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We describe in this review the historical evidence leading up to the concept and design of Vigil and subsequent clinical applications including safety and efficacy in a randomized, controlled Phase IIB trial. Vigil (gemogenovatucel-T) is a unique triple function targeted immunotherapy that demonstrates preclinical and clinical systemic anticancer activity. Construction of Vigil involves harvest of autologous malignant tissue for neoantigen targeting (ideally containing clonal neoantigens) followed by a two-day process involving transfection with a plasmid to provide a permissive 'training environment' for the patient's immune system. Transfected plasmid components contain an expressive human GMCSF DNA segment to enhance anticancer immune functional response and a second component expressing bi-shRNAfurin which reduces TGFβ isomers (TGFβ1 and TGFβ2) thereby reducing cancer inhibition of the targeted immune response. Results generated to date justify advancement to confirmatory clinical trials supporting product regulatory approval. Plain Language Summary Vigil is an anticancer treatment that employs three methods of enhancing the body's immune system to identify and kill cancer cells. The construction of Vigil involves cancer cells from the same person being treated (personalized therapy) in combination with added anticancer genetic signals to enhance the number and function anti-anticancer immune cells and to guide the immune cells to the cancer and not to normal organs of the body. In this manner, an army of immune cells are created that can move to attacking the cancer using blood vessels to get to the cancer anywhere it tries to grow in the body. One study (Phase I) performed with this product to determine safety and dose range demonstrated an optimal dose and schedule. Another study (Phase IIA) showed initial clinical benefit. A third more complex study (Phase IIB) in patients treated with Vigil compared with standard of care without Vigil demonstrated the ability to prolong the patients life and time without their cancer getting worse without any significant side effects associated with the treatment in a unique subset of ovarian cancer patients, those with the ability to repair their DNA. Based on the composite of these results, Vigil is an attractive targeted immunotherapy justified for late-stage clinical testing. Article highlights Vigil is a novel triple function immunotherapy designed to deliver personalized clonal neoantigens. Historical background Expression of GMCSF has been extensively studied and demonstrates safety, efficacy and immune activation in various solid tumor malignancies. Modulation of both GMCSF and TGFβ impact anticancer immune response specifically related to clinical benefit in association with GMCSF up regulation and TGFβ down regulation. bi-shRNA mechanism bi-shRNA is designed to take advantage of both cleave-dependent and cleavage independent RISC loading thus decreasing mRNA and subsequent protein expression to block signals associated with cancer progression. Vigil: mechanism Vigil is constructed from autologous tumor cells transfected with a plasmid encoding a GMCSF expressive unit, bi-shRNA directed to furin and clonal neoantigens. Clonal neoantigens are associated with increased clinical benefit to immune therapies. Vigil plasmid Vigil plasmid is produced using GMP manufacturing. Vigil construction & product delivery Vigil is constructed via a 2 day manufacturing process consisting of tissue dissociation, electroporation and irradiation. Preparation of the drug product The drug substance is formulated to appropriate concentration using freeze media. Every Vigil batch/lot is tested for product release criteria which has been verified for regulatory suitability. Vigil clinical experience 230 patients have received 1433 doses over various clinical trials in solid tumors. Vigil Phase I testing in solid tumor cancer Phase I testing of Vigil demonstrated manufacturing optimization, appropriate dose, safety and immune response in advanced solid tumor patients. Vigil Phase I/II testing in Ewing's sarcoma Vigil has been tested as monotherapy and in combination with temozolomide/irinotecan in Ewings sarcoma and demonstrated safety and evidence of efficacy. Vigil Phase IIA/IIB evaluation in ovarian cancer In Phase IIA trial in newly diagnosed Stage IIIB/IV ovarian cancer patients, Vigil demonstrated immune activation via ELISpot assay which correlated with clinical benefit. In Phase IIB trial also in newly diagnosed Stage IIIB/IV ovarian cancer patients, Vigil demonstrated improved RFS and OS in BRCA-wt patients. This benefit was further enhanced in patients with HRP molecular profile. In both trials, Vigil demonstrated no ≥ Grade 3 adverse events. Vigil-related biomarkers Several biomarkers have been identified retrospectively including TP53 mutation, and high ENTPD1 expression. Conclusion Vigil demonstrates a strong safety profile combined with durable clinical benefit. [ABSTRACT FROM AUTHOR]

