGROUND: The treatment of squamous cell carcinoma of the lung (SqCC) patients who failed with multi-line treatment is still limited. Immunotherapy with immune checkpoint inhibitors as the main treatment has made a breakthrough in advanced lung cancer. The personalized neoantigen-based cancer vaccine, another immunotherapy based on the theory of adaptive immune responses, has been developed rapidly in recent years. The combination of neoantigen vaccines against anti-PD-1/PD-L1 at the same time (or successively) has obvious appeal as previous clinical trials reported in melanoma, and is likely to be the first combination therapy to be formally examined in clinical trials. Here, We report a case of SqCC treated with dendritic cell-based neoantigen vaccine combined with immune checkpoint inhibitor. CASE SUMMARY: A 68-year-old male squamous cell carcinoma of the lung patient, who disease relapse after multi-line treatments that including chemotherapy, radiotherapy, targeted therapy, and antiangiogenic therapy, was enrolled in this study. Whole-exome and transcriptome sequencing were used to evaluate patient's mutations and predict the potential neoantigens for vaccine. Seventeen neoantigen peptides were selected and then synthesized to generate autologous dendritic cell (DC)-based neoantigen vaccine. At last, 1.38 × 108 DC-based neoantigen vaccine was subcutaneously injected into the patient's body (on days 1, 7, 15, 22 and 30) in combination with immune checkpoint inhibitor (PD-l antibody, dose 4mg/kg followed by 2 mg/kg biweekly). By following-up to 10 months after vaccination, we found this refractory advanced SqCC patient has achieved partial remission. The immunogenicity of each of the 17 neo-epitopes administered in this study was analyzed by IFNγ ELISpot in CD4+ and CD8+ T cells in blood samples. Responses were detected against 64.71% (11/17) of the predicted neo-epitopes. CONCLUSION: In summary, these results show that the dendritic cell based neoantigen vaccine combined with immune checkpoint inhibitor is safe and well tolerated in advanced lung cancer patients who failed with multi-line treatments. The neo-antigen vaccine can cause T cell immune response in vivo. The bioinformatics prediction algorithm helps to select high-quality neoantigens. Moreover, our work has introduced a framework for testing neoantigen-based vaccine combinatorial strategies in patients with advanced lung cancer. Citation Format: Song Gao, Zhongzheng Zhu, Jiaqian Wang, Juemin Fang, Yu Zhao, Zhuqing Liu, Guochao Wei, Huanlong Qin, Yuquan Wei, Heng Xu, Li Yang, Qing Xu. Effective personalized neoantigen-based cancer vaccine combined with immune checkpoint inhibitor in the treatment of a patients with advanced squamous cell lung cancer failed with multi-line treatments [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5577.

Due to the complex structure and massive volume of large equipment in petrochemical enterprises, it was very difficult to carry out inspection and maintenance work. The traditional expert system used a single knowledge base and reasoning machine, so the processing efficiency and prediction accuracy were low. In this paper, the dimensionality reduction which is used to process a large amount of physical information collected by the sensors, remove redundant components and extract main characteristic parameters. Meanwhile, combined with the powerful pattern recognition and judgment ability of fuzzy neural network, the forward reasoning mechanism and error back propagation keeping continuous training correction until meeting the accuracy requirements, the expert system gave the equipment fault prediction conclusion. Finally, taking main fan oil station circulating oil pump and motor of heavy oil catalytic cracking unit and nine stages of bearing damage as monitoring objects, the fault predictions was implemented by the following steps: data collection, feature extraction, dimension reduction of big data and expert system with the fusion of fuzzy neural network, and it is proved that the expert system with fuzzy neural network based on dimension reduction can greatly improve the convergence speed.

