First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors.

BACKGROUND: Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors. METHODS: Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every 4 weeks (Q4W)) intravenously. Dose-expansion: patients with melanoma (n=10) and NSCLC (n=20) who progressed on prior anti-programmed death receptor 1/programmed death ligand-1 and/or anti-cytotoxic T-lymphocyte-associated antigen 4 (melanoma) received ivuxolimab 30 mg Q2W intravenously plus utomilumab 20 mg Q4W intravenously. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and immune-related RECIST (irRECIST). Paired tumor biopsies and whole blood were collected to assess pharmacodynamic effects and immunophenotyping. Whole blood samples were collected longitudinally for immunophenotyping. RESULTS: Dose-escalation: 57 patients were enrolled; 2 (3.5%) patients with melanoma (0.3 mg/kg+20 mg and 0.3 mg/kg+100 mg) achieved partial response (PR), 18 (31.6%) patients achieved stable disease (SD); the disease control rate (DCR) was 35.1% across all dose levels. Dose-expansion: 30 patients were enrolled; 1 patient with NSCLC achieved PR lasting >77 weeks. Seven of 10 patients with melanoma (70%) and 7 of 20 patients with NSCLC (35%) achieved SD: median (range) duration of SD was 18.9 (13.9-49.0) weeks for the melanoma cohort versus 24.1 (14.3-77.9+) weeks for the NSCLC cohort; DCR (NSCLC) was 40%. Grade 3-4 treatment-emergent AEs were reported in 28 (49.1%) patients versus 11 (36.7%) patients in dose-escalation and dose-expansion, respectively. There were no grade 5 AEs deemed attributable to treatment. Ivuxolimab area under the concentration-time curve increased in a dose-dependent manner at 0.3-3 mg/kg doses. CONCLUSIONS: Ivuxolimab+utomilumab was found to be well tolerated and demonstrated preliminary antitumor activity in selected groups of patients. TRIAL REGISTRATION NUMBER: NCT02315066.

A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients with Locally Advanced or Metastatic Cancers.

PURPOSE: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a costimulatory receptor expressed on activated CD4+ and CD8+ T cells. Induction of OX40 following antigen recognition results in enhanced T-cell activation, proliferation, and survival, and OX40 targeting shows therapeutic efficacy in preclinical studies. We report the monotherapy dose-escalation portion of a multicenter, phase I trial (NCT02315066) of ivuxolimab (PF-04518600), a fully human immunoglobulin G2 agonistic monoclonal antibody specific for human OX40. PATIENTS AND METHODS: Adult patients (N = 52) with selected locally advanced or metastatic cancers received ivuxolimab 0.01 to 10 mg/kg. Primary endpoints were safety and tolerability. Secondary/exploratory endpoints included preliminary assessment of antitumor activity and biomarker analyses. RESULTS: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade ≤2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at ≥0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4+ central memory T-cell proliferation and activation, and clonal expansion of CD4+ and CD8+ T cells in peripheral blood were observed at 0.1 to 3.0 mg/kg. Increased immune cell infiltrate and OX40 expression were evident in on-treatment tumor biopsies. CONCLUSIONS: Ivuxolimab was generally well tolerated with on-target immune activation at clinically relevant doses, showed preliminary antitumor activity, and may serve as a partner for combination studies.

Association of Tumor Mutational Burden and Immune Gene Expression with Response to PD-1 Blockade by Sasanlimab Across Tumor Types and Routes of Administration.

BACKGROUND: Sasanlimab is a monoclonal antibody that binds to the programmed cell death receptor 1 (PD-1). Anti-PD-1 monoclonal antibodies have improved patient clinical outcomes; however, not all treated patients derive clinical benefit. Further insights on potential biomarkers beyond PD-L1 expression levels would help to identify the patients most likely to respond to treatment. OBJECTIVE: This study evaluated tumor biopsies from patients treated with intravenous or subcutaneous sasanlimab to identify biomarkers of response and characterize pharmacodynamic activity. METHODS: Anti-PD-1/PD-ligand 1 (PD-L1)-naive patients with advanced solid tumors received sasanlimab intravenously at 1, 3, or 10 mg/kg every 3 weeks (n = 23) or subcutaneously at 300 mg every 4 weeks (n = 15). Best tumor percentage change from baseline was determined by RECIST. Whole-exome DNA and RNA sequencing were performed in tumor samples collected from treated patients at protocol-defined timepoints. PD-L1 and CD8 protein expression were evaluated in tumor biopsies by immunohistochemistry. Associations with response were assessed by linear regression analysis. RESULTS: Baseline tumor mutational burden (TMB), as well as PD-L1 and CD8 expression, were significantly associated with response to sasanlimab across the multiple dose levels, routes of administration, and range of tumor types evaluated. TMB is an independent biomarker from the various tumor inflammatory genes and signatures evaluated. Gene set enrichment analysis showed that higher baseline expression levels of genes related to the interferon-γ and PD-1 signaling pathways and the cell cycle were significantly associated with response to sasanlimab across tumor types. No differences were observed between routes of administration with regard to response to sasanlimab for the biomarkers of interest (TMB, PD-L1, CD8, and interferon-γ signature). Evaluation of pharmacodynamic changes showed increased tumor expression of genes enriched in adaptive immune response pathways. CONCLUSIONS: Our findings indicate an active, immunomodulatory mechanism for the anti-PD-1 antibody sasanlimab across different tumor types and routes of administration. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02573259; registered October 2015.

Electrically reconfigurable non-volatile metasurface using low-loss optical phase-change material.

Active metasurfaces promise reconfigurable optics with drastically improved compactness, ruggedness, manufacturability and functionality compared to their traditional bulk counterparts. Optical phase-change materials (PCMs) offer an appealing material solution for active metasurface devices with their large index contrast and non-volatile switching characteristics. Here we report a large-scale, electrically reconfigurable non-volatile metasurface platform based on optical PCMs. The optical PCM alloy used in the devices, Ge2Sb2Se4Te (GSST), uniquely combines giant non-volatile index modulation capability, broadband low optical loss and a large reversible switching volume, enabling notably enhanced light-matter interactions within the active optical PCM medium. Capitalizing on these favourable attributes, we demonstrated quasi-continuously tuneable active metasurfaces with record half-octave spectral tuning range and large optical contrast of over 400%. We further prototyped a polarization-insensitive phase-gradient metasurface to realize dynamic optical beam steering.

Reconfigurable all-dielectric metalens with diffraction-limited performance.

Active metasurfaces, whose optical properties can be modulated post-fabrication, have emerged as an intensively explored field in recent years. The efforts to date, however, still face major performance limitations in tuning range, optical quality, and efficiency, especially for non-mechanical actuation mechanisms. In this paper, we introduce an active metasurface platform combining phase tuning in the full 2π range and diffraction-limited performance using an all-dielectric, low-loss architecture based on optical phase change materials (O-PCMs). We present a generic design principle enabling binary switching of metasurfaces between arbitrary phase profiles and propose a new figure-of-merit (FOM) tailored for reconfigurable meta-optics. We implement the approach to realize a high-performance varifocal metalens operating at 5.2 µm wavelength. The reconfigurable metalens features a record large switching contrast ratio of 29.5 dB. We further validate aberration-free and multi-depth imaging using the metalens, which represents a key experimental demonstration of a non-mechanical tunable metalens with diffraction-limited performance.

Addressing resistance to immune checkpoint inhibitor therapy: an urgent unmet need.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various cancers by reversing the immunosuppressive mechanisms employed by tumors to restore anticancer immunity. Although ICIs have demonstrated substantial clinical efficacy, patient response can vary in depth and duration, and many do not respond at all or eventually develop resistance. ICI resistance mechanisms can be tumor-intrinsic, related to the tumor microenvironment or patient-specific factors. Multiple resistance mechanisms may be present within one tumor subtype, or heterogeneity exists among patients with the same tumor type. Consequently, designing effective combination treatment strategies is challenging. This review will discuss ICI resistance mechanisms, and summarize findings from key preclinical and clinical trials of ICIs, to identify potential treatment strategies or pathways to overcome ICI resistance.

Ovarian cancer: new strategies and emerging targets for the treatment of patients with advanced disease.

Recently approved therapies have contributed to a significant progress in the management of ovarian cancer; yet, more options are needed to further improve outcomes in patients with advanced disease. Here we review the rationale and ongoing clinical trials of novel combination strategies involving chemotherapy, poly ADP ribose polymerase, programmed death 1 (PD-1)/PD-ligand 1 immune checkpoint and/or vascular endothelial growth factor receptor inhibitors. Further, we discuss novel agents aimed at targets associated with ovarian cancer growth or progression that are emerging as potential new treatment approaches. Among them, agents targeted to folate receptor α, tissue factor, and protein kinase-mediated pathways (WEE1 kinase, phosphatidylinositol-3 kinase α, cell cycle checkpoint kinase 1/2, ATR kinase) are currently in clinical development as mono- or combination therapies. If successful, findings from these extensive development efforts may further transform treatment of patients with advanced ovarian cancer.

Pharmacologic Properties and Preclinical Activity of Sasanlimab, A High-affinity Engineered Anti-Human PD-1 Antibody.

Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.

Airway profile of bioactive lipids predicts early progression of lung disease in cystic fibrosis.

BACKGROUND: Previously, we showed that abnormal levels of bioactive lipids in bronchoalveolar lavage fluid (BALF) from infants with cystic fibrosis (CF) correlated with early structural lung damage. METHOD: To extend these studies, BALF bioactive lipid measurement by mass spectrometry and chest computed tomography (CT, combined with the sensitive PRAGMA-CF scoring method) were performed longitudinally at 2-year intervals in a new cohort of CF children (n = 21, aged 1-5 yrs). RESULTS: PRAGMA-CF, neutrophil elastase activity, and myeloperoxidase correlated with BALF lysolipids and isoprostanes, markers of oxidative stress, as well as prostaglandin E2 and combined ceramide precursors (Spearman's Rho > 0.5; P < 0.01 for all). Multiple protein agonists of inflammation and tissue remodeling, measured by Olink protein array, correlated positively (r = 0.44-0.79, p < 0.05) with PRAGMA-CF scores and bioactive lipid levels. Notably, levels of lysolipids, prostaglandin E2 and isoprostanes at first BALF predicted the evolution of PRAGMA-CF scores 2 years later. In wild-type differentiated primary bronchial epithelial cells, and in CFTR-inducible iCFBE cells, treatment with a lysolipid receptor agonist (VPC3114) enhanced shedding of pro-inflammatory and pro-fibrotic proteins. CONCLUSIONS: Together, our findings suggest that bioactive lipids in BALF correlate with and possibly predict structural lung disease in CF children, which supports their use as biomarkers of disease progression and treatment efficacy. Furthermore, our data suggest a causative role of airway lysolipids and oxidative stress in the progression of early CF lung disease, unveiling potential therapeutic targets.

Analog Coupled Oscillator Based Weighted Ising Machine.

We report on an analog computing system with coupled non-linear oscillators which is capable of solving complex combinatorial optimization problems using the weighted Ising model. The circuit is composed of a fully-connected 4-node LC oscillator network with low-cost electronic components and compatible with traditional integrated circuit technologies. We present the theoretical modeling, experimental characterization, and statistical analysis our system, demonstrating single-run ground state accuracies of 98% on randomized MAX-CUT problem sets with binary weights and 84% with 5-bit weight resolutions. Solutions are obtained within 5 oscillator cycles, and the time-to-solution has been demonstrated to scale directly with oscillator frequency. We present scaling analysis which suggests that large coupled oscillator networks may be used to solve computationally intensive problems faster and more efficiently than conventional algorithms. The proof-of-concept system presented here provides the foundation for realizing such larger scale systems using existing hardware technologies and could pave the way towards an entirely novel computing paradigm.

Broadband transparent optical phase change materials for high-performance nonvolatile photonics.

