Baseline circulating unswitched memory B cells and B-cell related soluble factors are associated with overall survival in patients with clear cell renal cell carcinoma treated with nivolumab within the NIVOREN GETUG-AFU 26 study.

BACKGROUND: The phase II NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with metastatic clear cell renal cell carcinoma (m-ccRCC) in a 'real-world setting'. We conducted a translational-research program to determine whether specific circulating immune-cell populations and/or soluble factors at baseline were predictive of clinical outcomes in patients with m-ccRCC treated with nivolumab within the NIVOREN study. METHODS: Absolute numbers of 106 circulating immune-cell populations were prospectively analyzed in patients treated at a single institution within the NIVOREN trial with available fresh-whole-blood, using dry formulation panels for multicolor flow cytometry. In addition, a panel of 14 predefined soluble factors was quantified for each baseline plasma sample using the Meso-Scale-Discovery immunoassay. The remaining patients with available plasma sample were used as a validation cohort for the soluble factor quantification analysis. Tumor immune microenvironment characterization of all patients included in the translational program of the study was available. The association of blood and tissue-based biomarkers, with overall survival (OS), progression-free survival (PFS) and response was analyzed. RESULTS: Among the 44 patients, baseline unswitched memory B cells (NSwM B cells) were enriched in responders (p=0.006) and associated with improved OS (HR=0.08, p=0.002) and PFS (HR=0.54, p=0.048). Responders were enriched in circulating T follicular helper (Tfh) (p=0.027) and tertiary lymphoid structures (TLS) (p=0.043). Circulating NSwM B cells positively correlated with Tfh (r=0.70, p<0.001). Circulating NSwM B cells correlated positively with TLS and CD20 +B cells at the tumor center (r=0.59, p=0.044, and r=0.52, p=0.033) and inversely correlated with BCA-1/CXCL13 and BAFF (r=-0.55 and r=-0.42, p<0.001). Tfh cells also inversely correlated with BCA-1/CXCL13 (r=-0.61, p<0.001). IL-6, BCA-1/CXCL13 and BAFF significantly associated with worse OS in the discovery (n=40) and validation cohorts (n=313). CONCLUSION: We report the first fresh blood immune-monitoring of patients with m-ccRCC treated with nivolumab. Baseline blood concentration of NSwM B cells was associated to response, PFS and OS in patients with m-ccRCC treated with nivolumab. BCA-1/CXCL13 and BAFF, inversely correlated to NSwM B cells, were both associated with worse OS in discovery and validation cohorts. Our data confirms a role for B cell subsets in the response to immune checkpoint blockade therapy in patients with m-ccRCC. Further studies are needed to confirm these findings.

Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic melanoma.

BACKGROUND: A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics. RESULTS: 19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5-2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2-1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS. CONCLUSION: When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation. TRIAL REGISTRATION NUMBER: NCT01557114.

A Cross-Sectional Study of Prisoners in Mexico City Comparing Prevalence of Transmissible Infections and Chronic Diseases with That in the General Population.

OBJECTIVES: To describe patterns of transmissible infections, chronic illnesses, socio-demographic characteristics and risk behaviors in Mexico City prisons, including in comparison to the general population, to identify those currently needing healthcare and inform policy. MATERIALS AND METHODS: A cross-sectional study among 17,000 prisoners at 4 Mexico City prisons (June to December 2010). Participation was voluntary, confidential and based on informed consent. Participants were tested for HIV, Hepatitis B & C, syphilis, hypertension, obesity, and, if at risk, glucose and cholesterol. A subset completed a questionnaire on socio-demographic characteristics and risk behaviors. Positive results were delivered with counseling and treatment or referral. RESULTS: 76.8% (15,517/20,196) of men and 92.9% (1,779/1,914) of women participated. Complete data sets were available for 98.8%. The following prevalence data were established for transmissible infections: HIV 0.7%; syphilis: Anti-TP+/VDRL+ 2.0%; Hepatitis B: HBcAb 2.8%, HBsAg 0.15%; Anti-HCV 3.2%. Obesity: 9.5% men, 33.8% women. Compared with national age- and sex-matched data, the relative prevalence was greater for HIV and syphilis among women, HIV and Hepatitis C in men, and all infections in younger participants. Obesity prevalence was similar for women and lower among male participants. The prevalence of previously diagnosed diabetes and hypertension was lower. Questionnaire data (1,934 men, 520 women) demonstrated lower educational levels, increased smoking and substance use compared to national data. High levels of non-sterile tattooing, physical abuse and histories of sexual violence were found. CONCLUSION: The study identified that health screening is acceptable to Mexico City prisoners and feasible on a large-scale. It demonstrated higher prevalence of HIV and other infections compared to national data, though low rates compared to international data. Individual participants benefited from earlier diagnosis, treatment and support. The data collected will also enable the formulation of improved policy for this vulnerable group.