7062 Background: Cancer is a group of genetic diseases that result from changes in the genome of cells in the body, leading them to grow uncontrollably. Recent researches suggest Chromosome instability (CIN), which is defined as an increased rate of chromosome gains and losses, manifests as cell-to-cell karyotypic heterogeneity and drives cancer initiation and evolution. Methods: In the past two years, we initiated iStopCancer project, and characterized 4515 ‘best available’ minimal-invasive samples from cancer patients and 1501 plasma samples from non-tumor diseases by using low-pass whole genome sequencing. DNA from ‘best available’ minimal-invasive samples, including peripheral plasma, urines, pancreatic juice, bile and effusions were analyzed by low coverage whole genome sequencing followed by the UCAD Bioinformatics workflow to characterize the CINs. In total, 32T bp nucleotide (coverage =1.7X for each sample) were collected. All the data can be visualized on website: http://www.istopcancer.net/pgweb/cn/istopcancer.jsp . Results: 3748(83%) of tumors present detectable CIN (CIN score>1000) in minimal-invasive samples. The missed cancer patients were majorly from patients with either tumor size less than 2cm or less-aggressive cancers, including thyroid cancer, low-grade urothelial carcinoma, lung cancer in-situ, et al. Of the 1501 non-tumor individuals, 30(2.0%) present detectable CIN (|Z|>=3) at the time of sample collection, 24(80.0%) was diagnosed as tumor patient in 3-6 months follow-up. There were 9 (0.59%) of non-cancer individuals without detectable CIN were also reported as tumor patients during 6-month following up. In summary, the positive and negative prediction value is 80.0% and 99.4% respectively. The false alarms were majorly from patients with EBV activations, which indicates virus may interference chromosome stability and drove virus-associated carcinogenesis. For the patient with repeated detections, plasma cfDNA CIN dynamics predicted clinical responses and disease recurrences. Quick clearance of plasma cfDNA CIN in 2-3 weeks was found in 153 (83.6%) patients. Meanwhile, no quick clearance was found in majority of SDs/PDs (73/88=83.0%). Furthermore, cfDNA CIN predicts clinical response 2-8 weeks ahead of traditional biomarkers (CEA, CA15-3, CA199, AFP et al). Conclusions: Large-scale low coverage whole genome sequencing data provides useful information for cancer detection and managements.

3039 Background: The limitations of chimeric antigen receptor T cells (CAR-T) in solid tumors are immunosuppressive tumor microenvironment and difficult infiltration to tumor. In order to reduce on-target off-tumor toxicities and circumvent the immune-suppressive tumor microenvironment(TME), we modified autologous CAR-T to be specific for mesothelin (MSLN) on cancer cells and secrete PD-1 antibodies (aPD1-MSLN-CAR T cells). Here, we report the safety and efficacy of aPD1-MSLN-CAR T cells in 10 patients with relapsed/refractory solid cancers in this single-arm, open-label, first-in-human phase I pilot study (ClinicalTrial.gov: NCT03615313). Methods: aPD1-MSLN-CAR T cells were prepared from peripheral blood mononuclear cells and engineered using PiggyBac Transposon System to target MSLN and secrete PD-1 antibodies. 10 patients with mesothelin positive relapsed/refractory solid cancers after failure to standard therapies were treated with aPD1-MSLN-CAR T cells for two or more cycles until disease progression or intolerable toxicity. The dose escalation of CAR T cells was designed to be 5×106/kg, 5×107/kg, and 1×108/kg, respectively. Adverse events were evaluated according to CTCAE-V4.03 and clinical response was assessed by RECIST 1.1. CAR expression was analyzed using quantitative real-time polymerase chain reaction. PD-1 antibodies were detected by ELISA. Serum IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α were measured using flow cytometry. Results: The most common adverse events were mild fatigue and fever. Abdominal pain was also observed in 1 patient. Grade 1 and 2 cytokine release syndromes were observed without neurologic symptoms in 10 patients. After aPD1-MSLN-mRNA-CAR T cells treatment, 2 patients (20%) achieved partial response (PR), 4 (40%) remained stable (SD), and the rest 4 (40%) patients developed disease progression (PD). The median PFS was 97 days [95% CI (13, 180)] estimated by Kaplan-Meier method. Conclusions: These findings lend support that the combination of modified CAR T cells targeting MSLN with PD1 inhibition for solid tumors is safe. Modified CAR-T cells expressing PD-1 antibodies maybe an option to improve CAR-T efficacy as a result of refined TME. Clinical trial information: NCT03615313 . [Table: see text]

Sialic acid-binding immunoglobulin-like lectin 15 (Siglec 15) is a novel immunomodulatory target and was identified as an immune suppressor in the tumor microenvironment. Accurate assessment of Siglec 15 expression levels is critical for cancer prognosis and treatment. In this work, a natural receptor-based immunoelectrochemical sensor is designed to mimic the interaction between Siglec 15 and DNAX-activation protein (DAP 12) in the cellular signal pathway. DAP 12 labeled with the electrochemical signal molecule Fc is recognized by Siglec 15 through specific interaction on the electrode surface and used as the signal reporter. Anti-Siglec 15 modified MNPs (MNPs-Ab) were used as the extraction agent for the magnetic extraction of target analytes in complex matrices. Free Anti-Siglec 15 will "squeeze out" the DAP 12-Fc to bind the Siglec 15 on the electrode surface, resulting a sensitive electrochemical signal change according to the Siglec 15 concentration in sample. Natural receptor-based competitive assay ensure the efficient binding between antibody and Siglec 15 and decrease the nonspecific interaction. Therefore, this simple natural receptor-based competitive assay with sensitivity and selectivity has potential for practical clinical application.

Circulating tumor cells (CTCs) are an important biomarker of cancer and are valuable in evaluating the risk of metastatic progression and in facilitating precise therapeutic treatments. In this paper, a dual-selective strategy was constructed to achieve the sensitive detection of CTCs. Cell membrane fragment-functionalized AuNPs (M-AuNPs) and folic acid-functionalized AuNPs (FA-AuNPs) were fabricated and characterized. CTCs membrane containing the specific junction plakoglobin (JUP) could be captured onto Anti-JUP-modified gold chip selectively. FA-AuNPs can bind with M-AuNPs through the overexpressed FA receptors in the CTCs membrane. These double selective recognitions through the specific interaction between JUP and Anti-JUP, FA and FA receptor can ensure the sensor’s accuracy and specificity. The ultra-sensitive CTCs detection was achieved through multi-signal amplifications, including cell membrane fragments, M-AuNPs and FA-AuNPs. The biosensor constructed here has a low detection limit of 1 cell within the linear range of 101–105 cell mL−1. The low detection limit is in accordance with clinical detection standards. Owing to its outstanding selectivity, sensitivity, and stability, this new biosensor strategy for detecting CTCs offers new possibilities for clinical testing.

Extrahepatic metastasis confers unfavorable patient prognosis in patients with hepatocellular carcinoma (HCC), however, reliable markers allowing prediction of extrahepatic metastasis at the time of initial diagnosis are still lacking. This study was to identify gene-level copy number aberrations (CNAs) related to extrahepatic metastasis-free survival of HCC patients, and further examine the associations between CNAs and gene expression. Array comparative genomic hybridization (aCGH) and expression array were used to analyze gene CNAs and expression levels, respectively. The associations between CNAs of a panel of 20 genes and extrahepatic metastasis-free survival were analyzed in 66 patients with follow-up period of 1.6-90.5 months. The gene expression levels between HCCs with and without gene CNA were compared in 109 patients with HCC. We observed that gains at MDM4 and BCL2L1, and losses at APC and FBXW7 were independent prognostic markers for extrahepatic metastasis-free survival of HCC patients. Integration analysis of aCGH and expression data showed that MDM4 and BCL2L1 were significantly upregulated in HCCs with gene gain, while APC and FBXW7 were significantly downregulated in HCCs with gene loss. We concluded that gene gains at MDM4 and BCL2L1, and losses at APC and FBXW7, with concordant expression changes, were associated with extrahepatic metastasis-free survival of HCC patients and have potential to act as novel prognostic markers.

Copy number aberrations (CNAs) in chromosome arm 8q have been associated with unfavorable clinical outcomes of several cancers and progressive tumor characteristics of hepatocellular carcinoma (HCC). This study was to identify correlation of CNAs in 8q with clinical outcomes of HCC patients, and further screen for differentially expressed genes in outcome-related CNAs. Array comparative genomic hybridization and expression arrays were performed to detect CNAs and expression levels, respectively. The correlations between CNAs in 8q and outcomes were analyzed in 66 patients, with a median follow-up time of 45.0 months (range, 2.6-108.6 months). One hundred and nine cases were further evaluated to identify differentially expressed genes in the potential outcome-related CNAs. Copy number gain in 8q was observed in 22 (33.3%) of the 66 HCC cases. The most recurrent gains (with frequencies >20%) were 8q13.3-21.3,8q21.3-23.3,8q23.3-24.13,8q24.13-24.3, and 8q24.3. Survival analysis showed that 8q24.13-24.3 gain was significantly associated with reduced overall survival (jP=0.010). Multivariate Cox analysis identified 8q24.13-24.3 gain as an independent prognostic factor for poor overall survival (HR=2.47; 95% CI=1.16-5.26; Р=0.019). Apanel of 17 genes within the 8q24.13-24.3 region, including ATAD2,SQLE,PVT1,ASAP1, and NDRG1 were significantly upregulated in HCCs with 8q24.13-24.3 gain compared to those without. These results suggest that copy number gain at 8q24.13-24.3 is an unfavorable prognostic marker for HCC patients, and the potential oncogenes ATAD2,SQLE, PVT1, ASAP1,and NDRG1 within the regional gain, may contribute coordinately to the 8q24.13-24.3 gain-related poor prognosis.

6616 Background: Watson for Oncology (WFO) is an artificial intelligent clinical decision-support system (AI-CDSS) developed by IBM and trained by Memorial Sloan Kattering Cancer Center to assist in cancer care by providing evidence-based treatment options with priority. However, there are disagreements argue that WFO recommends “unsafe and incorrect” cancer treatments. Also, guidelines and drug availability in China are different from USA. Therefore, a quality control system of WFO is urgently needed to help oncologists better use WFO in China. Methods: Experts from medical oncology, surgical oncology, radiology, intervention, radiology and pathology etc. forming a Multiple Disciplinary Team (MDT) to score Watson recommendations in 6 aspects (shown in the table). Results: With this quality control system, the value of WFO was carefully evaluated by MDT. Recommendations with higher score(especially more than 80) were more standardized, reasonable and evidence-based thus more likely to be chosen. Localization and drug availability problem was solved by taking Chinese guidelines and drug approval into evaluation within this scoring system. Treatment options unsuitable or unavailable for patients by the system will be removed and replaced by the advices of MDT. Conclusions: Reliability and security are the top concerns of applying new technology in healthcare. With the MDT quality control system, AI-CDSS can be used safely and efficiently before it is fully mature. Also, the accuracy and advancement are assessed in this system to help oncologists better use WFO in China in the future. Indicators evaluating the WFO recommendations. [Table: see text]

6545 Background: IBM Watson for Oncology (WFO) is developed with artificial intelligence to assist the oncologists in treatment decision-making by providing evidence-based treatment recommendations with priority and personality. We have been exploring the value of applying WFO in teaching and remote consulting among members in the hospital union to improve medical quality and conformity. Methods: Four modes were followed to apply WFO to teaching and remote consulting. Firstly, a teaching hospital conducted instructional teaching for a primary hospital through WFO, or a primary hospital consulted with a teaching hospital on cancer treatment combined with WFO. Secondly, a teaching hospital conducted conference-based teaching and remote consulting for two or three primary hospitals through demonstrating WFO. Thirdly, we cooperated with other teaching hospitals to carry out interactive discussions on cases through WFO with several primary hospitals. Fourthly, we cooperated with other teaching hospitals to conduct WFO demonstration and discussion for several primary hospitals. Remote communication was performed by using third-party video conference software. A survey was conducted to collect feedback from 56 primary hospitals in our hospital union. Results: More than 80% of primary hospitals were willing to learn the standardized treatment and recent treatment progress of tumors by participating in WFO remote consulting in our hospital. The value of four modes to promote the standardized cancer treatment and improve the medical quality and conformity in primary hospitals were all recognized. WFO also contributed to academic exchanges and learning among high-level teaching hospitals, and facilitated the use of artificial intelligence in oncology therapy more rational and appropriate. Conclusions: Non-standardization in cancer care remains to be a big problem in primary hospitals in China. Although limitation of WFO exists in the complex cases of certain tumor types, the rational use of WFO in the teaching and remote consulting could help and promote the standardized cancer treatment in China.

e18504Background: Watson for Oncology (WFO) is a cognitive computing system developed by IBM to assist in tumor therapy which was trained by the Memorial Sloan Caitlin Cancer Center (MSKCC) for fou...

As a potential electrolyte for lithium-ion batteries, a porous polymer electrolyte membrane based on poly(vinylidenefluoride-hexafluoropropylene) (PVDF-HFP) was prepared by a phase inversion method. The casting solution, effects of the solvent and non-solvent and addition of micron scale TiO 2 particles were investigated. The membranes were characterized by SEM, XRD, AC impedance, and charge/discharge tests. By using acetone as the solvent and water as the non-solvent, the prepared membranes showed good ability to absorb and retain the lithium ion containing electrolyte. Addition of micron TiO 2 particles to the polymer electrolyte was found to enhance the tensile strength, electrolyte uptake, ion conductivity and the electrolyte/electrode interfacial stability of the membrane.