Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines.

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

Application of the Statistical Method to Convert Published PASI 50/75/90/100 into Absolute PASI Response Rate in Patients with Moderate-to-Severe Plaque Psoriasis Treated with Tildrakizumab Based on Data from the Two Pivotal Phase 3 Studies reSURFACE 1 and reSURFACE 2.

BACKGROUND: Absolute Psoriasis Area and Severity Index (PASI) is a key endpoint in psoriasis management. Petto et al. [Pharm Stat. 2019;18(1):4-21] developed a statistical method to estimate the proportion of patients reaching absolute PASI response given baseline PASI score and proportion of patients achieving relative improvements at predefined time points. OBJECTIVES: To test this method on clinical data from two phase 3 tildrakizumab trials (reSURFACE 1/2) comparing estimated absolute PASI ≤1/≤2/≤3/≤5 responses with reference responses from clinical databases. METHODS: Reference PASI responses of ≤1/≤2/≤3/≤5 were extracted from clinical databases. Estimation of absolute PASI ≤1/≤2/≤3/≤5 response rates at week (W) 12 and W28 by treatment and trial were performed. Differences between estimated and reference responses were analysed. Bland-Atman limits of agreement and Passing-Bablok regression to assess variations between estimated and reference responses were performed. RESULTS: Differences between estimated and reference absolute PASI ≤1/≤2/≤3/≤5 responses at W12 and W28 by treatment and trial were of little clinical relevance with an overall mean difference in PASI response proportion of -2.2% (e.g., for the tildrakizumab 100-mg arm, original proportions of patients achieving PASI of ≤1/≤2/≤3/≤5 at W28 were 38.5%/52.2%/63.5%/73.9% and 39.8%/54.8%/63.6%/76.9% [reSURFACE 1 and 2, respectively] vs. estimated proportions of 33.2%/49.8%/62.5%/78.3% and 34.3%/51.6%/64.5%/79.9%). Limits of agreement were -7.1% to 1.4% at W12 and -6.8% to 4.3% at W28. Scatterplots revealed linearity that stood the cusum test in Passing-Bablok regression with slope 1.14 (95% confidence intervals: 1.06 to 1.20). CONCLUSION: Good estimates of absolute PASI response rates were achieved with the application of the statistical method to tildrakizumab data reported in the phase 3 studies, in particular in the verum study arms. Our data support the method provided by Petto et al. [2019] to estimate proportions of psoriasis patients reaching absolute PASI value thresholds using relative PASI improvements.

Efficacy of dimethyl fumarate treatment for moderate-to-severe plaque psoriasis: presentation extracts from the 29th EADV virtual congress, 29-31 October 2020.

Background: The 29th EADV Virtual Congress took place between the 29th-31st of October 2020. On October 29th, there was a Session on systemic treatment in which Professors Ulrich Mrowietz and Mar Llamas-Velasco presented the latest research on the efficacy of dimethyl fumarate (DMF) treatment for moderate-to-severe plaque psoriasis (BRIDGE and DIMESKIN 1 studies, respectively). The accepted DMF abstract from Professor Matthias Augustin, on the SKILL study, is also presented here. Results: Data from either prospective interventional (BRIDGE) or non-interventional (DIMESKIN 1, SKILL) studies among patients with moderate-to-severe psoriasis showed that DMF provides a positive efficacy profile in all four body regions included in the Psoriasis Area and Severity Index assessment (head and neck, trunk, upper and lower extremities) and a particularly interesting profile (strong efficacy) in the head and neck region. These findings may be of special interest to patients with scalp psoriasis who have been using topical therapies for a long time. Patient-reported outcomes (quality of life, pruritus) also improved during the 24 weeks of DMF treatment. The safety profile of DMF was similar to the previously described with fumaric acid esters. Conclusions: In summary, these results confirm the favorable efficacy and safety profile of DMF in long-term treatment.

Altered host-gut microbes symbiosis in severely malnourished anorexia nervosa (AN) patients undergoing enteral nutrition: An explicative factor of functional intestinal disorders?

BACKGROUND: Functional intestinal disorders (FIDs) are frequently observed in patients with anorexia nervosa (AN). Relationship between FIDs and a potential gut microbiota dysbiosis has been poorly explored. OBJECTIVE: We aimed to determine an association between FIDs severity and dysbiosis of the intestinal microbiota in a severely malnourished patient population with AN undergoing enteral nutrition. DESIGN: Faecal microbiota of AN (DSM IVr criteria) female inpatients were collected and compared to healthy controls based on 16S rRNA profiling. The severity of FIDs was evaluated in patients and healthy controls using Francis Score. RESULTS: Thirty-three patients (BMI: 11,7 ± 1,5; Age: 32 ± 12) and 22 healthy controls (BMI: 21 ± 2; age: 36 ± 12) were included. A marked dysbiosis was identified in AN patients compared to healthy controls (p = 0.03). Some potentially pathogenic bacterial genera (Klebsiella, Salmonella) were more abundant in AN patients whereas, other bacterial symbionts (Eubacterium and Roseburia) involved in immune balance were significantly less abundant in patients than controls. Severity of FIDs was strongly correlated with several microbial genera (r = -0.581 for an unknown genus belonging to Peptostreptococcaceae family; r = 0.392 for Dialister, r = 0.444 for Robinsoniella and r = 0.488 for Enterococcus). Other associations between dysbiosis, clinical and biological characteristics were identified including severity of undernutrition (BMI). CONCLUSION: Observed gut microbiota dysbiosis in malnourished patients with anorexia nervosa is correlated with the severity of FIDs and other metabolic disturbances, which strongly suggests an altered host-microbe symbiosis.

Restoration of a healthy intestinal microbiota normalizes portal hypertension in a rat model of nonalcoholic steatohepatitis.

Portal hypertension (PH) drives most of the clinical complications in chronic liver diseases. However, its progression in nonalcoholic steatohepatitis (NASH) and its association with the intestinal microbiota (IM) have been scarcely studied. Our aim was to investigate the role of the IM in the mechanisms leading to PH in early NASH. The experimental design was divided in two stages. In stage 1, Sprague-Dawley rats were fed for 8 weeks a high-fat, high-glucose/fructose diet (HFGFD) or a control diet/water (CD). Representative rats were selected as IM donors for stage 2. In stage 2, additional HFGFD and CD rats underwent intestinal decontamination, followed by IM transplantation with feces from opposite-diet donors (heterologous transplant) or autologous fecal transplant (as controls), generating four groups: CD-autotransplanted, CD-transplanted, HFGFD-autotransplanted, HFGFD-transplanted. After IM transplantation, the original diet was maintained for 12-14 days until death. HFGFD rats developed obesity, insulin resistance, NASH without fibrosis but with PH, intrahepatic endothelial dysfunction, and IM dysbiosis. In HFGFD rats, transplantation with feces from CD donors caused a significant reduction of PH to levels comparable to CD without significant changes in NASH histology. The reduction in PH was due to a 31% decrease of intrahepatic vascular resistance compared to the HFGFD-autotransplanted group (P < 0.05). This effect occurs through restoration of the sensitivity to insulin of the hepatic protein kinase B-dependent endothelial nitric oxide synthase signaling pathway. CONCLUSION: The IM exerts a direct influence in the development of PH in rats with diet-induced NASH and dysbiosis; PH, insulin resistance, and endothelial dysfunction revert when a healthy IM is restored. (Hepatology 2018;67:1485-1498).