Christopher J. Hoimes

Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study

Importance The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. Objective To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. Design, Setting, and Participants This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein. Intervention Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects. Main Outcomes and Measures Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1). Results A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis). Conclusions and Relevance Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC. Trial Registration clinicaltrials.gov Identifier: NCT01693562

Targeted nanotechnology for cancer imaging.

Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit significant advantages including increased contrast sensitivity, binding avidity and targeting specificity. Considering the various nanoparticle designs and their adjustable ability to target a specific site and generate detectable signals, nanoparticles can be optimally designed in terms of biophysical interactions (i.e., intravascular and interstitial transport) and biochemical interactions (i.e., targeting avidity towards cancer-related biomarkers) for site-specific detection of very distinct microenvironments. This review seeks to illustrate that the design of a nanoparticle dictates its in vivo journey and targeting of hard-to-reach cancer sites, facilitating early and accurate diagnosis and interrogation of the most aggressive forms of cancer. We will report various targeted nanoparticles for cancer imaging using X-ray computed tomography, ultrasound, magnetic resonance imaging, nuclear imaging and optical imaging. Finally, to realize the full potential of targeted nanotechnology for cancer imaging, we will describe the challenges and opportunities for the clinical translation and widespread adaptation of targeted nanoparticles imaging agents.

The effect of hyperbranched polyglycerol coatings on drug delivery using degradable polymer nanoparticles

A key attribute for nanoparticles (NPs) that are used in medicine is the ability to avoid rapid uptake by phagocytic cells in the liver and other tissues. Poly(ethylene glycol) (PEG) coatings has been the gold standard in this regard for several decades. Here, we examined hyperbranched polyglycerols (HPG) as an alternate coating on NPs. In earlier work, HPG was modified with amines and subsequently conjugated to poly(lactic acid) (PLA), but that approach compromised the ability of HPG to resist non-specific adsorption of biomolecules. Instead, we synthesized a copolymer of PLA-HPG by a one-step esterification. NPs were produced from a single emulsion using PLA-HPG: fluorescent dye or the anti-tumor agent camptothecin (CPT) were encapsulated at high efficiency in the NPs. PLA-HPG NPs were quantitatively compared to PLA-PEG NPs, produced using approaches that have been extensively optimized for drug delivery in humans. Despite being similar in size, drug release profile and in vitro cytotoxicity, the PLA-HPG NPs showed significantly longer blood circulation and significantly less liver accumulation than PLA-PEG. CPT-loaded PLA-HPG NPs showed higher stability in suspension and better therapeutic effectiveness against tumors in vivo than CPT-loaded PLA-PEG NPs. Our results suggest that HPG is superior to PEG as a surface coating for NPs in drug delivery.

Surface modified poly(β amino ester)-containing nanoparticles for plasmid DNA delivery.

The use of biodegradable polymers provides a potentially safe and effective alternative to viral and liposomal vectors for the delivery of plasmid DNA to cells for gene therapy applications. In this work we describe the formulation of a novel nanoparticle (NP) system containing a blend of poly(lactic-co-glycolic acid) and a representative poly(beta-amino) ester (PLGA and PBAE respectively) for use as gene delivery vehicles. Particles of different weight/weight (wt/wt) ratios of the two polymers were characterized for size, morphology, plasmid DNA (pDNA) loading and surface charge. NPs containing PBAE were more effective at cellular internalization and transfection (COS-7 and CFBE41o-) than NPs lacking the PBAE polymer. However, along with these delivery benefits, PBAE exhibited cytotoxic effects that presented an engineering challenge. Surface coating of these blended particles with the cell-penetrating peptides (CPPs) mTAT, bPrPp and MPG via a PEGylated phospholipid linker (DSPE-PEG2000) resulted in NPs that reduced surface charge and cellular toxicity to levels comparable with NPs formulated with only PLGA. Additionally, these coated nanoparticles showed an improvement in pDNA loading, intracellular uptake and transfection efficiency, when compared to NPs lacking the surface coating. Although all particles with a CPP coating outperformed unmodified NPs, respectively, bPrPp and MPG coating resulted in 3 and 4.5× more pDNA loading than unmodified particles and approximately an order of magnitude improvement on transfection efficiency in CFBE41o- cells. These results demonstrate that surface-modified PBAE containing NPs are a highly effective and minimally toxic platform for pDNA delivery.

Redefining hormone resistance in prostate cancer

Prostate cancer relies on signaling through the androgen receptor (AR) for maintenance and progression; and androgen-deprivation therapy remains a cornerstone of treatment for advanced prostate cancer. An effective clinical classification of prostate cancer should account for the extent of the disease as well as the mechanisms that are driving the growth of the tumor. The previous terms hormone-sensitive and hormone-refractory described response to treatment. It has become clear that these terms do not reflect the mechanism of disease relapse; however over the last decade there has been a better understanding of androgen-receptor mediated signaling effects and incomplete suppression of androgens in prostate cancer. The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) now recommends addressing the spectrum of clinical states based on castration status as this ligand-centered terminology can more accurately describe the patients’ disease, and ultimately provides a useful framework for patient management and drug development. Optimized use of androgen-deprivation therapy, low molecular weight inhibitors of adrenal androgen biosynthesis, and new AR antagonists are promising new therapeutics that can further define the meaning of castrate state. As hormone resistance is redefined to include patients that are refractory to treatments that ablate adrenal and in situ tumoral androgens, a meaningful new clinical state in patients will be forged. We propose a model for incorporating these patients into the current PCWG2 conceptualization of the disease.

Treatment of invasive brain tumors using a chain-like nanoparticle

Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood-tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small-molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the αvβ3 integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By 2 hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. In vivo efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof-of-concept for a broadly improved method for glioblastoma treatment.

Radiomics Analysis on FLT-PET/MRI for Characterization of Early Treatment Response in Renal Cell Carcinoma: A Proof-of-Concept Study

Studying early response to cancer treatment is significant for patient treatment stratification and follow-up. Although recent advances in positron emission tomography (PET) and magnetic resonance imaging (MRI) allow for evaluation of tumor response, a quantitative objective assessment of treatment-related effects offers localization and quantification of structural and functional changes in the tumor region. Radiomics, the process of computerized extraction of features from radiographic images, is a new strategy for capturing subtle changes in the tumor region that works by quantifying subvisual patterns which might escape human identification. The goal of this study was to demonstrate feasibility for performing radiomics analysis on integrated PET/MRI to characterize early treatment response in metastatic renal cell carcinoma (RCC) undergoing sunitinib therapy. Two patients with advanced RCC were imaged using an integrated PET/MRI scanner. [18 F] fluorothymidine (FLT) was used as the PET radiotracer, which can measure the degree of cell proliferation. Image acquisitions included test/retest scans before sunitinib treatment and one scan 3 weeks into treatment using [18 F] FLT-PET, T2-weighted (T2w), and diffusion-weighted imaging (DWI) protocols, where DWI yielded an apparent diffusion coefficient (ADC) map. Our framework to quantitatively characterize treatment-related changes involved the following analytic steps: 1) intraacquisition and interacquisition registration of protocols to allow voxel-wise comparison of changes in radiomic features, 2) correction and pseudoquantification of T2w images to remove acquisition artifacts and examine tissue-specific response, 3) characterization of information captured by T2w MRI, FLT-PET, and ADC via radiomics, and 4) combining multiparametric information to create a map of integrated changes from PET/MRI radiomic features. Standardized uptake value (from FLT-PET) and ADC textures ranked highest for reproducibility in a test/retest evaluation as well as for capturing treatment response, in comparison to high variability seen in T2w MRI. The highest-ranked radiomic feature yielded a normalized percentage change of 63% within the RCC region and 17% in a spatially distinct normal region relative to its pretreatment value. By comparison, both the original and postprocessed T2w signal intensity appeared to be markedly less sensitive and specific to changes within the tumor. Our preliminary results thus suggest that radiomics analysis could be a powerful tool for characterizing treatment response in integrated PET/MRI.

Bladder Cancer, Version 2.2016 Featured Updates to the NCCN Guidelines

The NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer. These NCCN Guidelines Insights discuss important updates to the 2018 version of the guidelines, including implications of the 8th edition of the AJCC Cancer Staging Manual on treatment of muscle-invasive bladder cancer and incorporating newly approved immune checkpoint inhibitor therapies into treatment options for patients with locally advanced or metastatic disease.

Characteristics and Survival of Malignant Cardiac Tumors A 40-Year Analysis of >500 Patients

Background— The aim of this study was to investigate the incidence, histopathology, demographics, and survival associated with primary malignant cardiac tumors (PMCTs). Methods and Results— We queried the Surveillance, Epidemiology and End Results (SEER) 18 registry from the National Cancer Institute for all PMCTs diagnosed from 1973 to 2011. We describe PMCT histopathology and incidence, comparing characteristics and survival of these patients with those of patients with extracardiac malignancies of similar histopathology. From a total of 7 384 580 cases of cancer registered in SEER, we identified 551 PMCTs (0.008%). The incidence of PMCT diagnosis is 34 cases per 100 million persons and has increased over time (25.1 in 1973–1989, 30.2 in 1990–1999, and 46.6 in 2000–2011). Most patients are female (54.1%) and white (78.6%) with median age at diagnosis of 50 years. The most common PMCTs are sarcomas (n=357, 64.8%), followed by lymphomas (n=150, 27%) and mesotheliomas (n=44, 8%). Most patients are diagnosed with tissue sample (96.8%). Although use of chemotherapy is not documented in SEER, 19% of patients received radiation and 44% had surgery. After a median follow-up of 80 months, 413 patients had died. The 1-, 3-, and 5-year survival rates were 46%, 22%, and 17% and have improved over the eras, with 1-, 3-, and 5-year survival rates of 32%, 17%, and 14% for 1973 to 1989 and 50%, 24%, and 19% for 2000 to 2011 ( P =0.009). Cardiac sarcomas and mesotheliomas are the most lethal PMCTs, with 1-, 3-, 5-year survival rates of 47%, 16%, and 11% and of 51%, 26%, and 23% compared with 59%, 41%, and 34% for lymphomas, respectively (log rank test P <0.001). Patients with cardiac lymphomas and sarcomas are younger and have worse survival than patients with extracardiac disease of similar histopathology ( P <0.001). Conclusions— PMCTs are extremely rare and continue to be associated with poor prognosis. Over the past 5 decades, the incidence and survival of patients diagnosed with PMCT appear to have increased. Compared with those with extracardiac cancers of similar histopathology, patients with PMCTs are often younger and have worse survival. # CLINICAL PERSPECTIVE {#article-title-40}Background— The aim of this study was to investigate the incidence, histopathology, demographics, and survival associated with primary malignant cardiac tumors (PMCTs). Methods and Results— We queried the Surveillance, Epidemiology and End Results (SEER) 18 registry from the National Cancer Institute for all PMCTs diagnosed from 1973 to 2011. We describe PMCT histopathology and incidence, comparing characteristics and survival of these patients with those of patients with extracardiac malignancies of similar histopathology. From a total of 7 384 580 cases of cancer registered in SEER, we identified 551 PMCTs (0.008%). The incidence of PMCT diagnosis is 34 cases per 100 million persons and has increased over time (25.1 in 1973–1989, 30.2 in 1990–1999, and 46.6 in 2000–2011). Most patients are female (54.1%) and white (78.6%) with median age at diagnosis of 50 years. The most common PMCTs are sarcomas (n=357, 64.8%), followed by lymphomas (n=150, 27%) and mesotheliomas (n=44, 8%). Most patients are diagnosed with tissue sample (96.8%). Although use of chemotherapy is not documented in SEER, 19% of patients received radiation and 44% had surgery. After a median follow-up of 80 months, 413 patients had died. The 1-, 3-, and 5-year survival rates were 46%, 22%, and 17% and have improved over the eras, with 1-, 3-, and 5-year survival rates of 32%, 17%, and 14% for 1973 to 1989 and 50%, 24%, and 19% for 2000 to 2011 (P=0.009). Cardiac sarcomas and mesotheliomas are the most lethal PMCTs, with 1-, 3-, 5-year survival rates of 47%, 16%, and 11% and of 51%, 26%, and 23% compared with 59%, 41%, and 34% for lymphomas, respectively (log rank test P<0.001). Patients with cardiac lymphomas and sarcomas are younger and have worse survival than patients with extracardiac disease of similar histopathology (P<0.001). Conclusions— PMCTs are extremely rare and continue to be associated with poor prognosis. Over the past 5 decades, the incidence and survival of patients diagnosed with PMCT appear to have increased. Compared with those with extracardiac cancers of similar histopathology, patients with PMCTs are often younger and have worse survival.

Nanoparticles for urothelium penetration and delivery of the histone deacetylase inhibitor belinostat for treatment of bladder cancer

UNLABELLED Nearly 40% of patients with non-invasive bladder cancer will progress to invasive disease despite locally-directed therapy. Overcoming the bladder permeability barrier (BPB) is a challenge for intravesical drug delivery. Using the fluorophore coumarin (C6), we synthesized C6-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), which were surface modified with a novel cell penetrating polymer, poly(guanidinium oxanorbornene) (PGON). Addition of PGON to the NP surface improved tissue penetration by 10-fold in intravesically-treated mouse bladder and ex vivo human ureter. In addition, NP-C6-PGON significantly enhanced intracellular uptake of NPs compared to NPs without PGON. To examine biological activity, we synthesized NPs that were loaded with the histone deacetylase (HDAC) inhibitor belinostat (NP-Bel-PGON). NP-Bel-PGON exhibited a significantly lower IC50 in cultured bladder cancer cells, and sustained hyperacetylation, when compared to unencapsulated belinostat. Xenograft tumors treated with NP-Bel-PGON showed a 70% reduction in volume, and a 2.5-fold higher intratumoral acetyl-H4, when compared to tumors treated with unloaded NP-PGON. FROM THE CLINICAL EDITOR These authors demonstrate that PLGA nanoparticles with PGON surface functionalization result in greatly enhanced cell penetrating capabilities, and present convincing data from a mouse model of bladder cancer for increased chemotherapy efficacy.