A Phase I Open-Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies

Lessons Learned

• The novel therapeutic vaccine hVEGF_26–104/RFASE was found to be safe and well tolerated in patients with cancer.
• hVEGF_26–104/RFASE failed to induce seroconversion against native hVEGF₁₆₅ and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VEGF) levels nor clinical benefit was observed.
• Remarkably, hVEGF_26–104/RFASE induced VEGF₁₆₅-neutralizing antibodies in a nonhuman primate model. The absence of seroconversion in human calls for caution in the interpretation of efficacy of human vaccines in nonhuman primates.

     

Plaque Composition as a Predictor of Plaque Ulceration in Carotid Artery Atherosclerosis: The Plaque At RISK Study

BACKGROUND AND PURPOSE:Plaque ulceration is a marker of previous plaque rupture. We studied the association between atherosclerotic plaque composition at baseline and plaque ulceration at baseline and follow-up.MATERIALS AND METHODS:We included symptomatic patients with a carotid stenosis of <70% who underwent MDCTA and MR imaging at baseline (n = 180). MDCTA was repeated at 2 years (n = 73). We assessed the presence of ulceration using MDCTA. Baseline MR imaging was used to assess the vessel wall volume and the presence and volume of plaque components (intraplaque hemorrhage, lipid-rich necrotic core, and calcifications) and the fibrous cap status. Associations at baseline were evaluated with binary logistic regression and reported with an OR and its 95% CI. Simple statistical testing was performed in the follow-up analysis.RESULTS:At baseline, the prevalence of plaque ulceration was 27% (49/180). Increased wall volume (OR  = 12.1; 95% CI, 3.5–42.0), higher relative lipid-rich necrotic core (OR = 1.7; 95% CI, 1.3–2.2), higher relative intraplaque hemorrhage volume (OR = 1.7; 95% CI, 1.3–2.2), and a thin-or-ruptured fibrous cap (OR = 3.4; 95% CI, 1.7–6.7) were associated with the presence of ulcerations at baseline. In 8% (6/73) of the patients, a new ulcer developed. Plaques with a new ulceration at follow-up had at baseline a larger wall volume (1.04 cm³ [IQR, 0.97–1.16 cm³] versus 0.86 cm³ [IQR, 0.73–1.00 cm³]; P = .029), a larger relative lipid-rich necrotic core volume (23% [IQR, 13–31%] versus 2% [IQR, 0–14%]; P = .002), and a larger relative intraplaque hemorrhage volume (14% [IQR, 8–24%] versus 0% [IQR, 0–5%]; P < .001).CONCLUSIONS:Large atherosclerotic plaques and plaques with intraplaque hemorrhage and lipid-rich necrotic cores were associated with plaque ulcerations at baseline and follow-up.

Atherosclerosis in the carotid arteries is one of the leading causes of ischemic stroke with arterio-arterial embolism as the main mechanism.^1,2 The degree of lumen stenosis and the symptomatic status of the patient are currently used for risk assessment and treatment decision-making.^3,4 Patients with severe (≥70%) and moderate (50%–69%) carotid artery stenosis benefit from carotid endarterectomy; however, the number needed to treat to prevent recurrent stroke is relatively high.⁵ Moreover, almost half of neurologic events occur in patients with a low degree of stenosis.^6,7 This finding has triggered investigations into other markers that may help to identify patients with a high risk of recurrent stroke. Much attention has been paid to markers of atherosclerosis, like plaque composition and plaque ulceration, with the aim of identifying vulnerable plaques.⁸ These vulnerable plaques have a high risk of rupture, which results in thrombus formation and embolization of plaque material and/or thrombus migrating into the intracranial circulation, thereby causing vascular occlusion and a subsequent ischemic stroke.²Plaque composition is predictive of future cerebrovascular events.^9-12 Atherosclerotic plaque ulceration, visible as plaque-surface disruption, which is a marker of previous plaque rupture, is also correlated with recurrent symptoms and associated with a higher risk of ischemic stroke.^13,14 However, the relation between vulnerable plaque components and plaque rupture is rarely investigated. Both plaque composition and ulceration can be assessed in vivo with different imaging modalities, but MR imaging is the best technique to assess plaque composition due to its superior soft-tissue contrast,¹⁵ whereas MDCTA exceeds MR imaging in the detection of plaque ulcerations due to its excellent spatial resolution with the possibility of multiplanar reconstruction.^16,17Most previous studies investigated the relation between plaque ulcerations and plaque features using a cross-sectional study design. Generally, it was found that intraplaque hemorrhage (IPH), large lipid-rich necrotic core (LRNC), and thinning or ruptured fibrous cap were associated with the presence of ulcerations,^18-21 while the presence of calcifications was inversely related to ulcerations.¹⁹ A prospective study in asymptomatic patients with severe carotid artery stenosis revealed that LRNC volume was a predictor of new surface disruption.^22,23 The aim of the current study was to investigate, in symptomatic patients with mild-to-moderate (30%–69%) carotid artery stenosis, which plaque components at baseline are predictive of plaque rupture at follow-up.     

IGF-1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER-positive breast cancer

Preclinical studies indicate that activated IGF-1R can drive endocrine resistance in ER-positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF-1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF-1R-mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF-1R, p-IGF-1R/InsR, p-ERα(Ser118), p-ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p-IGF-1R/InsR and PI3K/MAPK pathway activation in MCF-7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth-stimulating and -inhibiting conditions. Patients with ER+, IGF-1R-positive breast cancer without p-IGF-1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p-IGF-1R/InsR-positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p-ERα(Ser118) or p-ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF-7 cells, IGF-1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF-1R overexpression. This could be abrogated by the dual IGF-1R/InsR inhibitor linsitinib, but not by the IGF-IR-selective antibody 1H7. In MCF-7 and T47D cells, stimulation of the IGF-1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p-IGF-1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF-1R is driving tamoxifen resistance to be abrogated by linsitinib.     

Identification of HPV genotypes causing cervical precancer using tissue-based genotyping

Identification of high-risk human papillomavirus genotypes causing cervical precancer is crucial for informing HPV vaccine development and efficacy studies, and for determining which types to include in next-generation genotyping assays. Co-occurrence of hrHPV infections is common and complicates carcinogenicity assessment; accurate attribution requires tissue-based genotyping of precancers. We included all women with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) from the Biopsy Study, an observational study of 690 women enrolled between 2009 and 2012 at the University of Oklahoma. Tissue-based genotyping, including whole tissue sections (WTS) and laser-capture microdissection (LCM), was performed on all precancers with multiple hrHPV infections detected in cytology, totaling over 1,800 HPV genotyping assays. Genotype attribution was compared to hierarchical and proportional hrHPV-type attribution models. Of 276 women with CIN2+, 122 (44.2%) had multiple hrHPV genotypes in cytology. Of 114 women with genotyping data, 94 had one or more hrHPV detected in tissue. Seventy-one women (75.5%) had a single causal hrHPV genotype, while 23 women had multiple hrHPV genotypes causing CIN2+. Ten women had multiple causal infections in a single biopsy, contrary to the previous notion that each lesion is caused by a single type only. While HPV16 was the predominant causal hrHPV genotype using all approaches, the hierarchical model overattributed HPV16, whereas other causal hrHPV genotypes, particularly HPV18 and HPV35, were underattributed. Understanding true causal genotypes is important for the evaluation of vaccine efficacy, to estimate the extent of unmasking, and for type-specific risk assessment in screening and management.     

Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort

Endometrial cancer (EC) incidence rates vary ~10-fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low-risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow-up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m²), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m²) and HT use (to all non-HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks.