Citations

Abstract Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10−6) was observed in the meta-analysis (PGxE = 1.2 ×10−6, PJoint = 4.2 ×10−7). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

Background: Diabetes is a risk factor associated with pancreatic ductal adenocarcinoma (PDAC), and new adult-onset diabetes can be an early sign of pancreatic malignancy. Development of blood-based biomarkers to identify diabetic patients who warrant imaging tests for cancer detection may represent a realistic approach to facilitate earlier diagnosis of PDAC in a risk population. Methods: A spectral library-based proteomic platform was applied to interrogate biomarker candidates in plasma samples from clinically well-defined diabetic cohorts with and without PDAC. Random forest algorithm was used for prediction model building and receiver operating characteristic (ROC) curve analysis was applied to evaluate the prediction probability of potential biomarker panels. Results: Several biomarker panels were cross-validated in the context of detection of PDAC within a diabetic background. In combination with carbohydrate antigen 19-9 (CA19-9), the panel, which consisted of apolipoprotein A-IV (APOA4), monocyte differentiation antigen CD14 (CD14), tetranectin (CLEC3B), gelsolin (GSN), histidine-rich glycoprotein (HRG), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), plasma kallikrein (KLKB1), leucine-rich alpha-2-glycoprotein (LRG1), pigment epithelium-derived factor (SERPINF1), plasma protease C1 inhibitor (SERPING1), and metalloproteinase inhibitor 1 (TIMP1), demonstrated an area under curve (AUC) of 0.85 and a two-fold increase in detection accuracy compared to CA19-9 alone. The study further evaluated the correlations of protein candidates and their influences on the performance of biomarker panels. Conclusions: Proteomics-based multiplex biomarker panels improved the detection accuracy for diagnosis of early stage PDAC in diabetic patients.

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.

4508 Background: The combination of dual immune checkpoint inhibitors (ICI) T (anti–CTLA-4) and D (anti–PD-L1) showed tolerability with a promising objective response rate (ORR) in the initial cohort of this study (NCT02519348). Subsequent evaluation of pts with solid tumors treated with increasing doses of T suggested priming with a higher dose of T may induce a stronger immune response and enhance anti-tumor activity. Thus, the randomized expansion cohorts comprised 4 arms evaluating T and D as monotherapies and 2 T+D regimens, including a novel T+D regimen featuring a single, priming dose of T. Methods: ICI-naïve pts with aHCC who progressed on, were intolerant to, or refused sorafenib were randomized to one of two T+D combinations: T300+D (T 300 mg + D 1500 mg 1 dose followed by D Q4 weekly [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses] followed by D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W). Safety was the primary endpoint. ORR by blinded, independent central review using RECIST v1.1, duration of response (DoR), circulating lymphocytes, and overall survival (OS) were assessed. Results: At data cut-off (09/02/2019), 332 pts were enrolled. Median follow-ups were 11.7 months (mo) for T300+D, 14.6 (T75+D), 8.9 (D), and 15.8 (T). Treatment-related adverse event (trAE) incidences are shown (Table); no deaths were attributed to trAEs for T300+D or T. The T300+D arm had the highest confirmed ORR (DoR not reached [NR]) and longest OS (Table). A unique proliferative T cell profile was identified for pts in the T300+D arm, suggesting additive biologic activity for the combination, and showed pts with an OR exhibited high cytotoxic (CD8) counts. Conclusions: The encouraging clinical activity and tolerable safety profile suggest T300+D provides the best benefit-risk profile as opposed to T75+D or monotherapies. The unique pharmacodynamic activity of the T300+D regimen further supports its use in aHCC. T300+D and D are being evaluated in the ongoing phase III HIMALAYA study (NCT03298451) in first-line HCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348 . [Table: see text]

TPS3172 Background: Bladder cancer is a leading cause of cancer death in the United States. Over 90% of bladder cancer cases are urothelial carcinomas (UC) that may present as a non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Standard of care for NMIBC includes transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and immunotherapy with Bacillus Calmette-Guerin (BCG). Patients (pts) with high-grade BCG-refractory NMIBC or MIBC undergo RC, which involves complete bladder removal and pelvic lymphadenectomy. RC severely impacts quality of life with significant morbidity. Oncolytic viruses are showing promise in UC, and MV-NIS has proven efficacy in other tumor types. MV-NIS is an investigational oncolytic measles virus with an excellent safety profile, irrespective of route of administration (n > 100). MV-NIS-related adverse events are limited to infusion reactions and transient CBC changes, and little local toxicity is anticipated with intravesical therapy. Clinical efficacy of this oncolytic may be related to absence of measles immunity. Based on this, the clinical strategy for MV-NIS is focused on targeting immune-privileged sites via intra-tumoral or intravesical routes, alone or in combination with checkpoint inhibitors. We hypothesize that intravesical therapy with oncolytic MV-NIS can improve clinical outcomes for (a) BCG refractory NMIBC pts to avoid or delay the need for RC; and (b) MIBC pts undergoing RC. Methods: This study is enrolling pts undergoing RC who are ineligible to receive neoadjuvant chemotherapy. The trial has 2 stages to (a) determine the safety and tolerability of intravesical MV-NIS, and (b) assess preliminary efficacy. Part (a) includes 4-24 pts in a timing cohort with doses administered at increasing durations (1-4 weeks) prior to RC to establish safety of a single MV-NIS dose. Part (b) includes an expansion cohort (n = 12) to evaluate the safety and efficacy of 2 intravesical doses of MV-NIS at 2-week intervals prior to RC. Safety is assessed using NCI-CTCAE V5 and Clavien-Dindo grading of operative complications. The efficacy endpoint is pathologic stage at time of RC (pT0 rate), which can be compared to pre-study TURBT stage. Additional exploratory studies include PK and PD analyses in urine, blood and tumor. Enrollment is ongoing at 2 Mayo Clinic sites (Rochester, MN and Jacksonville, FL) and the study has now progressed from the timing cohort into the expansion cohort. Clinical trial information: NCT03171493 .

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma & endometrial cancer. Enrolled pts with NSCLC & melanoma will be recent CPI-progressors, whereas enrolled HCC & endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, & immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .

3090 Background: VV1 (Voyager V1) is derived from VSV, an RNA virus with low human seroprevalence, engineered to replicate selectively in and kill human cancer cells. In Part 1 of this study, we demonstrated the safety of intratumoral VV1 and dose-response, using serum IFNβ as a biomarker; we observed viral replication in tumor and concomitant lymphocyte/neutrophil trafficking (SITC 2018). 2 other studies suggested greater efficacy and higher IFNβ levels with IV administration. Longer infusion durations were reported to mitigate infusion reactions (IRRs) for another oncolytic. Methods: We studied 3 different infusion durations of VV1 monotherapy at the recommended phase 2 IV dose (1.7 x 1010 TCID50) in patients with advanced solid tumors. Endpoints included safety, preliminary anti-tumor activity, viral titers, IFNβ PD and shedding. Patients received IV VV1 once on D1 and were monitored for DLT over 21 days with efficacy assessments every 6 weeks. IRRs were classified using Lee 2014 criteria for CRS as either constitutional symptoms only (G1) or involving hypotension (G2). Results: 18 patients were treated at 30, 60 and 180-minute durations (n = 7, 5 and 6, respectively). No DLTs, deaths or G3-4 related IRR AEs were observed. Most pts were female (67%), white (100%), with ECOG PS 0 (61%) and median 4 lines of prior systemic therapy (range 1-14) for colorectal (CRC; 56%), squamous cell carcinoma (11%), pheochromocytoma (11%), sarcoma (11%) or other (11%) cancers. The table shows results (number of patients) by infusion duration. Conclusions: There was no difference in safety between the 3 infusion durations, while efficacy and PD markers suggested better anti-tumor effect with 30-minute infusion. VV1 is safe for caregivers, with no viral shedding. Part 3 of this study will now treat CRC patients with VV1 in combination with a checkpoint inhibitor (avelumab). A 5-arm phase 2 basket study in combination with cemiplimab is proceeding with 30-minute infusions. Clinical trial information: NCT02923466 . [Table: see text]

AIMS To report the major characteristics and clinical outcomes of COVID-19 patients treated with ACE inhibitors and ARBs and compare the different effects of the two drugs for outcomes of COVID-19 patients. METHODS This is a retrospective, two-center case series of 198 consecutive COVID-19 patients with a history of hypertension. RESULTS Among 198 patients, 58 (29.3%) and 16 (8.1%) were on were on ARB and ACEI, respectively. Patients who were on ARB or ACEI/ARB had a significantly lower rate of severe illness and ARDS when compared with patients treated with ACEI alone or not receiving RAAS blocker (P＜0.05). The Kaplan-Meier survival curve showed that patients with ARB in their antihypertensive regimen had a trend towards a higher survival rate when compared with individuals without ARB (adjusted hazard ratio, 0.27; 95% CI, 0.07-1.02; P=0.054). The occurrence rates of severe illness, ARDS, and death were similar in the two groups regardless of receiving ACEI. The Cox-regression analysis to compared ACEI vs. ARB groups showed a significantly lower mortality rate in the ARB group (adjusted hazard ratio, 0.03; 95% CI, 0.00-0.58; P=0.02). CONCLUSIONS Our data may provide some evidence of using ARB, but not ACEI, was associated with a reduced rate of severe illness and ARDS, indicating their potential protective impact in COVID-19. Further large sample sizes and multiethnic populations are warranted to confirm our findings.

Abstract Background: Viral vectors based on the Edmonston strain of measles virus (MV-Edm) selectively destroy all tumor cell lines tested in vitro. The oncolytic activity of the virus is enhanced by expression of the thyroidal sodium iodide symporter (MV-NIS) that allows selective 131I uptake by infected tumor cells and eliminates myeloma tumor xenografts that are resistant to the parent virus. MV-NIS is being considered for therapy of patients with relapsed or refractory multiple myeloma. Advanced myeloma is associated with significant immunosuppression with the potential risk of uncontrolled virus proliferation. The number of agents with activity against MV is limited. Low energy (Auger) electrons have a short path length and selectively damage cells in which the isotope decays. Thus, we hypothesized that the Auger electron emitting isotope 125I, selectively taken up by cells expressing NIS, can be used to control viral proliferation. Methods: A replication competent MV that expressed both a soluble form of carcinoembryonic antigen (CEA) and NIS (MV-NICE) was rescued and characterized. Cells were infected with MV-NICE or control vectors and exposed to 125I with appropriate controls. CEA expression and viral titers were determined at different time points. The role of free radical generation on virus replication was explored. In vivo control of MV-NICE replication with 125I was attempted. Results: MV-NICE replication in vitro is inhibited by the selective uptake of 125I by cells expressing NIS. Extracellular decay of the isotope has no effect on virus proliferation. Auger electron damage is in part mediated by free radicals and abrogated by glutathione. In myeloma xenografts, control of MV-NICE with 125I was not possible under the conditions of the experiment. Conclusion: MV-NICE does not replicate faster in the presence of radiation under our experimental conditions. Auger electron emitting isotopes effectively stop propagation of MV vectors expressing NIS in vitro. Additional work is necessary to translate these observations in vivo.

Abstract Multiple myeloma remains incurable and novel therapeutics are urgently needed. We have shown that live attenuated Edmonston strain measles virus (MV-Edm) is potently oncolytic in multiple myeloma xenograft models and can efficiently infect CD138 sorted primary myeloma cells inducing extensive intercellular fusion which leads to cell death (Blood, 2001, v98, p2002). In contrast, the virus causes minimal damage to normal PHA-stimulated peripheral blood lymphocytes, fibroblasts and smooth muscle cells. To facilitate non-invasive imaging of sites of viral gene expression, we introduced the human thyroidal sodium iodide symporter (NIS) gene into the viral genome (MV-NIS). MV-NIS infected myeloma cells efficiently concentrate radioiodine which provides a basis for noninvasive imaging and destruction of infected tumors using beta emitters such as 131I (Blood, 2004, v103, p1641). Clinical translation of MV-NIS in patients with refractory myeloma is planned. However, the mechanism underlying the tumor selectivity of MV-Edm has not previously been defined. MV-Edm uses either of two cellular receptors for cell entry and cell fusion; CD46, a regulator of complement activation, is expressed on all nucleated cells, wheras SLAM (signaling lymphocyte activation molecule) is expressed only on activated B lymphocytes, T lymphocytes, and monocytes, and is not present on myeloma plasma cells. Using a panel of CHO cell transfectants, we demonstrated that MV-Edm -mediated cell killing increases exponentially above a threshold CD46 receptor density (Can Res, 2004, v64, p4919). We subsequently obtained bone marrow aspirates from 18 myeloma patients and performed multi-parameter flow cytometry to determine the relative expression levels of CD46 on the myeloma plasma cells versus the rest of the hematopoietic cells in the bone marrow. The myeloma cells expressed significantly higher levels (5-fold) of CD46 receptors (MFI=294.9 + 204.4, means ± SD) on their cell surfaces compared to hematopoietic cells of the erythroid, myeloid and lymphoid lineages (MFI=58.6 ± 9.0). Analysis of the myeloma array data generated by the Shaughnessy lab indicated that, in comparison to plasma cells from healthy volunteers (2997 ± 1053, n=30, means ± SD), primary myeloma cells express 2-fold elevated levels of CD46 mRNA (6592 ± 4029, n=72, p=0.001, Wilcoxon signed rank test). Taken together, these findings provide strong support for the hypothesis that selective destruction of myeloma cells by oncolytic measles viruses is a direct consequence of their overexpression of the cellular receptor CD46.