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Background: The POTENT trial compared the safety and efficacy of tipranavir/ritonavir (TPV/r) to darunavir/ritonavir (DRV/r), each with an optimized background regimen (OBR) in triple-class experienced HIV-1-infected patients with resistance to more than one protease inhibitor (PI). Methodology/Principal Findings: POTENT was a prospective, open-label study of triple-class (PI, non-nucleoside reverse transcriptase inhibitors [NNRTI], nucleoside reverse transcriptase inhibitors [NRTI]), treatment-experienced, HIVpositive patients. Subjects were randomized to either TPV/r (500/200mg twice daily) or DRV/r (600/100mg twice daily) on a genotype-guided, investigatorselected OBR. CD4+ counts andHIV viral loads were assayed at key timepoints. The primary endpoint was time to virologic failure (viral load >-500 copies/mL). POTENT was prematurely terminated due to slow enrollment. Thirty-nine patients were treated with either TPV/r (n= 19) or DRV/r (n= 20); 82% were male, 77%White, with mean age of 43.6 years. Mean baselineHIV RNA was 3.9 log10 copies/mL.Median prior antiretrovirals was 11, with no prior raltegravir or maraviroc exposure. Raltegravir was the most common novel class agent in the OBRs (n = 14 TPV/r; n = 12DRV/r). In both groups, patients achieved mean viral load decreases >-2 log10 copies/mL by week 8, and by week 12 mean CD4+ counts rose by 40–50 cells/mm 3 . Total observation time was 32 weeks. Drug-related adverse events were reported in 21% (TPV/r) and 25% (DRV/r) of patients. Conclusions/Significance: TPV/r- and DRV/r-based regimens showed similar short-term safety and efficacy. These data support the use of next-generation PIs such as tipranavir or darunavir with novel class antiretroviral agents (integrase inhibitors, CCR5 antagonists, or fusion inhibitors). Trial Registration: Clinicaltrials.gov NCT00517192

Background: The POTENT trial compared the safety and efficacy of tipranavir/ritonavir (TPV/r) to darunavir/ritonavir (DRV/r), each with an optimized background regimen (OBR) in triple-class experienced HIV-1-infected patients with resistance to more than one protease inhibitor (PI).Methodology/Principal Findings: POTENT was a prospective, open-label study of triple-class (PI, non-nucleoside reverse transcriptase inhibitors [NNRTI], nucleoside reverse transcriptase inhibitors [NRTI]), treatment-experienced, HIVpositive patients. Subjects were randomized to either TPV/r (500/200mg twice daily) or DRV/r (600/100mg twice daily) on a genotype-guided, investigatorselected OBR. CD4+ counts andHIV viral loads were assayed at key timepoints. The primary endpoint was time to virologic failure (viral load >-500 copies/mL).POTENT was prematurely terminated due to slow enrollment. Thirty-nine patients were treated with either TPV/r (n= 19) or DRV/r (n= 20); 82% were male, 77%White, with mean age of 43.6 years. Mean baselineHIV RNA was 3.9 log10 copies/mL.Median prior antiretrovirals was 11, with no prior raltegravir or maraviroc exposure. Raltegravir was the most common novel class agent in the OBRs (n = 14 TPV/r; n = 12DRV/r). In both groups, patients achieved mean viral load decreases >-2 log10 copies/mL by week 8, and by week 12 mean CD4+ counts rose by 40–50 cells/mm3. Total observation time was 32 weeks. Drug-related adverse events were reported in 21% (TPV/r) and 25% (DRV/r) of patients.Conclusions/Significance: TPV/r- and DRV/r-based regimens showed similar short-term safety and efficacy. These data support the use of next-generation PIs such as tipranavir or darunavir with novel class antiretroviral agents (integrase inhibitors, CCR5 antagonists, or fusion inhibitors).Trial Registration: Clinicaltrials.gov NCT00517192

The results of many cancer gene therapy clinical trials to date suggest that improvements must be made to increase gene delivery, expression levels, and/or potency of the genes in order to induce tumour regression. However, increasing any of these parameters will require additional safeguards to protect surrounding normal cells. Our goal is to develop adenoviral vector systems that target tumour cells transcriptionally (using various tumour- and tissue- specific promoters) as well as transductionally (by modifying the viral fiber protein to enhance binding to receptors on the tumour cell surface).We have isolated a novel promoter from the mammaglobin (MGB) gene that displays over ten-fold increase in expression levels in breast cancer cells relative to normal non-tumour cells (Shi, et al., 2004, Mol. Ther., 10:758-767; Shi, et al., 2006, J. Gene Med, in press). We have since developed a breast cancer targeted adenoviral (Ad) vector encoding the \"suicide gene\" herpes simplex virus (HSV)-1 thymidine kinase (TK) under the control of the MGB promoter (AdMGBTK). HSV-TK was chosen for this study because, in combination with nucleoside analogs, it has potential not only as a therapeutic, but also as an agent for non-invasive imaging of gene transfer in vivo. AdMGBTK, in combination with the prodrug ganciclovir (GCV), induces breast cancer-specific killing at levels comparable to a universal cytomegalovirus (CMV) TK vector. Combination with a radiolabeled TK substrate allows Positron Emission Tomography (PET) imaging in vivo, which has never been performed on breast cancer targeted vectors.In addition, we have engineered a modified-fiber virus to contain the ligand-binding domain of heregulin-α (HRG-α) within the fiber protein of Ad. HRG-α is a ligand for ErbB3 and ErbB4 receptors, both of which are over-expressed in many cancer types, including breast cancer. This modified-fiber virus demonstrated enhanced infection of tumour cells bearing ErbB3 and ErbB4. Generation of a vector expressing TK under the control of the MGB promoter and encapsidated within an HRG-modified fiber virus is in progress. This combination of transcriptional and translational targeting is expected to produce a highly specific breast cancer-targeted adenoviral vector which has potential as a clinical therapeutic.

PurposeAlthough lymphocyte activation gene-3 (LAG-3) directed therapies demonstrate promising clinical anti-cancer activity, only a subset of patients seems to benefit and predictive biomarkers are lacking. Here, we explored the potential use of the anti-LAG-3 antibody tracer [89Zr]Zr-BI 754111 as a predictive imaging biomarker and investigated its target specific uptake as well as the correlation of its tumor uptake and the tumor immune infiltration.MethodsPatients with head and neck (N = 2) or lung cancer (N = 4) were included in an imaging substudy of a phase 1 trial with BI 754091 (anti-PD-1) and BI 754111 (anti-LAG-3). After baseline tumor biopsy and [18F]FDG-PET, patients were given 240 mg of BI 754091, followed 8 days later by administration of [89Zr]Zr-BI 754111 (37 MBq, 4 mg). PET scans were performed 2 h, 96 h, and 144 h post-injection. To investigate target specificity, a second tracer administration was given two weeks later, this time with pre-administration of 40 (N = 3) or 600 mg (N = 3) unlabeled BI 754111, followed by PET scans at 96 h and 144 h post-injection. Tumor immune cell infiltration was assessed by immunohistochemistry and RNA sequencing.ResultsTracer uptake in tumors was clearly visible at the 4-mg mass dose (tumor-to-plasma ratio 1.63 [IQR 0.37-2.89]) and could be saturated by increasing mass doses (44 mg: 0.67 [IQR 0.50–0.85]; 604 mg: 0.56 [IQR 0.42–0.75]), demonstrating target specificity. Tumor uptake correlated to immune cell-derived RNA signatures.Conclusions[89Zr]Zr-BI-754111 PET imaging shows favorable technical and biological characteristics for developing a potential predictive imaging biomarker for LAG-3-directed therapies.Trial registrationClinicalTrials.gov, NCT03780725. Registered 19 December 2018

Background. Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV–coinfected patients. Methods. In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination. To assess potential drug interactions, geometric mean ratios and 90% confidence intervals for PK parameters were calculated. Safety was evaluated. Results. Efavirenz decreased faldaprevir area under the concentration-time curve (AUC) by 35%, C max by 28%, and C min by 46%, consistent with induction of CYP3A by efavirenz. Tenofovir decreased faldaprevir AUC by 22%, which was not considered to be clinically relevant. Faldaprevir had no clinically relevant effects on darunavir or tenofovir PK (15% and 22% AUC increase, respectively). Adverse events were consistent with the known safety profiles of faldaprevir and the antiretrovirals being examined. Conclusions. No clinically significant interactions were observed between faldaprevir and darunavir/ritonavir or tenofovir. A potentially clinically relevant decrease in faldaprevir exposure was observed when coadministered with efavirenz; this decrease can be managed using the higher of the 2 faldaprevir doses tested in phase 3 trials (240 mg once daily as opposed to 120 mg once daily).