Citations

Abstract Background: The live attenuated non-pathogenic Edmonston MV vaccine strain has advantages as an oncolytic platform given its tumor specificity, potent bystander effect, and ability to be engineered and retargeted. MV-NIS expresses the human thyroidal sodium-iodide symporter (NIS) and is selectively oncolytic, entering tumor cells through CD46 (overexpressed on many cancers, including breast cancer of all subtypes) and Nectin-4. NIS expression in MV-NIS infected cells permits noninvasive monitoring of virus spread by SPECT-CT imaging of Tc-99m pertechnetate or I-123 uptake. Methods: NCT01846091 is a standard 3+3 phase I trial of a single IT administration of MV-NIS in pts with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) or metastatic breast cancer (MBC). Primary objectives are (a) safety and tolerability and (b) maximally tolerated single dose. The secondary clinical objective is to preliminarily assess antitumor efficacy at and away from the MV injection site. Key eligibility criteria were: absence of standard therapy with life prolonging intent; at least one lesion >1 cm amenable to percutaneous injection; and no impending visceral crisis. MV-NIS was administered on D1 with mandatory SPECT-CT at baseline (BL) and on D3&D8; repeat SPECT-CT on D15&D21 if the prior result was positive; mandatory tumor biopsies on D3&D21; optional tumor biopsies on D8&D15; assessments for viremia and viral shedding at BL and on D3,D8,D15,D21; and standard imaging for restaging at BL,D21,W6,W12. Results: Accrual completed with 12 evaluable pts (6 SCCHN and 6 MBC) at 3 dose levels (108, 3x108, 109 TCID50). The MBC group included 5 HR+/HER2- pts and 1 pt with mixed HR+/HER2- and HR+/HER2+ disease. 5 pts had evidence of disease progression prior to study participation. No dose limiting toxicities were observed among the MBC pts; AEs possibly related to MV-NIS in this group were gr2 fatigue, gr1 flu-like illness, gr2 lymphopenia (all n=1). No SCCHN responses were observed. Best response for the MBC pts was: stable disease (SD) >6 wks, n=4; clinical response, n=1; progression, n=1. One MBC pt with SD for 12 wks had positive SPECT/CT imaging at and away from the injection site on D3&D8 and was the only pt seronegative for measles IgG antibodies prior to MV-NIS exposure. The MBC pt who responded after initial MV-NIS exposure was the only pt with low viral RNA in blood (D3); she received additional doses at W9&W13 without toxicity through an expanded access protocol exemption and had disease progression by W19. No viral shedding was detected from mouth rinse or urine in any pt. MV was detected in tumor samples from all pts treated at the highest dose level. Additional blood and tissue analyses are in progress. Conclusion: These results demonstrate the safety of IT MV-NIS administration, provide early evidence of biologic activity in MBC, and support the possibility of viral replication in tumors remote from the IT injection site. A MV strain encoding the immunomodulatory neutrophil activating protein transgene has been constructed (MV-s-NAP) with preclinical evidence of improved antitumor activity and immunogenicity. The phase I MV-s-NAP trial will start recruitment in Fall 2018. Citation Format: Liu MC, Peng K-W, Federspiel MJ, Russell SJ, Brunton BA, Zhou Y, Packiriswamy N, Hubbard JM, Loprinzi CL, Peethambaram PP, Ruddy KJ, Allred JB, Galanis E, Okuno SH. Phase I trial of intratumoral (IT) administration of a NIS-expressing derivative manufactured from a genetically engineered strain of measles virus (MV) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-03.

