Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not ...only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.
The discovery of activating BRAF mutations in melanomas has led to the investigation of small molecular inhibitors targeting BRAF mutation and MEK, a downstream protein within the mitogen‐activated ...protein kinase (MAPK) pathway. This article reviews the role of mutant BRAF in melanoma and summarizes the results of clinical trials evaluating inhibitors of BRAF and MEK in BRAF‐mutant melanoma. We further describe recent findings on the mechanisms of resistance to BRAF inhibitors and discuss ongoing efforts to combine BRAF inhibitors with other targeted agents. Finally, we review the results of immunotherapy in BRAF‐mutant melanoma and address the current status of efforts to either combine or determine the optimal sequence of these two distinct treatment approaches. Although the recent advances in melanoma therapy have been dramatic, greater understanding of melanoma biology coupled with the successful development of several new treatments and combination regimens will further improve patient outcomes in the future.
Clinical Pharmacology & Therapeutics (2013); 95 1, 24–31 advance online publication 27 November 2013. doi:10.1038/clpt.2013.197
Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy ...for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma.
In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population.
At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval CI, 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment.
Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).
Programmed death ligand-1 (PD-L1) expression in nonclear-cell RCC (non-ccRCC) and its association with clinical outcomes are unknown.
Formalin-fixed paraffin-embedded (FFPE) specimens were obtained ...from 101 patients with non-ccRCC. PD-L1 expression was evaluated by immunohistochemistry in both tumor cell membrane and tumor-infiltrating mononuclear cells (TIMC). PD-L1 tumor positivity was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrate and percentage of positive cells was used. Baseline clinico-pathological characteristics and outcome data time to recurrence (TTR) and overall survival (OS) were correlated with PD-L1 staining.
Among 101 patients, 11 (10.9%) were considered PD-L1+ in tumor cells: 2/36 (5.6%) of chromophobe RCC, 5/50 (10%) of papillary RCC, 3/10 (30%) of Xp11.2 translocation RCC and 1/5 (20%) of collecting duct carcinoma. PD-L1 positivity (PD-L1+) in tumor cells was significantly associated with higher stage (P = 0.01) and grade (P = 0.03), as well as shorter OS (P < 0.001). On the other hand, PD-L1 positivity by TIMC was observed in 57 (56.4%) patients: 13/36 (36.1%) of chromophobe RCC, 30/50 (60%) of papillary RCC, 9/10 (90%) of Xp11.2 translocation RCC and 5/5 (100%) of collecting duct carcinoma. A trend toward shorter OS was observed in patients with PD-L1+ in TIMC (P = 0.08). PD-L1+ in both tumor cell membrane and TIMC cells were associated with shorter TTR (P = 0.02 and P = 0.03, respectively).
In non-ccRCC, patients with PD-L1+ tumors appear to have worse clinical outcomes, although only PD-L1 positivity in tumor cells is associated with higher tumor stage and grade.
In recent years, there has been dramatic expansion of the treatment armamentarium for patients with advanced renal cell carcinoma (aRCC), including drugs targeting vascular endothelial growth factor ...and mammalian target of rapamycin (mTOR) pathways. Despite these advances, patient outcomes remain suboptimal, underscoring the need for therapeutic interventions with novel mechanisms of action. The advent of immunotherapy with checkpoint inhibitors has led to significant changes in the treatment landscape for several solid malignancies. Specifically, drugs targeting the programmed death 1 (PD-1) and cytotoxic T-lymphocyte associated antigen (CTLA-4) pathways have demonstrated considerable clinical efficacy and gained regulatory approval as single-agent or combination therapy for the treatment of patients with metastatic melanoma, non-small cell lung cancer, aRCC, advanced squamous cell carcinoma of the head and neck, urothelial cancer and Hodgkin lymphoma. In aRCC, the PD-1 inhibitor nivolumab was approved in both the United States and Europe for the treatment of patients who have received prior therapy, based on improved overall survival compared with the mTOR inhibitor everolimus. Other checkpoint inhibitors, including the CTLA-4 inhibitor ipilimumab in combination with several agents, and the PD-L1 inhibitor atezolizumab, are in various stages of clinical development in patients with aRCC. In this review, current evidence related to the clinical use of checkpoint inhibitors for the treatment of patients with aRCC is discussed, including information on the frequency and management of unconventional responses and the management of immune-related adverse events. In addition, perspectives on the future use of checkpoint inhibitors are discussed, including the potential value of treatment beyond progression, the potential use in earlier lines of care or in combination with other agents, and the identification of biomarkers to guide patient selection and enable individualization of therapy.
The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell ...carcinoma (aRCC). We report updated efficacy data from the second interim analysis.
Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1–positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population.
Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 95% confidence interval (CI) 0.490–0.777}; one-sided P < 0.0001; median 13.8 (95% CI 10.1–20.7) versus 7.0 months (95% CI 5.7–9.6); overall population: HR 0.69 (95% CI 0.574–0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1–15.3) versus 8.0 months (95% CI 6.7–9.8). OS data were immature PD-L1+ population: HR 0.828 (95% CI 0.596–1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616–1.027); one-sided P = 0.0392.
Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.
NCT02684006.
•Avelumab plus axitinib significantly prolonged progression-free survival versus sunitinib in advanced renal cell carcinoma.•Although overall survival data were immature, results favored the combination over sunitinib across prespecified subgroups.•Adjusting for subsequent use of PD-1/PD-L1 inhibitors in the sunitinib arm predicted a survival benefit for the combination.•Among all randomized patients, avelumab plus axitinib had a longer mean duration of response than sunitinib.•Avelumab plus axitinib prolonged progression-free survival on next-line therapy versus sunitinib.
A cyber-physical system (CPS) is composed of tightly-integrated computation, communication and physical elements. Medical devices, buildings, mobile devices, robots, transportation and energy systems ...can benefit from CPS co-design and optimization techniques. Cyber-physical vehicle systems (CPVSs) are rapidly advancing due to progress in real-time computing, control and artificial intelligence. Multidisciplinary or multi-objective design optimization maximizes CPS efficiency, capability and safety, while online regulation enables the vehicle to be responsive to disturbances, modeling errors and uncertainties. CPVS optimization occurs at design-time and at run-time. This paper surveys the run-time cooperative optimization or co-optimization of cyber and physical systems, which have historically been considered separately. A run-time CPVS is also cooperatively regulated or co-regulated when cyber and physical resources are utilized in a manner that is responsive to both cyber and physical system requirements. This paper surveys research that considers both cyber and physical resources in co-optimization and co-regulation schemes with applications to mobile robotic and vehicle systems. Time-varying sampling patterns, sensor scheduling, anytime control, feedback scheduling, task and motion planning and resource sharing are examined.
Phospholipid bilayer Nanodiscs are novel model membranes derived from high-density lipoprotein particles and have proven to be useful in studies of membrane proteins. Membrane protein enzymology has ...been hampered by the inherent insolubility of membrane proteins in aqueous environments and has necessitated the use of model membranes such as liposomes and detergent-stabilized micelles. Current model membranes display a polydisperse particle size distribution and can suffer from problems of inconsistency and instability. It is also unclear how well they mimic biological lipid bilayers. In contrast, Nanodiscs, the particle size of which is constrained by a coat of scaffold proteins, are relatively monodisperse, stable model membranes with a “nativelike” lipid bilayer. Nanodiscs have already been used to study a variety of membrane proteins, including cytochrome P450s, seven-transmembrane proteins, and bacterial chemoreceptors. These proteins are simultaneously monomerized, solubilized, and incorporated into the well-defined membrane environment provided by Nanodiscs. Nanodiscs may also provide useful insights into the thermodynamics and biophysics of biological membranes and binding of small molecules to membranes.
In response to the COVID-19 pandemic, there has been a rapid growth in the use of telehealth/telemedicine that will likely be sustained in the postpandemic setting. Mobile health applications (apps) ...can be used as part of the telehealth encounter to monitor patient-reported outcomes (PROs) and enhance patient-provider communication.
A systematic review was performed of mobile health apps with symptom trackers. We searched the iOS App Store and Android Google Play using the words cancer, oncology, and symptom tracker. Apps were included if they incorporated a symptom tracking function that could allow patients with cancer to record symptoms and PROs. Apps were evaluated using the mobile apps rating scale, which includes engagement, functionality, aesthetics, information, and app subjective quality.
The initial search yielded 1189 apps, with 101 apps eligible after title and description screening. A total of 41 apps met eligibility criteria and were included in this study. The majority of apps (73%, n = 30) were general health/pain symptom trackers, and 27% (n = 11) were cancer-specific. The app quality mean scores assessed using the mobile apps rating scale ranged from 2.43 to 4.23 (out of 5.00). Only 1 app has been trialed for usability among patients with cancer.
Although various symptom tracking apps are available, cancer-specific apps remain limited. Future collaboration between oncologists, app developers, and patients to optimize PRO assessment and integration with telehealth/telemedicine encounters to increase symptom recognition and enhance patient-provider communication is urgently needed.
Irregular streaks are important clues for Melanoma (a potentially fatal form of skin cancer) diagnosis using dermoscopy images. This paper extends our previous algorithm to identify the absence or ...presence of streaks in a skin lesions, by further analyzing the appearance of detected streak lines, and performing a three-way classification for streaks, Absent, Regular, and Irregular, in a pigmented skin lesion. In addition, the directional pattern of detected lines is analyzed to extract their orientation features in order to detect the underlying pattern. The method uses a graphical representation to model the geometric pattern of valid streaks and the distribution and coverage of the structure. Using these proposed features of the valid streaks along with the color and texture features of the entire lesion, an accuracy of 76.1% and weighted average area under ROC curve (AUC) of 85% is achieved for classifying dermoscopy images into streaks Absent, Regular, or Irregular on 945 images compiled from atlases and the internet without any exclusion criteria. This challenging dataset is the largest validation dataset for streaks detection and classification published to date. The data set has also been applied to the two-class sub-problems of Absent/Present classification (accuracy of 78.3% with AUC of 83.2%) and to Regular/Irregular classification (accuracy 83.6% with AUC of 88.9%). When the method was tested on a cleaned subset of 300 images randomly selected from the 945 images, the AUC increased to 91.8%, 93.2% and 90.9% for the Absent/Regular/Irregular, Absent/Present, and Regular/Irregular problems, respectively.
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