McGill, James M., Margaret S. Yen, Oscar W. Cummings, Gianfranco Alpini, Gene LeSage, Karen E. Pollok, Barbara Miller, Steven K. Engle, and Ann P. Stansfield. Interleukin-5 inhibition of biliary cell chloride currents and bile flow. Am J Physiol Gastrointest Liver Physiol 280: G738-G745, 2001.--Recent studies have detected significant elevations of interleukin (IL)-5 mRNA in the liver parenchyma of patients with both primary biliary cirrhosis and acute rejection after liver transplantation. In both of these disorders, intrahepatic biliary epithelial cells (BECs) are the targets of injury. We hypothesized that BECs may themselves express IL-5 receptors that may modulate key biliary functions. RNAs coding for IL-5[Alpha] and -[Beta] receptors were amplified by RT/PCR from a biliary cell line derived from a human cholangiocarcinoma (Mz-ChA-1) and verified by DNA sequencing. IL-5 receptor distribution was detected immunocytochemically on Mz-ChA-1 cells, immortalized murine BEC, bile duct-ligated rat liver, and isolated cholangiocytes. Patch-clamp studies on Mz-ChA-1 cells showed that IL-5 inhibits 5'-N-ethylcarboxamidoadenosine-stimulated chloride currents. Additional functional studies showed that IL-5 inhibits secretin-induced bile flow. We conclude that BECs express IL-5 receptors and that IL-5 modulates BEC chloride currents and fluid secretion. Since IL-5 has previously been associated with cholestatic liver disease, we speculate that IL-5 may contribute to liver injury through its effects on biliary secretion. cholestatic liver disease; chloride channel; patch-clamp recording

Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist. Male Sprague-Dawley rats aged 8 to 10 weeks were assigned to control, active control, swimming, or drug-induced cardiac hypertrophy groups. While the relative heart weights from both the swimming and drug-induced cardiac hypertrophy groups were increased 15% after 28 days of dosing, the serum NT-proANP and NT-proBNP values were only increased in association with cardiac hypertrophy caused by compound administration. Serum natriuretic peptide concentrations did not change in response to adaptive physiologic cardiac hypertrophy induced by a 28-day swimming protocol. These data support the use of natriuretic peptides as fluid biomarkers for the distinction between physiological and drug-induced cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Objective: Rapid electrical activity in pulmonary veins (PVs) has been proposed as a mechanism for focal atrial fibrillation. The way in which the myocardial sleeve inside PVs can form a substrate for focal activity is not well understood. Therefore, we have studied tissue structure and connexin distribution at the veno-atrial transition in the dog. Methods: In adult mongrel dogs, the anatomy of the PV area was studied. Tissue structure in individual veins was assessed in formalin fixed sections using Masson's Trichrome staining. Gap junction protein distribution was examined using antibodies against connexin40 (Cx40) and connexin43 (Cx43). The ultrastructure of myocytes in myocardial sleeves was studied using electron microscopy. Results: Individual PVs in the dog had a gross morphology similar to that observed in the human, with myocardial sleeves extending into the veins for 4–20 mm. In all veins examined, myocytes in myocardial sleeves had a normal atrial morphology and anti-desmin staining pattern. Cx43 was expressed throughout the sleeve at levels comparable to normal atrial myocardium. By contrast, Cx40 expression was lower in myocardial sleeves than in the rest of the left atrium. Myocytes in the sleeve, which were ultrastructurally similar to normal atrial myocytes, were predominantly organized in a circumferential pattern. Conclusions: PVs in the dog and various canine models of heart disease will be a suitable model for (patho)physiology of the veno-atrial transition. Myocytes in myocardial sleeves are similar to normal atrial myocytes. The circumferential orientation of these myocytes may provide a substrate for rapid circular reentry. [ABSTRACT FROM AUTHOR]

Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys33ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (P<0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.