Abstract Background: PARP inhibitor (PARPi) monotherapy has previously demonstrated clinical activity only in patients with a germline BRCA mutation (BRCAmut), while single-agent anti-programmed cell death protein 1 (PD-1) therapy has achieved response rates of only 5–20% in advanced triple negative breast cancer (TNBC). In preclinical studies, PARP inhibition enhanced anti-tumor immunity, increased infiltration of proliferating CD8+ T cells, and synergized with anti-PD-1 agents in BRCA wildtype (wt) tumors. TOPACIO is a fully enrolled, phase I/II trial of niraparib + pembrolizumab (pembro) in advanced TNBC. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations. In this study, we conducted exploratory biomarker analyses to evaluate their potential correlation with durable clinical benefit (any complete response [CR] or partial response [PR] regardless of duration or stable disease [SD] for ≥16 weeks) beyond BRCA mutations. Method: ORR was assessed by RECIST v1.1. Duration of disease control (DDC) was defined as time from first dose of study treatment to radiologic disease progression or death. Tumor mutational status of homologous recombination repair (HRR) and other DNA damage repair (DDR) pathway genes was determined using an NGS panel. Immunoprofiling was conducted using NanoString IO360 panel complimented with 30 DNA repair spike-ins. Tumor immune micro-environment was characterized using multiplex immuno-fluorescence (CycIF). PD-L1 status was determined using the Agilent/DAKO 22C3 IHC clinical trial assay. Results: Of 46 evaluable patients, 20 achieved durable clinical benefit (any CR/PR or SD≥16 weeks) with niraparib + pembro combination, of which 8 were tumor BRCA wild type (wt), and 1 was BRCA unknown. Of the 9 BRCAwt/unknown patients, 5 had deleterious mutations in HRR/DDR pathway genes, whereas the remaining 4 had no mutations (HRR/DDR wt). Mutations that were associated with response include CHEK1 (CR; DDC=10.3 mos), ATR (CR; DDC=6.4 mos), PALB2 (PR; DDC=3.5 mos), BLM (SD; DDC=8.1 mos), and NBN/RAD51C (SD; DDC=3.7 mos). Of 4 patients that had no identified mutations (HRR/DDR wt), 1 patient had CR; DDC=10.3 mos, and the remaining 3 patients had SD with DDC ranging from ∼4-8 mos. Of note, all 4 HRR/DDR wt patients were also PD-L1-negative. Table:Durable clinical benefit in BRCAwt/unknown patientsHRR/DRR MutationsPD-L1 StatusBest ResponseDDC (Months)CHEK1+CR10.3†ATR+CR6.4PALB2*UnknownPR3.5BLM-SD8.1NBN/RAD51C+SD3.7None-CR10.3†None-SD8.2None-SD4.2None-SD3.9*BRCA status unknown; †Treatment is ongoing. Conclusion: Patients with mutations beyond BRCA achieved durable clinical benefit with niraparib + pembro treatment; five of these patients had DDC >6 mos. Mutations in genes that are associated with the HRR/DDR pathway appear to confer sensitivity to niraparib + anti-PD1. Additional translational analyses, including immunoprofiling and CycIF, will be presented. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner Hendrickson A, Forero A, Anders C, Wulf G, Dillon P, Lynce F, Zarwan C, Erban J, Färkkilä A, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube B, Telli ML. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-02.

Papilledema is optic nerve swelling caused by increased intracranial pressure, which has the potential to cause significant vision loss. Papilledema is typically bilateral and symmetric but can sometimes be asymmetric and even unilateral. The cause for this asymmetry is unknown. The purpose of this study was to utilize ultrasound vibro-elastography (UVE) to assess for biomechanical differences in eyes with papilledema. Nine patients with papilledema and 9 age-matched controls were enrolled. An external harmonic vibration was used to generate wave propagation through the eyelid with three excitation frequencies of 100, 150, and 200 Hz. A 6.4 MHz ultrasound probe was used to noninvasively measure the wave propagation in the posterior sclera to provide shear wave speeds and viscoelasticity (fit with Voigt model). The magnitudes of the shear wave speed and viscoelasticity of the idiopathic intracranial hypertension patients’ posterior sclera were significantly higher than those of healthy subjects. Moreover, for patients with unilateral papilledema, the magnitudes of wave speed and viscoelasticity of the posterior sclera were statistically higher in eyes with papilledema than in the contralateral eyes without papilledema. UVE provides a noninvasive technique to measure the viscoelastic properties of the posterior sclera, which is stiffer in eyes with papilledema.

