Publications

<p>Supplementary Figure 2. Pancreatic cells are resistant to VV-gp100 oncolysis but sensitive to CAR T cell-mediated cytotoxicity.</p>

To improve understanding of avian influenza in humans by presenting a case of avian influenza (H(5)N(1)).Clinical and laboratory data of this case of avian influenza (H(5)N(1)) in humans were described, and related literature was reviewed.The female patient was 31 years old. She lived in epidemic district of avian influenza and had a history of close contact with sick poultry. The patient initially presented fever and chills accompanied by myalgia, and then followed by cough, blood-tinged sputum, dyspnea and frequent diarrhea. Laboratory findings indicated leukopenia, dysfunction of cellular immunity, abnormal enzymes of liver, and hypoxia. Patchy infiltration involved two lungs progressed rapidly on chest radiograph. ECG showed that T waves of V(1 - 5) were reverted. The patient was diagnosed with avian influenza (H(5)N(1)) by hemagglutination inhibition and microneutralization assay combined with epidemiological and clinical data. Supportive therapy, corticosteroids, antibacterial, and antiviral agents were administered. Complications were treated accordingly during the course. She got better overtime and recovered. The laboratory abnormalities and chest radiograph returned to normal before discharge. The patient's relatives and doctors involved in the medical care were free from infection.Supportive treatment is important for patients with avian influenza. Complications should be prevented and treated in time.

Background Clinical trials of immunotherapy have excluded patients with pre-existing autoimmune disease. While the safety and efficacy of single agent ipilimumab and anti-PD1 antibodies in patients with autoimmune disease has been examined in retrospective studies, no data are available for combination therapy which has significantly higher toxicity risk. We sought to establish the safety and efficacy of combination immunotherapy for patients with advanced melanoma and pre-existing autoimmune diseases. Methods We performed a retrospective study of patients with advanced melanoma and pre-existing autoimmune disease who received combination ipilimumab and anti-PD1 at 10 international centers from March 2015 to February 2020. Data regarding the autoimmune disease, treatment, toxicity and outcomes were examined in patients. Results Of the 55 patients who received ipilimumab and anti-PD1, the median age was 63 years (range 23–83). Forty-six were treated with ipilimumab and nivolumab and nine with ipilimumab and pembrolizumab. Eighteen patients (33%) had a flare of their autoimmune disease including 4 of 7 with rheumatoid arthritis, 3 of 6 with psoriasis, 5 of 10 with inflammatory bowel disease, 3 of 19 with thyroiditis, 1 of 1 with Sjogren’s syndrome, 1 of 1 with polymyalgia and 1 of 1 with Behcet’s syndrome and psoriasis. Eight (44%) patients ceased combination therapy due to flare. Thirty-seven patients (67%) had an unrelated immune-related adverse event (irAE), and 20 (36%) ceased combination immunotherapy due to irAEs. There were no treatment-related deaths. Patients on immunosuppression (OR 4.59; p=0.03) had a higher risk of flare. The overall response rate was 55%, with 77% of responses ongoing. Median progression free survival and overall survival were 10 and 24 months, respectively. Patients on baseline immunosuppression had an overall survival of 11 months (95% CI 3.42 to 18.58) compared with 31 months without (95% CI 20.89 to 41.11, p=0.005). Conclusions In patients with pre-existing autoimmune disease, not on immunosuppression and advanced melanoma, combination ipilimumab and anti-PD1 has similar efficacy compared with previously reported trials. There is a risk of flare of pre-existing autoimmune disorders, particularly in patients with inflammatory bowel disease and rheumatologic conditions, and patients on baseline immunosuppression.

Sepsis is the dysregulated host response to an infection which leads to life-threatening organ dysfunction. Metabolomic profiling in bio-fluid or tissue is vital for elucidating the pathogenesis of sepsis and evaluating therapeutic effects of medication. In this study, an untargeted metabolomics approach was applied to study the metabolic changes in lung tissue of septic rats induced by cecal ligation and puncture (CLP) and investigate the treatment effects of Xubijing injection (XBJ). Metabolomics analyses were performed on ultra-high performance liquid chromatography-Q Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap-HRMS) together with multivariate statistical analysis. A total of 26 differential metabolites between CLP and sham-operated group were identified. The altered metabolic pathways included energy metabolism, amino metabolism, lipid metabolism, fatty acid metabolism and hormone metabolism. Among the 26-varied metabolites, 15 were significantly regulated after XBJ treatment. The metabolic pathway network of sepsis was drawn to interpret the pathological feature of lung damage caused by sepsis and the underlying regulating mechanism of XBJ on the molecular levels. Our findings display that LC-MS-based metabolomics is a useful tool for uncovering the underlying molecular mechanism of sepsis, and XBJ may exert therapeutic effect by regulating multiple metabolic pathways.

Supplementary Figure from Tumor Genomic Testing for >4,000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib)

Abstract Background The human microbiome plays an important role in cancer. Accumulating evidence indicates that commensal microbiome-derived DNA may be represented in minute quantities in the cell-free DNA of human blood and could possibly be harnessed as a new cancer biomarker. However, there has been limited use of rigorous experimental controls to account for contamination, which invariably affects low-biomass microbiome studies. Results We apply a combination of 16S-rRNA-gene sequencing and droplet digital PCR to determine if the specific detection of cell-free microbial DNA (cfmDNA) is possible in metastatic melanoma patients. Compared to matched stool and saliva samples, the absolute concentration of cfmDNA is low but significantly above the levels detected from negative controls. The microbial community of plasma is strongly influenced by laboratory and reagent contaminants introduced during the DNA extraction and sequencing processes. Through the application of an in silico decontamination strategy including the filtering of amplicon sequence variants (ASVs) with batch dependent abundances and those with a higher prevalence in negative controls, we identify known gut commensal bacteria, such as Faecalibacterium , Bacteroides and Ruminococcus , and also other uncharacterised ASVs. We analyse additional plasma samples, highlighting the potential of this framework to identify differences in cfmDNA between healthy and cancer patients. Conclusions Together, these observations indicate that plasma can harbour a low yet detectable level of cfmDNA. The results highlight the importance of accounting for contamination and provide an analytical decontamination framework to allow the accurate detection of cfmDNA for future biomarker studies in cancer and other diseases.

TPS531 Background: Pembrolizumab leads to responses in ~20% of metastatic bladder cancer patients. Irradiation of bladder cancer cells in-vitro and in-vivo leads to upregulation of PD-L1, and in immunocompetent mouse models blockade of PD-L1 leads to delayed tumour growth following irradiation. Randomised data from PACIFIC trial in NSCLC shows the addition of PD-L1 inhibition to chemoradiation significantly prolongs PFS. A trial of chemoradiotherapy with pembrolizumab will assess safety and synergy of the combination in localised bladder cancer. Methods: This pilot study enrols patients with maximally resected non-metastatic muscle invasive bladder cancer, who either wish for bladder preservation or are ineligible for cystectomy. This study will assess the safety and feasibility of combining pembrolizumab with chemoradiotherapy in ECOG 0-1 patients without contraindications to pembrolizumab. The study has enrolled 4 of a planned 30 patients. All patients treated with 64Gy of radiation therapy in 32 fractions over 6 weeks, 2 days. Cisplatin 35mg/m 2 IV concurrently weekly for 6 doses with radiation. Pembrolizumab commences concurrently with radiation and is given 200mg IV q21 days for 7 doses. Surveillance cystoscopy is performed 12 & 24 weeks after the commencement of chemoradiotherapy to assess response to therapy. Patients will enter follow up with clinical assessment, cystoscopy and CT staging performed at intervals until close of study. The primary endpoint assessed will be safety, as defined by a satisfactorily low rate of unacceptable toxicity (G3-4 adverse events or failure of completion of planned chemotherapy and radiotherapy according to defined parameters). The secondary endpoint will be efficacy, as assessed by the proportion of patients achieving a best response of complete response based on the first two 12 and 24 week post chemoradiotherapy cystoscopic assessments. Exploratory analysis will include assessment of tumour histopathological, molecular, genetic and immunological parameters. It is expected that it will take two years to accrue the 30 patients across 5 Australian centres. NCT02662062. Clinical trial information: NCT02662062.

<div>Abstract<p><b>Purpose:</b> Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with <i>BRCA1/2</i> mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary <i>BRCA1/2</i> mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.</p><p><b>Experimental Design:</b> We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.</p><p><b>Results:</b> Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary <i>BRCA1/2</i> mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)].</p><p><b>Conclusions:</b> Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. <i>Clin Cancer Res; 19(19); 5485–93. ©2013 AACR</i>.</p></div>