NY-ESO-1-Specific Circulating CD4+ T Cells in Ovarian Cancer Patients Are Prevalently TH1 Type Cells Undetectable in the CD25+FOXP3+Treg Compartment

Spontaneous CD4+ T-cell responses to the tumor-specific antigen NY-ESO-1 (ESO) are frequently found in patients with epithelial ovarian cancer (EOC). If these responses are of effector or/and Treg type, however, has remained unclear. Here, we have used functional approaches together with recently developed MHC class II/ESO tetramers to assess the frequency, phenotype and function of ESO-specific cells in circulating lymphocytes from EOC patients. We found that circulating ESO-specific CD4+ T cells in EOC patients with spontaneous immune responses to the antigen are prevalently TH1 type cells secreting IFN-γ but no IL-17 or IL-10 and are not suppressive. We detected tetramer+ cells ex vivo, at an average frequency of 1∶25000 memory cells, that is, significantly lower than in patients immunized with an ESO vaccine. ESO tetramer+ cells were mostly effector memory cells at advanced stages of differentiation and were not detected in circulating CD25+FOXP3+Treg. Thus, spontaneous CD4+ T-cell responses to ESO in cancer patients are prevalently of TH1 type and not Treg. Their relatively low frequency and advanced differentiation stage, however, may limit their efficacy, that may be boosted by immunogenic ESO vaccines

Antiretroviral drug exposure and response in obese and morbidly obese people with HIV: a study combining modelling and Swiss HIV Cohort data.

BACKGROUND Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals. METHODS Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5-60 kg/m2. Therapeutic drug monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. The model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and non-obese individuals. RESULTS The PBPK model predicted an average reduction in ARVs exposure of ∼20% and trough concentrations of ∼6% in obese (BMI ≥30 kg/m2) compared to non-obese (BMI 18.5-25 kg/m2) consistent with observed clinical data. Etravirine and rilpivirine were the most impacted especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load compared to non-obese PWH. CONCLUSIONS The concentrations of ARVs are modestly reduced in obese with no negative impact on the virological response. Our data provide reassurance that standard dose of ARVs is suitable in obese PWH including those who gained substantial weight with some of the first-line ARVs

Antiretroviral drug exposure and response in obese and morbidly obese people with HIV: a study combining modelling and Swiss HIV Cohort data

BACKGROUND: Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals. METHODS: Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5-60 kg/m2. Therapeutic drug monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. The model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and non-obese individuals. RESULTS: The PBPK model predicted an average reduction in ARVs exposure of ∼20% and trough concentrations of ∼6% in obese (BMI ≥30 kg/m2) compared to non-obese (BMI 18.5-25 kg/m2) consistent with observed clinical data. Etravirine and rilpivirine were the most impacted especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load compared to non-obese PWH. CONCLUSIONS: The concentrations of ARVs are modestly reduced in obese with no negative impact on the virological response. Our data provide reassurance that standard dose of ARVs is suitable in obese PWH including those who gained substantial weight with some of the first-line ARVs

Safety and antitumor activity of pembrolizumab in advanced programmed death Ligand 1-positive endometrial cancer: Results from the KEYNOTE-028 study

Endometrial cancer (EC) identified at an early stage is successfully treated in a majority of patients with surgery with or without radiotherapy or chemotherapy. For patients with advanced disease, however, the prognosis is poor; 5-year survival rates are less than 50% in patients with lymph node metastases and less than 20% in those with peritoneal or distant metastases. Novel, more effective therapies are needed for patients with advanced or recurrent EC. Immune approaches are promising. The interaction of programmed death ligand 1 (PD-L1) with programmed death 1 (PD-1)-an immune checkpoint receptor expressed on tumor-infiltrating T cells-can lead to their functional inactivation and prevent tumor immune evasion. Targeted immune therapy directed against PD-1 or PD-L1 can result in objective tumor responses in a wide spectrum of cancers and could play a major role in treatment of EC. A positive correlation between tumor PD-L1 expression and clinical activity against a number of tumors using PD-1 pathway blockade was the rationale for assessing the safety and efficacy of a PD-1-blocking antibody, pembrolizumab, in 20 advanced, PD-L1positive solid tumor cohorts in the KEYNOTE-028 (NCT02054806) trial. The investigators report results from the EC cohort in this article. Eligible patients had locally advanced or metastatic PD-L1-positive EC progressing after standard therapy were eligible. Pembrolizumab 10 mg/kg was administered intravenously every 2 weeks up to 24 months or until disease progression or intolerable toxicity. The primary study efficacy end point was objective response rate by RECIST (Response Evaluation Criteria In Solid Tumors, version 1.1). Secondary end points assessed included safety, duration of response (DOR), progression-free survival, and overall survival. The data cutoff for this analysis was February 17, 2016. Seventy-five patients with advanced EC were screened for PD-L1 expression; 36 of these (48.0%) had PD-L1-positive tumors, and 24 (32.0%) were enrolled. Among these 24 patients, 15 (62.5%) had received at least 2 previous lines of therapy for advanced disease; 3 of these patients (13.0%) achieved confirmed partial response (95% confidence interval, 2.8%-33.6%); median DOR was not reached. At time of data cutoff, 2 patients were still receiving treatment and an ongoing response. An additional 2 patients (13.0%) achieved stable disease; median duration was 24.6 weeks. A partial response was achieved in 1 patient who had a polymerase E mutation. Treatment-related adverse effects (AEs) occurred in 13 patients (54.2%); more than 10% of patients experienced fatigue (n = 5; 20.8%), pruritus (n = 4; 16.7%), pyrexia (n = 3; 12.5%), and decreased appetite (n = 3; 12.5%). Only 4 patients (16.7%) experienced grade 3 treatment-related AEs. There were no grade 4 AEs or immune-mediated AEs or treatment discontinuation because of an AE. These data show that pembrolizumab has a favorable safety profile and durable antitumor activity in patients with heavily pretreated advanced PD-L1-positive EC. The safety and efficacy of pembrolizumab and the utility of biomarkers including PD-L1 in a cohort of patients with EC are being investigated in the phase 2 multicohort KEYNOTE-158 trial

Antiretroviral drug exposure and response in obese and morbidly obese people with HIV: a study combining modelling and Swiss HIV Cohort data

BACKGROUND: Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals. METHODS: Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5-60 kg/m2. Therapeutic drug monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. The model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and non-obese individuals. RESULTS: The PBPK model predicted an average reduction in ARVs exposure of approximately 20% and trough concentrations of approximately 6% in obese (BMI >/=30 kg/m2) compared to non-obese (BMI 18.5-25 kg/m2) consistent with observed clinical data. Etravirine and rilpivirine were the most impacted especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load compared to non-obese PWH. CONCLUSIONS: The concentrations of ARVs are modestly reduced in obese with no negative impact on the virological response. Our data provide reassurance that standard dose of ARVs is suitable in obese PWH including those who gained substantial weight with some of the first-line ARVs

Symptom burden and quality of life with chemotherapy for recurrent ovarian cancer : the Gynecologic Cancer InterGroup-Symptom Benefit Study

Objective The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with &amp;gt;= 3 lines of chemotherapy (PPS-ROC &amp;gt;= 3). Methods Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated &amp;gt;= 4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of &amp;lt;= 3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores &amp;gt;= 10 points above baseline in the QLQ-C30 summary score scale (range 0-100). Results Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC &amp;gt;= 3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC &amp;gt;= 3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p&amp;lt;0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC &amp;gt;= 3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline. Conclusion Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants.Funding Agencies|NHMRCNational Health and Medical Research Council of Australia [1063012, 570893]; Target Ovarian Cancer [UCL-P001AL]; Cancer Research UKCancer Research UK; UCL Cancer Trials Centre [C444/A15953]; Australian Government through Cancer AustraliaAustralian Government; NHMRC Program grantNational Health and Medical Research Council of Australia; Department of HealthEuropean Commission</p

Measure of Ovarian Symptoms and Treatment concerns (MOST) indexes and their associations with health-related quality of life in recurrent ovarian cancer

PURPOSE: The Measure of Ovarian Symptoms and Treatment (MOST) concerns is a validated patient-reported symptom assessment tool for assessing symptom benefit and adverse effects of palliative chemotherapy in women with recurrent ovarian cancer (ROC). We aimed to examine (i) how symptoms within MOST symptom indexes track together (i.e. co-occur) and (ii) the association between MOST symptom indexes and key aspects of health-related quality of life (HRQL). METHOD: A prospective cohort of women with ROC completed the MOST-T35, EORTC QLQ-C30 and EORTC QLQ-OV28 at baseline and before each cycle of chemotherapy. Analyses were conducted on baseline and end-of-treatment data. Exploratory factor analysis and hierarchical cluster analysis identified groups of co-occurring symptoms. Path models examined associations between MOST symptom indexes and HRQL. RESULTS: Data from 762 women at baseline and 681 at treatment-end who completed all 22 symptom-specific MOST items and at least one HRQL measure were analysed. Four symptom clusters emerged at baseline and treatment-end: abdominal symptoms, symptoms associated with peripheral neuropathy, nausea and vomiting, and psychological symptoms. Psychological symptoms (MOST-Psych) and symptoms due to disease (ovarian cancer) or treatment (MOST-DorT) were associated with poorer scores on QLQ-C30 and OV28 functioning domains and worse overall health at both time points. CONCLUSION: Four MOST symptom clusters were consistent across statistical methods and time points. These findings suggest that routine standardized assessment of psychological and physical symptoms in clinical practice with MOST plus appropriate symptom management referral pathways is an intervention for improving HRQL that warrants further research