Detecting Helicobacter pylori infection in hospitalized frail older patients: the challenge.

OBJECTIVES: Helicobacter pylori infection has not been well studied in older people, especially in hospitalized, frail patients. The aim of our study was to evaluate the prevalence of the infection in this population using five H. pylori diagnostic tests. DESIGN: Prospective observational study. SETTING: Geriatric acute care unit of the Department of Geriatrics (Hôpital Xavier Arnozan, Pessac, France). PARTICIPANTS: One hundred seven consecutively hospitalized patients with a diagnostic indication for upper gastrointestinal endoscopy. MEASUREMENTS: Geriatric assessment, information on drug intake, indication/results of gastric endoscopy, and results of H. pylori infection diagnostic tests (culture and histological analysis on biopsy specimens, serology, 13carbon-urea breath test (13C-UBT), detection of H. pylori stool antigens (HpSA)) were assessed for each included patient. RESULTS: Fifty-one patients (47.7%) were H. pylori positive with at least one test. 13C-UBT was more frequently positive than the other four tests, with a significant difference from culture, histological analysis, and HpSA (P <.05). Positive 13C-UBT results were significantly associated with H. pylori presence using histological analysis and neutrophil activity of the antrum and corpus. Antibiotic treatments significantly decreased the positivity rate of all of the tests performed, and severe corpus atrophy decreased the positivity rate of culture, histological analysis, and HpSA. CONCLUSIONS: Almost one-third of the H. pylori-positive patients would have remained undetected without performing the 13C-UBT. The low prevalence of H. pylori detection in these hospitalized, frail patients may be explained by the high frequency of current and previous antibiotic treatments.

Identification of strain-specific genes located outside the plasticity zone in nine clinical isolates of Helicobacter pylori.

Helicobacter pylori is a Gram-negative bacterium that is associated with the development of peptic ulcers and gastric carcinoma in humans. This species appears to be one of the most genetically variable bacteria described to date. The overall level of heterogeneity within strains of this organism was determined by comparing the genome sequences of two reference strains, J99 and 26695. The aim of this study was to measure the genetic diversity within strains of H. pylori by looking for strain-specific genes in nine H. pylori strains isolated from patients suffering from chronic gastritis (n=3), duodenal ulcers (n=3) or gastric cancer (n=3). Seven loci that contained strain-specific genes in strains J99 and 26695 were studied. These regions were subsequently amplified from most of the clinical isolates studied and their sequences were determined. ORFs were predicted from the sequence data and were compared to sequences within the databases. The results showed that the genes flanking the ORFs specific to either strain J99 or strain 26695 were also present in a similar configuration in the genomes of the nine clinical isolates. Moreover, in most regions, ORFs homologous to those found in the corresponding loci in the two reference strains were detected. However, in 10 regions, genes similar to those located at another locus in the genome of J99 or 26695 were found. Finally, six strain-specific genes were identified in three regions of three of the H. pylori strains isolated from patients with duodenal ulcers (n=2) and gastric cancer (n=1). Of these six genes, five were putative genes and one was an orthologue of a gene encoding a transposase in Thermotoga maritima. However, no association with disease was found for these genes.