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

Cardiovascular Risk Assessment and Therapeutic Implications in Rheumatoid Arthritis

Patients with rheumatoid arthritis (RA) suffer from a magnitude of excess cardiovascular risk. A paradoxical lipid pattern has been observed in rheumatoid arthritis patients where low levels of total cholesterol and low-density lipoprotein are associated with a higher risk of cardiovascular disease. This paper aims to break down the evidence explaining why patients with low to normal LDL, and total cholesterol have such excess cardiovascular risk. A component of the enhanced cardiovascular risk is systemic inflammation and the subsequent pro-atherogenic dyslipidemia patterns. Due to this “lipid paradox,” current risk algorithms and guidelines designed for the general population may underestimate cardiovascular risk in patients with rheumatoid arthritis. The purpose of this paper is to critically evaluate some of the discrepancies and layers of cardiovascular risk in RA patients, the role RA medication may have in mitigating or increasing cardiovascular risk, and the possible role of statin therapy

Intra-articular hyaluronic acids for osteoarthritis of the knee

Hyaluronic acids (HAs) are one modality in the arsenal for the treatment of osteoarthritis (OA) of the knee. Non-pharmacologic strategies, such as exercise therapy and weight loss, improve functional capacity and provide pain relief. When patients require adjunct pharmacologic therapy, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, intra-articular (IA) corticosteroids, duloxetine, HA, topical capsaicin, and, when necessary, opioid medications may be used. Current guidelines recommend caution with use of many of these therapies because of safety concerns, especially in patients with comorbidities. HAs provide pain relief for patients with mild-to-moderate knee OA without adversely affecting patients with comorbidities. With 15 HA preparations available, these agents vary according to origin of derivation, molecular weight, number of injections per series, and duration of effect. This article discusses the various HA preparations

Melatonin use in pediatrics: Evaluating the discrepancy in evidence based on country and regulations regarding production

Melatonin manufacturers in the United States have begun producing melatonin products specifically targeted for use in the pediatric population. This paper aims to critically evaluate the evidence available regarding the use of melatonin in children based on where the clinical trials are performed and the regulations regarding the production of melatonin in that country. Melatonin is regulated differently around the world with the least amount of regulation placed on OTC supplements in the United States. The majority of studies evaluating melatonin use in the pediatric population are conducted with children who have comorbidities, such as autism spectrum disorder or attention-deficit/hyperactivity disorder. Evidence supporting the use of US formulations of melatonin in the otherwise healthy pediatric population is non-existent. Based on the lack of safety regulations in place in the United States and the lack of evidence regarding US melatonin products, they should be used sparingly in the otherwise healthy pediatric population, if they are used at all

“Over-the-counter” cannabidiol (CBD) sold in the community pharmacy setting in Colorado

Introduction: The use of cannabidiol is becoming so popular that even pharmacies now carry over-the-counter (OTC) cannabidiol products in Colorado, USA. Objective: The primary goal of this study was to evaluate cannabidiol products sold in the community pharmacy setting to determine the content of cannabidiol and other active ingredients and the safety information that may be provided to individuals considering the use of these products. Methods: Documentation of cannabidiol products available for purchase in pharmacies was compiled by visiting chain and independent pharmacies within the state of Colorado. Cannabidiol products were documented for claims of use, dose, route, administration, additional ingredients, and cost. Results: In total, 60 cannabidiol products (15 oral, 44 topical, and one transdermal) were found in 35 pharmacies. The concentrations of oral cannabidiol varied from 10 to 60 mg/mL. In total, 13 (87%) of the oral products were labeled as “full spectrum.” Six (40%) of the oral cannabidiol products listed medium-chain triglycerides, a compound with evidence of increasing oral bioavailability. The amount of cannabidiol labeled on topical products varied from 30 mg cannabidiol/15 mL to 1000 mg cannabidiol. Some products did not indicate any quantity of cannabidiol or did provide the amount of hemp extract/oil but did not specify how much cannabidiol was present. In total, 29 (66%) of the topical products contained additional active ingredients: arnica, camphor, capsaicin, menthol, peppermint oil, white willow bark (salicylic acid), tea tree oil, and trolamine salicylate. Only one type of transdermal product for cannabidiol delivery was found, which provided a dose of 20 mg cannabidiol/24 h. Conclusion: The findings of this study illustrate the extensive variability of cannabidiol products and the importance of communication with people considering their use. Counseling those utilizing these products may help to avoid drug–drug or drug–supplement interactions and adverse events

Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Item does not contain fulltextUsing variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease