31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Wireless Home Blood Pressure Monitoring System With Automatic Outcome-Based Feedback and Financial Incentives to Improve Blood Pressure in People With Hypertension: Protocol for a Randomized Controlled Trial

BackgroundHypertension is prevalent in Singapore and is a major risk factor for cardiovascular morbidity and mortality and increased health care costs. Strategies to lower blood pressure include lifestyle modifications and home blood pressure monitoring. Nonetheless, adherence to home blood pressure monitoring remains low. This protocol details an algorithm for remote management of primary care patients with hypertension. ObjectiveThe objective of this study was to determine whether wireless home blood pressure monitoring with or without financial incentives is more effective at reducing systolic blood pressure than nonwireless home blood pressure monitoring (usual care). MethodsThis study was designed as a randomized controlled open-label superiority study. A sample size of 224 was required to detect differences of 10 mmHg in average systolic blood pressure. Participants were to be randomized, in the ratio of 2:3:3, into 1 of 3 parallel study arms :(1) usual care, (2) wireless home blood pressure monitoring, and (3) wireless home blood pressure monitoring with financial incentives. The primary outcome was the mean change in systolic blood pressure at month 6. The secondary outcomes were the mean reduction in diastolic blood pressure, cost of financial incentives, time taken for the intervention, adherence to home blood pressure monitoring, effectiveness of the framing of financial incentives in decreasing nonadherence to blood pressure self-monitoring and the adherence to antihypertensive medication at month 6. ResultsThis study was approved by SingHealth Centralised Institutional Review Board and registered. Between January 24, 2018 and July 10, 2018, 42 participants (18.75% of the required sample size) were enrolled, and 33 participants completed the month 6 assessment by January 31, 2019. ConclusionsDue to unforeseen events, the study was stopped prematurely; therefore, no results are available. Depending on the blood pressure information received from the patients, the algorithm can trigger immediate blood pressure advice (eg, Accident and Emergency department visit advice for extremely high blood pressure), weekly feedback on blood pressure monitoring, medication titration, or skipping of routine follow-ups. The inclusion of financial incentives framed as health capital provides a novel idea on how to promote adherence to remote monitoring, and ultimately, improve chronic disease management. Trial RegistrationClinicalTrials.gov NCT 03368417; https://clinicaltrials.gov/ct2/show/NCT03368417 International Registered Report Identifier (IRRID)DERR1-10.2196/2749

Cultural adaptation of a patient decision-aid for insulin therapy

Introduction Patient decision-aids (PDAs) support patients in selecting evidence-based treatment options. PDA is useful only if the user understands the content to make personalised decisions. Cultural adaptation is a process of adjusting health messages so that the information is accurate, relevant and understandable to users from a different population. A PDA has been developed to assist Malaysian patients with secondary drug failure to initiate insulin therapy to control their type 2 diabetes mellitus (T2DM). Likewise, patients with T2DM in neighbouring Singapore face similar barriers in commencing insulin treatment, which a PDA may facilitate decision-making in selecting personalised therapy. Objective The study aimed to explore the views and perceptions of Singaporean primary care providers on the Malaysia PDA to initiate insulin therapy and described the cultural adaptation process used in the design and development of a new PDA, which would be trialled in a Singapore primary healthcare institution. Method Qualitative research method was deployed to conduct one-to-one in-depth interviews of the healthcare providers at the trial site (SingHealth Polyclinics-SHP), including six primary care physicians and four nurses to gather their views and feedbacks on the Malaysian PDA. The interviews were transcribed, audited and analysed (standard content analysis) to identify themes relating to the content, layout, concerns of the original PDA and suggestions to the design of the new SHP PDA. Results Cultural adaptation of the new PDA includes change to the overall design, graphics (including pictograms), presentation styles, additional contextualised content (personalisation, subheadings, cost and treatment option), modified phrasing of the subtitles and concerns (choice of words) relevant to the new users. Conclusion A PDA on insulin therapy underwent cultural adaptation before its implementation in another population in a neighbouring country. Its relevance and effectiveness will be evaluated in future research. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ

Management of hypertension and multiple risk factors to enhance cardiovascular health in Singapore: The SingHypertension cluster randomized trial

Abstract Background Hypertension is a serious public health problem in Singapore and is associated with significant morbidity and mortality from cardiovascular disease (CVD) with considerable implications for health-care resources. The goal of the trial is to compare a multicomponent intervention (MCI) to usual care to evaluate the effectiveness and cost-effectiveness of the MCI for lowering blood pressure (BP) among adults with uncontrolled hypertension in Singapore primary-care clinics. Methods/design The study is a cluster randomized trial in eight polyclinics in Singapore: four deliver a structured MCI and four deliver usual care. The components of the MCI are: (1) an algorithm-driven antihypertensive treatment for all hypertensive individuals using single-pill combination (SPC) and lipid-lowering medication for high-risk hypertensive individuals, (2) a motivational conversation for high-risk hypertensive individuals, (3) telephone-based follow-ups of all hypertensive individuals by polyclinic nurses, and (4) discounts on SPC antihypertensive medications. The trial will be conducted with 1000 individuals aged ≥ 40 years with uncontrolled hypertension (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg, based on the mean of the last two of three measurements) in eight polyclinics in Singapore. The primary outcome is change in systolic BP from baseline to follow-up at 24 months post-randomization. The incremental cost of MCI per CVD disability adjusted life years (DALY) averted and quality adjusted life years (QALY) saved will be computed. Discussion The demonstration of an effective and cost-effective hypertension control program that is implementable in busy polyclinics would provide compelling evidence for upscaling the program across all primary-care centers in Singapore, and possibly other regional countries with a similar health-care structure. Trial registration Clinicaltrials.gov, NCT02972619. Registered on 23 November 2016

Additional file 1: of Management of hypertension and multiple risk factors to enhance cardiovascular health in Singapore: The SingHypertension cluster randomized trial

SPIRIT checklist. (DOC 123 kb

Additional file 2: of Management of hypertension and multiple risk factors to enhance cardiovascular health in Singapore: The SingHypertension cluster randomized trial

Treatment algorithm. (PDF 121 kb

Additional file 3: of Management of hypertension and multiple risk factors to enhance cardiovascular health in Singapore: The SingHypertension cluster randomized trial

Physician management checklist. (DOCX 20 kb

Additional file 4: of Management of hypertension and multiple risk factors to enhance cardiovascular health in Singapore: The SingHypertension cluster randomized trial

Telephone follow-up checklist. (DOCX 30 kb

Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study

Background Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe. Objectives The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions. Methods New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis. Results After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ∼27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease. Conclusions In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614