Many lung diseases including interstitial lung disease (ILD) are associated with changes in the lung’s biomechanical properties. ILD comprises a number of serious diseases in which fibrosis stiffens and damages lung tissue. Most ILDs are typically distributed in the lung’s peripheral and subpleural regions. Pulmonary function test (PFT) and high-resolution computed tomography (HRCT) are used to assess ILD. Ultrasonography is not widely used for lung assessment because ultrasound cannot image deep lung tissue. We have developed lung ultrasound surface wave elastography (LUSWE) for measuring superficial lung wave speed. In LUSWE, a 0.1-s harmonic vibration is generated on the chest wall of a subject using a handheld vibrator. An ultrasound probe is aligned with the vibration excitation in the same intercostal space to measure the generated surface wave propagation on the lung. A human subject is examined in a sitting position. The lung is tested at the total lung volume and through six intercostal spaces. Significant differences of surface wave speed between patients and controls were found in 6 lung regions and for 3 excitation frequencies. A positive correlation between LUSWE and clinical tests including HRCT and PTF was found. LUSWE may complement the clinical standard HRCT for assessing ILD.

Lung ultrasound (LUS) detects the presence of extravascular lung water (EVLW) through the visualization of B-Line artifacts. However, the qualitative nature of LUS limits its effectiveness in serial or longitudinal studies such as evaluating changes in EVLW at different time points in patients undergoing diuretic therapy for congestive heart failure. Lung ultrasound surface wave elastography (LUSWE) is a novel technique using a small handheld device that can measure superficial lung tissue elastic properties. We aimed to evaluate the use of LUSWE to measure quantitative changes in lung elasticity caused by acute changes in EVLW. We performed LUSWE on consecutive days in 14 patients hospitalized for acute congestive heart failure with evidence of pulmonary edema (clinical EVLW). From day#1 to day#2, the patients had an average diuresis of net negative 2.1 l associated with an average decrease in 13 B-Lines by lung ultrasound, signifying a reduction in EVLW. LUSWE analysis demonstrated a significant reduction (p < 0.05) in surface wave velocity in all interrogated intercostal spaces from day#1 to day#2. In summary, LUSWE performed at the bedside was able to demonstrate improvement in lung compliance (decreased elasticity) correlating with a reduction in EVLW in hospitalized patients being treated for congestive heart failure.

Biomechanical properties of the eye are important in understanding glaucoma. However, specific tissues that may be affected are unclear. In this study, we compared glaucomatous and normal eyes for differences in corneal tissue elasticity (as indicated by wave speed) and global ocular rigidity. Both eyes of 10 glaucoma patients and 10 normal controls, matched for age and intraocular pressure (IOP), were included. The ocular rigidity coefficient was calculated from supine IOP measured with and without a 10 g weight added to the tonometer. The wave speed in the cornea was measured by ultrasound surface wave elastography. With this technique, a spherical-tipped probe (4 mm diameter) was placed on the closed eyelid and vibrated at 100 Hz for 0.1 s. The wave speed was calculated using the phase gradient method. Measurements for normal and glaucoma eyes were compared using generalized estimating equation models. The corneal wave speed was similar between normal and glaucomatous eyes (P = 0.4). However, ocular rigidity was significantly lower in glaucomatous eyes (P < 0.001) compared with normal eyes. There was no difference in age or IOP (P > 0.3). Lower ocular rigidity in glaucomatous eyes suggests that a more compliant ocular shell may predispose to glaucoma. However, the lack of difference in the corneal wave speed suggests that corneal tissue is not significantly affected, and changes likely involve the sclera.

Hypertrophic scars and keloids are characterized by excessive fibrosis and can be functionally problematic. Indeed, hypertrophic scarring is characterized by wide, raised scars that remain within the original borders of injury and have a rapid growth phase. There is a need for quantitative scar measurement modalities to effectively evaluate and monitor treatments. We aim to assess the role of the non-invasive scar-measuring device, ultrasound surface wave elastography (USWE), in accurately evaluating scar metrics. Two sites of breast tissue were tested control and scar portions. In USWE, a small, local, and 0.1-s harmonic vibration at three excitation frequencies (100, 150, and 200 Hz) was generated on these sites, and the resulting surface wave speed was measured via an ultrasound probe with a central frequency of 6.4 MHz. There was a statistically significant difference in the wave speed at three frequencies of the scar portion between prior and after treatment, suggesting that the scar portion was softener after treatment. USWE provides an objective assessment of the reaction of the scar to injury and treatment response.