Optical phase change materials (O-PCMs), a unique group of materials featuring exceptional optical property contrast upon a solid-state phase transition, have found widespread adoption in photonic applications such as switches, routers and reconfigurable meta-optics. Current O-PCMs, such as Ge-Sb-Te (GST), exhibit large contrast of both refractive index (Δn) and optical loss (Δk), simultaneously. The coupling of both optical properties fundamentally limits the performance of many applications. Here we introduce a new class of O-PCMs based on Ge-Sb-Se-Te (GSST) which breaks this traditional coupling. The optimized alloy, Ge2Sb2Se4Te1, combines broadband transparency (1-18.5 µm), large optical contrast (Δn = 2.0), and significantly improved glass forming ability, enabling an entirely new range of infrared and thermal photonic devices. We further demonstrate nonvolatile integrated optical switches with record low loss and large contrast ratio and an electrically-addressed spatial light modulator pixel, thereby validating its promise as a material for scalable nonvolatile photonics.

Humanistic and economic impact of subcutaneous versus intravenous administration of oncology biologics.

More oncology biologics are becoming available for subcutaneous (sc.) administration and are expected to provide useful therapeutic options. We evaluated evidence published in the past 5 years to assess the humanistic and economic impact of sc. versus intravenous administration of approved cancer therapies and identify outcomes favoring either administration route. These publications focused predominantly on healthcare resource utilization and economic outcomes, demonstrating resource and cost savings with sc. administration. Patients reported a better health-related quality of life and preference for sc. formulations. Time-and-motion study analyses confirmed the convenience of sc. administration. These findings suggest that future availability of sc. oncology biologics, especially anti-PD-1/PD-ligand 1 antibodies due to their increased utility in various malignancies, may be beneficial for patients, healthcare providers and payers.

Assessment of Subcutaneous vs Intravenous Administration of Anti-PD-1 Antibody PF-06801591 in Patients With Advanced Solid Tumors: A Phase 1 Dose-Escalation Trial.

IMPORTANCE: We assessed feasibility of monthly subcutaneous administration of PF-06801591, a humanized immunoglobulin G4 monoclonal antibody that binds to the programmed cell death (PD-1) receptor and blocks its interaction with PD-1 ligands. OBJECTIVE: To evaluate the safety, efficacy, and pharmacokinetics of PF-06801591 administered intravenously vs subcutaneously. DESIGN, SETTING, AND PARTICIPANTS: Ongoing phase 1, open-label, multicenter, dose-escalation study of 40 patients, 18 years or older, with locally advanced or metastatic solid tumors, enrolled between March 8, 2016, and March 5, 2018, from 4 US medical centers. INTERVENTIONS: An intravenous dose of 0.5, 1, 3, or 10 mg/kg of PF-06801591 was administered every 3 weeks or a subcutaneous dose of 300 mg was administered every 4 weeks. Dose escalation occurred after 2 to 4 patients were enrolled per dose level, with additional patients enrolled in each cohort for further assessment. MAIN OUTCOMES AND MEASURES: The primary end points were dose-limiting toxic effects and safety. Secondary end points included pharmacokinetics, immunogenicity, PD-1 receptor occupancy, and efficacy. RESULTS: Of 40 enrolled patients (12 men and 28 women; mean [SD] age, 61 [13] years) in this phase 1 dose-escalation trial, 25 received PF-06801591 intravenously at escalating dose levels (0.5, 1, 3, or 10 mg/kg) and 15 patients received the monoclonal antibody subcutaneously at a single dose level. No dose-limiting toxic effects were observed. Grade 3 or higher treatment-related adverse events occurred in 4 (16%) patients treated intravenously and 1 (6.7%) patient treated subcutaneously. Immune-related adverse events occurred in 10 (40%) patients treated intravenously and 3 (20%) treated subcutaneously. No dose-adverse event associations were observed during intravenous dose escalation, and no serious skin toxic effects occurred with subcutaneous delivery. Responses were seen in 5 patients receiving PF-06801591 intravenously and in 2 patients treated subcutaneously for an overall objective response rate of 18.4%. Median overall survival was not reached with intravenous dosing vs 10.7 months with subcutaneous administration. Exposure to PF-06801591 increased in a dose-proportional manner over the range of intravenous doses. Median time to maximum observed serum concentration was 8 days after subcutaneous administration. Full PD-1 receptor occupancy was seen in all dose cohorts. CONCLUSIONS AND RELEVANCE: Anti-PD-1 antibody PF-06801591 was tolerable and showed antitumor activity in a variety of tumor types across all dose levels of intravenous and subcutaneous administration. Monthly subcutaneous administration of PF-06801591 offers a convenient, effective alternative to currently available intravenously administered checkpoint inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02573259.

Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics.

The increasing use of multiple immunomodulatory (IMD) agents for cancer therapies (e.g. antibodies targeting immune checkpoints, bispecific antibodies, and chimeric antigen receptor [CAR]-T cells), is raising questions on their potential immunogenicity and effects on treatment. In this review, we outline the mechanisms of action (MOA) of approved, antibody-based IMD agents, potentially related to their immunogenicity, and discuss the reported incidence of anti-drug antibodies (ADA) as well as their clinical relevance in patients with cancer. In addition, we discuss the impact of the administration route and potential strategies to reduce the incidence of ADA and manage treated patients. Analysis of published reports indicated that the risk of immunogenicity did not appear to correlate with the MOA of anti-programmed death 1 (PD-1)/PD-ligand 1 monoclonal antibodies nor to substantially affect treatment with most of these agents in the majority of patients evaluated to date. Treatment with B-cell depleting agents appears associated with a low risk of immunogenicity. No significant difference in ADA incidence was found between the intravenous and subcutaneous administration routes for a panel of non-oncology IMD antibodies. Additionally, while the data suggest a higher likelihood of immunogenicity for antibodies with T-cell or antigen-presenting cell (APC) targets versus B-cell targets, it is possible to have targets expressed on APCs or T cells and still have a low incidence of immunogenicity.

BMI Is a Better Body Proportionality Measure than the Ponderal Index and Weight-for-Length for Preterm Infants.

BACKGROUND: Clinicians have observed preterm infants in the neonatal intensive care unit growing disproportionally; however, the only growth charts that have been available were from preterm infants born in the 1950s which utilized the ponderal index. Prior to creating the recently published BMI curves, we found only 1 reference justifying the use of the ponderal index. OBJECTIVES: To determine the best measure of body proportionality for assessing growth in US preterm infants. METHODS: Using a dataset of 391,681 infants, we determined the body proportionality measure that was most correlated with weight and least correlated with length. We examined the sex-specific overall correlations and then stratified further by gestational age (GA). We then plotted the body proportionality measures versus length to visualize apparent discrepancies in the appropriate measure. RESULTS: The overall correlations showed weight/length3 (ponderal index) was the best measure but stratification by GA indicated that BMI (weight/length2) was the best measure. This seeming inconsistency was due to negative correlations between ponderal index and length at each GA. BMI, on the other hand, had a correlation with length across GAs, but was uncorrelated with length within GAs. Both ponderal index and BMI were positively correlated with weight. CONCLUSIONS: BMI is the appropriate measure of body proportionality for preterm infants, contrary to current practice.

Tracking the Fate and Origin of Clinically Relevant Adoptively Transferred CD8+ T Cells In Vivo.

Adoptively transferred tumor-specific cells can mediate tumor regression in cancers refractory to conventional therapy. Autologous polyclonal tumor-specific cytotoxic T cells (CTL) generated from peripheral blood and infused into patients with metastatic melanoma show enhanced persistence, compared to equivalent numbers of more extensively expanded monoclonal CTL, and are associated with complete remissions (CR) in select patients. We applied high-throughput T cell receptor Vß sequencing (HTTCS) to identify individual clonotypes within CTL products, track them in vivo post-infusion and then deduce the pre-adoptive transfer (endogenous) frequencies of cells ultimately responsible for tumor regression. The summed in vivo post-transfer frequencies of the top 25 HTTCS-defined clonotypes originally detected in the infused CTL population were comparable to enumeration by binding of antigen peptide-HLA multimers, revealing quantitative HTTCS is a reliable, multimer-independent alternative. Surprisingly, the polyclonal CTL products were composed predominantly of clonotypes that were of very low frequency (VLF) in the endogenous samples, often below the limit of HTTCS detection (0.001%). In patients who achieved durable CRs, the composition of transferred CTLs was dominated (57-90%) by cells derived from a single VLF clonotype. Thus, HTTCS now reveals that tumor-specific CTL enabling long-term tumor control originate from endogenous VLF populations that exhibit proliferative/survival advantages. Along with results indicating that naïve cell populations are most likely to contain cells that exist at VLF within the repertoire, our results provide a strong rationale for favoring T cells arising from VLF populations and with early-differentiation phenotypes when selecting subset populations for adoptive transfer.

Effect of anisotropic electron momentum distribution of surface plasmon on internal photoemission of a Schottky hot carrier device.

We recently reported that an Au/TiO2 photonic crystal device for photochemical energy conversion showed a sub-bandgap photoresponse centered at the surface plasmon polariton (SPP) resonant wavelength of this device. Here we developed a theoretical modeling of the internal photoemission in this device by incorporating the effects of anisotropic hot electron momentum distribution caused by SPP. The influences of interband and intraband transition, anisotropic momentum distribution of hot electrons by SPP are integrated to model the internal quantum efficiency (IQE) of this device. Near resonant wavelength, SPP dominates the electric field in the thin Au layer, which generates hot electrons with high enough momentum preferentially normal to the Schottky interface. Compared with the widely used Fowler's theory of internal photoemission, our model better predicts hot electron collection in Schottky devices. This model will provide a design guidance for tuning and enhancing photoresponse of Schottky hot carrier devices.

Electrically switchable diffractive waveplates with metasurface aligned liquid crystals.

Diffractive waveplates and equivalent metasurfaces provide a promising path for applications in thin film beam steering, tunable lenses, and polarization filters. However, fixed metasurfaces alone are unable to be tuned electronically. By combining metasurfaces with tunable liquid crystals, we experimentally demonstrate a single layer device capable of electrically switching a diffractive waveplate design at a measured peak diffraction efficiency of 35%, and a minimum switching voltage of 10V. Furthermore, the nano-scale metasurface aligned liquid crystals are largely independent of variations in wavelength and temperature. We also present a computational analysis of the efficiency limits of liquid crystal based diffractive waveplates, and compare this analysis to experimental measurements.

Surface plasmon assisted hot electron collection in wafer-scale metallic-semiconductor photonic crystals.

Plasmon assisted photoelectric hot electron collection in a metal-semiconductor junction can allow for sub-bandgap optical to electrical energy conversion. Here we report hot electron collection by wafer-scale Au/TiO2 metallic-semiconductor photonic crystals (MSPhC), with a broadband photoresponse below the bandgap of TiO2. Multiple absorption modes supported by the 2D nano-cavity structure of the MSPhC extend the photon-metal interaction time and fulfill a broadband light absorption. The surface plasmon absorption mode provides access to enhanced electric field oscillation and hot electron generation at the interface between Au and TiO2. A broadband sub-bandgap photoresponse centered at 590 nm was achieved due to surface plasmon absorption. Gold nanorods were deposited on the surface of MSPhC to study localized surface plasmon (LSP) mode absorption and subsequent injection to the TiO2 catalyst at different wavelengths. Applications of these results could lead to low-cost and robust photo-electrochemical applications such as more efficient solar water splitting.

Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma.

PURPOSE: Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma. METHODS: In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (10(6) plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (10(8) plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered intravenously every 3 weeks for four infusions, beginning in week 6. The primary end point was incidence of dose-limiting toxicities. Secondary end points were objective response rate by immune-related response criteria and safety. RESULTS: Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4 weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4 months). Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The objective response rate was 50%, and 44% of patients had a durable response lasting ≥ 6 months. Eighteen-month progression-free survival was 50%; 18-month overall survival was 67%. CONCLUSION: T-VEC with ipilimumab had a tolerable safety profile, and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapy.