Adjuvant Dose Research Articles

Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands Work Additively via MyD88 To Induce Protective Antiviral Immunity in Mice.

We previously demonstrated that the combination of synthetic small-molecule Toll-like receptor 4 (TLR4) and TLR7 ligands is a potent adjuvant for recombinant influenza virus hemagglutinin, inducing rapid and sustained immunity that is protective against influenza viruses in homologous, heterologous, and heterosubtypic murine challenge models. Combining the TLR4 and TLR7 ligands balances Th1 and Th2-type immune responses for long-lived cellular and neutralizing humoral immunity against the viral hemagglutinin. Here, we demonstrate that the protective response induced in mice by this combined adjuvant is dependent upon TLR4 and TLR7 signaling via myeloid differentiation primary response gene 88 (MyD88), indicating that the adjuvants function in vivo via their known receptors, with negligible off-target effects, to induce protective immunity. The combined adjuvant acts via MyD88 in both bone marrow-derived and non-bone marrow-derived radioresistant cells to induce hemagglutinin-specific antibodies and protect mice against influenza virus challenge. The protective efficacy generated by immunization with this adjuvant and recombinant hemagglutinin antigen is transferable with serum from immunized mice to recipient mice in a homologous, but not a heterologous, H1N1 viral challenge model. Depletion of CD4+ cells after an established humoral response in immunized mice does not impair protection from a homologous challenge; however, it does significantly impair recovery from a heterologous challenge virus, highlighting an important role for vaccine-induced CD4+ cells in cross-protective vaccine efficacy. The combination of the two TLR agonists allows for significant dose reductions of each component to achieve a level of protection equivalent to that afforded by either single agent at its full dose.IMPORTANCE Development of novel adjuvants is needed to enhance immunogenicity to provide better protection from seasonal influenza virus infection and improve pandemic preparedness. We show here that several dose combinations of synthetic TLR4 and TLR7 ligands are potent adjuvants for recombinant influenza virus hemagglutinin antigen induction of humoral and cellular immunity against viral challenges. The components of the combined adjuvant work additively to enable both antigen and adjuvant dose sparing while retaining efficacy. Understanding an adjuvant's mechanism of action is a critical component for preclinical safety evaluation, and we demonstrate here that a combined TLR4 and TLR7 adjuvant signals via the appropriate receptors and the MyD88 adaptor protein. This novel adjuvant combination contributes to a more broadly protective vaccine while demonstrating an attractive safety profile.

171P - Composite index of risk shows that benefit from adjuvant dose dense chemotherapy is not confined to triple negative breast cancer

Background: Compared with the standard interval adjuvant chemotherapy, dose-dense schedule is proved to increase disease-free survival (DFS) in node-positive early breast cancer (EBC) patients (pts). To date, GIM2 is the only trial supporting the role of dose-dense chemotherapy in pts with hormone receptor-negative (HR-) or hormone receptor-positive tumours (HR+) (Del Mastro et al. Lancet 2015). To further refine the evidence of treatment effect in the HR+ subgroup, a composite index of risk was developed including clinico-pathological features. Methods: The randomized phase III GIM2 trial enrolled 2091 pts with node-positive EBC (primary endpoint: DFS). A continuous, composite measure of treatment benefit was determined from a Cox model incorporating potential predictive factors (age: 25-40/41-55/56-71; histological grade: 1 + 2/3; HR status: positive/negative; ki-67 levels: ≤20%/>20%). Subpopulation treatment effect pattern plot methodology was used to reveal differential treatment effects on DFS according to composite index. The study analyzed the cohort of pts with HER2- (N = 1127) disease with a special focus on HR+ disease (N = 980). Results: On average, the magnitude of benefit with dose dense chemotherapy versus standard chemotherapy widely varied according to composite measure of specific features. In the HER2- subgroup, the highest benefit was observed in pts with G3, HR-, >10 positive nodes, age <40 yrs, ki-67 > 20% (hazard ratio for DFS 0.57, 95% CI 0.35-0.94). Notably, among pts with HR+ disease, the following clinic-pathological characteristics conferred the highest benefit: G3, ≥4 positive nodes, age ≥56 yrs, ki-67 > 20% (hazard ratio for DFS 0.66, 95% CI 0.38-1.15). Conclusions: Composite risk evaluation and corresponding subpopulation treatment effect pattern plot methodology suggest that benefit of dose dense adjuvant chemotherapy is not confined to triple negative EBC. Legal entity responsible for the study: Gruppo Italiano Mammella Funding: None Disclosure: All authors have declared no conflicts of interest.

The dual trigger study: Rationale and study design of a prospective double-blind randomized clinical trial comparing pregnancy rates after co-administration of low dose hCG at the time of GnRH agonist trigger or 35h later for the prevention of OHSS.

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian stimulation. The use of gonadotropin releasing hormone (GnRH) agonist for the trigger of oocyte maturation is effective in the prevention of OHSS although it may result in a lower pregnancy rate. The use of adjuvant low dose human chorionic gonadotropin (hCG) at the time of trigger or at the time of oocyte retrieval may improve pregnancy rates. The goal of this dual trigger study is to evaluate the safety and efficacy of the use of low dose hCG administered at the time of GnRH agonist trigger or 35 h later as well as the potential impact on pregnancy rates. The population will consist of 82 women undergoing IVF treatment who are at risk of developing OHSS. This study will be a single center prospective randomized double-blind placebo controlled trial. The randomization schedule will be administered by the Investigational Drug Services of the University. After controlled ovarian stimulation, induction of oocyte maturation will be achieved using a GnRH agonist and patients will be randomized to receive either low dose hCG 1000 IU at the time of trigger and placebo at oocyte retrieval (Study group) or placebo at the time of trigger and hCG 1500 IU at the time of oocyte retrieval (Control group). The main outcomes will be live birth rates and incidence of OHSS. Two ancillary studies will include a quality of life survey and serum assessment of independent corpus luteum function.

Identifying an Optimal Adjuvant Radiotherapy Dose for Extremity and Trunk Merkel Cell Carcinoma Following Resection

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine neoplasm with a high risk of recurrence following resection. Despite a rising incidence over the past 3 decades, there is a paucity of prospective data owing to the rarity of this disease. To determine the optimal adjuvant radiation therapy (RT) dose following resection of localized MCC of the extremities or trunk. Using the National Cancer Database, a large national database consisting of a heterogeneous population and treatment settings, we retrospectively analyzed a cohort of 2093 patients 18 years or older with stage I to III MCC of the extremities and/or trunk treated with definitive surgery and adjuvant RT between 1998 and 2011. Exclusion criteria included receiving treatment with palliative intent, preoperative RT, non-external-beam RT, and radiation dose of 30 Gy or lower or 70 Gy or higher. Cox proportional hazards regression model was used to compare overall survival (OS) between RT dose groups, accounting for age, sex, race, stage, surgery type, margin status, comorbidities, and use of chemotherapy. Radiation therapy dose was categorized into 4 groups: group 1 received the lowest dose (>30 to <40 Gy); group 2, the next lowest (40 to <50 Gy); group 3, the second highest dose (50 to 55 Gy); and group 4, the highest dose (>55 to 70 Gy). Overall survival. Data from 2093 patients were analyzed; there were 1293 men (61.8%) and 800 women (38.2%) (median age, 73 years). After a median follow-up of 37 months for the entire cohort, 904 deaths were reported. The 3-year OS rates for groups 1, 2, 3, and 4 were 41.8%, 69%, 69.2%, and 66%, respectively (omnibus P < .001). Compared with group 3 (50 to 55 Gy), equivalent OS was seen in group 2 (40 to <50 Gy; adjusted hazard ratio [AHR], 0.89; 95% CI, 0.63-1.27; P = .52) and group 4 (>55 to 70 Gy; AHR, 1.18; 95% CI, 0.93-1.48; P = .17), but worse OS was found in group 1 (>30 to <40 Gy; AHR, 2.63; 95% CI, 1.44-4.80; P < .001). Adjuvant RT dose from 40 to lower than 50 Gy appears adequate for extremities and/or trunk stage I to III MCC, with OS equivalent to that found at higher-dose regimens (>50 to 70 Gy).

Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial.

BackgroundKetamine has recently become an agent of interest as an acute treatment for severe depression and as the anaesthetic for electroconvulsive therapy (ECT). Subanaesthetic doses result in an acute reduction in depression severity while evidence is equivocal for this antidepressant effect with anaesthetic or adjuvant doses. Recent systematic reviews call for high-quality evidence from further randomised controlled trials (RCTs).AimsTo establish if ketamine as the anaesthetic for ECT results in fewer ECT treatments, improvements in depression severity ratings and less memory impairment than the standard anaesthetic.MethodDouble-blind, parallel-design, RCT of intravenous ketamine (up to 2 mg/kg) with an active comparator, intravenous propofol (up to 2.5 mg/kg), as the anaesthetic for ECT in patients receiving ECT for major depression on an informal basis. (Trial registration: European Clinical Trials Database (EudraCT): 2011-000396-14 and clinicalTrials.gov: NCT01306760.)ResultsNo significant differences were found on any outcome measure during, at the end of or 1 month following the ECT course.ConclusionsKetamine as an anaesthetic does not enhance the efficacy of ECT.

Long term follow up of patients with locally advanced triple negative breast cancer treated with adjuvant high dose chemotherapy and autologous stem cell transplantation: A single center experience.

e12590 Background: Adjuvant high dose chemotherapy (HDC) with Autologous Hematopoietic Stem Cell Transplantation (AuSCT) as part treatment of high risk locally advanced breast cancer has remained controversial. Multiple trials reported disease free survival (DFS) without Overall survival (OS) resulting in its abandonment in early 2000s. However, post hoc analysis of these trials consistently reported DFS and OS benefit in young and triple negative breast cancer (TNBC) subgroups. This has not been re-evaluated till date. Recent European registry reports coupled with improved transplant related mortality (TRM) and still poor out-come of standard of care in TNBC subgroup has generated renewed interest. We report long term out-come of locally advanced high risk TNBC treated with HDC and AuSCT treated in Karmanos Cancer Institute from 1995 to 2001 Methods: Majority of the patients were treated with Adriamycin and Taxane based induction chemotherapy. Patients without evidence of metastatic disease proceeded to HDC and AuSCT using Carmustine 600mg/sqm Cyclophosphamide 5.6gm/sqm and Cisplatin 165mg/sqm (STAMP 1 regimen). This is followed with loco- regional radiation per protocol. Results: 72 hormone negative patients with Lymph Node(LN) &gt; 4 or inflammatory breast cancers were selected from 576 treated for advanced or metastatic breast cancer. 33 patients were TNB with HER2 status of 39 patients unknown. Median time from diagnosis to stem cell transplantation was 6 months. Median age at diagnosis was 47yrs. Mean LN involvement was 9 with 90% having (4-20) LN positivity. With median follow up of 16 years,10yrs DFS and OS were both 62.5%. Median follow up for DFS and OS was not reached.TRM was 9% mostly from pulmonary toxicity. Conclusions: This study of locally advanced high risk TNBC treated with adjuvant HDC and AuSCT have high 10yr OS of 62.5% compared to current standard of care. With the current improvement in TRM, reevaluation of this strategy through clinical trials in this subgroup whose outcome remain poor is reasonable.

Use of circulating tumor DNA to predict survival in patients with resected high-risk stage II/III melanoma.

9583 Background: Patients with high-risk stage II/III resected melanoma commonly develop metastatic disease. Adjuvant high dose interferon and ipilimumab 10mg/kg are associated with survival benefit, but at the expense of toxicity. At present, we cannot differentiate between patients who will progress to stage IV disease or those cured by surgery. Circulating tumor DNA (ctDNA) is a biomarker of disease progression in many cancers including stage IV melanoma, however its utility in the adjuvant setting has not been investigated. Methods: We performed droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma of 161 stage IIB, IIC/III high-risk melanoma patients enrolled in AVAST-M; a randomized study of bevacizumab vs. observation. Baseline plasma samples were collected within 12 weeks of surgery for both arms. Results: Mutant BRAF or NRASctDNA was detectable ( &gt; 1 copy of mutant ctDNA) in 12% (19/161) of patients. Patients with detectable ctDNA had a decreased disease free interval (DFI; hazard ratio [HR] 3.12; 95% confidence interval [CI] 1.79-5.47; p &lt; 0.0001) and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80-5.79; p &lt; 0.0001) vs. those with undetectable ctDNA. One year DFI rate for patients with detectable ctDNA was 26% (95% CI 10-47%) vs. 74% (95% CI 66-81%) for those with undetectable ctDNA. One year DMFI rate for patients with detectable ctDNA was 37% (95% CI 17-57%) vs. 84% (95% CI 77-89%) with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for N classification and performance status (PS) (DFI HR 3.48; 95% CI 1.95-6.19, p &lt; 0.0001; DMFI HR 3.41, 95% CI 1.88-6.20, p &lt; 0.0001). Five year overall survival (OS) rate for patients with detectable ctDNA was 33% (95% CI 14-55%) vs. 65% (95% CI 56-72%) for those with undetectable ctDNA. OS was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.4-4.96); p = 0.003) and remained significant after adjustment for PS (HR 2.5, 95% CI 1.32-4.74, p = 0.005). Conclusions: CtDNA is predictive of relapse and survival in high-risk, resected melanoma and can potentially aid stratification of patients for adjuvant therapy.

Multicenter phase 2 study to identify the optimal neo-adjuvant combination scheme of ipilimumab (IPI) and nivolumab (NIVO) (OpACIN-neo).

TPS9600 Background: The outcome of high risk stage IIIb and IIIc melanoma patients is poor, with a 5 year overall survival (OS) rate of &lt; 50%. Adjuvant high dose IPI significantly improves 5 year progression free survival (PFS) and OS. In stage IV patients the combination of IPI and NIVO improves response rates (RR) and PFS compared to monotherapy, but at cost of higher toxicity. Neo-adjuvant treatment may be a favorable approach as immune checkpoint inhibition (ICI) is of greatest value at the moment of TCR triggering and therefore dependent on the amount of antigen present. The phase Ib OpACIN study comparing neo-adjuvant and adjuvant IPI and NIVO showed that neo-adjuvant treatment is feasible as all patients underwent surgery on time. The neo-adjuvant pathological RR was 80%, although 18/20 patients (90%) stopped early due to ≥1 grade 3 or 4 immune-related adverse events (irAEs). To date (median follow-up 45 wks), none of the 8 responders in the neo-adjuvant arm have relapsed. This raises the question whether the neo-adjuvant IPI and NIVO schedule can be adjusted to reduce toxicity but preserve efficacy. Methods: The aim of the multi-center phase 2 OpACIN-neo trial is to identify an optimal neo-adjuvant combination scheme of IPI and NIVO. 90 patients with resectable stage III melanoma will be randomized 1:1:1 between three combination schemes of IPI and NIVO. Patients in arm A will receive 2 courses standard regimen IPI 3mg/kg + NIVO 1mg/kg q3wks, in arm B IPI 1mg/kg + NIVO 3mg/kg q3wks, and in arm C 2 courses of IPI 3mg/kg q3wks directly followed (2-24hr) by 2 courses NIVO 3mg/kg q2wks. All patients will undergo surgery at week 6. The primary endpoints are rate of grade 3/4 irAEs, pathological RR, and radiologic RECIST 1.1. An interim analysis is planned after 13 patients have been accrued to each arm (according to the Simon 2-stage design). Major inclusion criteria are: ≥1 measurable lymph node metastases (according to RECIST 1.1) that can be biopsied, no history of in-transit metastases in the last 6 months, and naïve for ICI. Baseline biopsies and blood samples (week 0, 6, 12) will be taken for translational research. The first center started inclusion in December 2016, until now 2 patients have been enrolled. Clinical trial information: NCT02977052.

Defluoridation of South Tunisian Brackish Water by Alum Coagulation/Flocculation: A Preliminary Work

Fluoride removal from aqueous solution was investigated using the chemical coagulation-flocculation by alum in reason of the efficiency and the simplicity of the process. Preliminary experiments were carried out to study the effect of some operating parameters such as: pH, initial fluoride concentration, coagulant dose, adjuvant coagulation dose, flocculent dose and settling time. Obtained experimental results showed that the treatment of fluoride by alum coagulation causes acidification of the solution. The effect of the initial pH solution on fluoride removal is negligible. Experimental results proved that coagulation process is effective in waters with low or medium levels of fluoride. Defluoridation rate was seen to increase with increasing coagulant and adjuvant coagulation doses. Optimal flocculent dose and optimal settling time were found 4.2 mg L-1 of FABI and 60 min respectively. Subsequently, experimental design methodology using two-level full factorial design was applied to optimize the defluoridation by coagulation-flocculation. Therefore, four operating parameters which are supposed to affect the removal efficiency were chosen: initial fluoride concentration, coagulant dose, coagulation adjuvant dose and settling time. From the statistical analysis, it is inferred that the four studied parameters have an influence on the fluoride removal. In fact, initial fluoride concentration has a positive effect unlike coagulant dose, coagulation adjuvant dose and settling time. Experiment tests were performed to evaluate the efficiency of coagulation-flocculation process for south Tunisian brackish water with high fluoride concentration. The obtained results showed that fluoride removal reached 59%.

Indirect effects of immunological tolerance to a regular dietary protein reduce cutaneous scar formation.

Oral tolerance refers to the specific inhibition of immune responsiveness to T-cell-dependent antigens contacted through the oral route before parenteral immunization. Oral tolerance to one protein does not inhibit immune responses to other unrelated proteins, but parenteral injection of tolerated antigens plus adjuvant into tolerant, but not normal, mice inhibits immune responses to antigens injected concomitantly or soon thereafter. The inhibitory effect triggered by parenteral injection of tolerated proteins is known as bystander suppression or indirect effects of oral tolerance. Intraperitoneal injection of ovalbumin (OVA) plus alum adjuvant in OVA-tolerant mice soon before skin injury inhibits inflammation and improves cutaneous wound healing. However, as OVA is not a regular component of mouse chow, we tested whether indirect effects could be triggered by zein, the main protein of corn that is regularly present in mouse chow. We show that intraperitoneal injection of a single dose (10μg) of zein plus alum adjuvant soon before skin injury in mice reduces leucocyte infiltration but increase the number of T cells and the expression of resistin-like molecule-α (a marker of alternatively activated macrophages) in the wound bed, increases the expression of transforming growth factor-β3 in the newly formed epidermis and reduces cutaneous scar formation. These results suggest that indirect effects of oral tolerance triggered by parenteral injection of regular dietary components may be further explored as one alternative way to promote scarless wound healing.

Prognostic factors in prostate cancer patients treated by radical external beam radiotherapy.

The aim of this paper was to analyze, retrospectively, in prostate cancer patients treated in our Centre with external beam radiotherapy, the prognostic factors and their impact on the outcome in terms of cancer-specific survival (CSS), biochemical disease-free survival (BDFS) and clinical disease-free survival (CDFS). From October 1999 and March 2012, 1080 patients were treated with radiotherapy at our Institution: 87% of them were classified as ≤cT2, 83% had a Gleason Score (GS) ≤7, their mean of iPSA was 18 ng/mL, and the rate of clinical positive nodes was 1%. The mean follow-up was 81 months. The statistically significant prognostic factors for all groups of patients at both, univariate and multivariate analysis, were the GS and the iPSA. In intermediate- and high- or very-high-risk patients at multivariate analysis other prognostic factors for CSS were positive nodes on computed tomography (CT) scan and rectal preparation during the treatment; for BDFS, the prognostic factors were patient risk classification, positive lymph nodes on CT scan and rectal/bladder preparation; for CDFS, the prognostic factors were the number of positive core on biopsy (P=0.003), positive lymph nodes on CT scan, and radiotherapy (RT) dose. In high/very-high risk patient group at multivariate analysis other prognostic factors for CSS were clinical/radiological stage and RT dose, for BDFS they were adjuvant hormone therapy, clinical/radiological stage, and RT dose >77.7 Gy, and for CDFS they were clinical/radiological stage and RT dose >77.7 Gy. The results of this study confirm the prognostic factors described in the recent literature, with the addition of rectal/bladder preparation, generally known for its effect on toxicity but not yet on outcome.

Role of low-molecular-weight heparins in prevention of thromboembolic complication after transarterial chemoembolization in hepatocellular carcinoma.

Portal vein thrombosis (PVT) is a common complication after transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). This is the first clinical study to evaluate the role of low-molecular-weight heparins (LMWHs) with TACE in HCC for the prevention of thromboembolism complications (PVT). This study was carried out on 40 patients with HCC requiring TACE who presented to the Tropical Medicine Department, Tanta University and Interventional Radiology Department of Ain-Shams University Hospitals starting from April 2015. Patients were divided in two groups: group I included 20 patients with HCC treated by TACE only. Group II included 20 patients with HCC treated by TACE and an adjuvant dose of LMWH. Radiological assessment of efficacy of procedure and detection of PVT as a complication was performed using ultrasound abdomen and pelvis and triphasic spiral computed tomography with contrast. This study was carried out on 40 patients with HCC requiring TACE who presented to the Tropical Medicine Department of Tanta University and Interventional Radiology Department of Ain-Shams University Hospitals. The incidence of PVT after TACE was higher in group I than group II, with seven cases in group I and only one case in group II. LMWH with TACE in HCC is strongly recommended for prevention of thromboembolism complications (PVT). However, larger randomized-controlled studies are needed to confirm these obvious findings.

Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials

BackgroundNovel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant. MethodsBCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150μg) and adjuvant (0, 100, 500nmol) doses of the H4:IC31 vaccine (n=106) or placebo (n=18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4+ T cell responses. ResultsH4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4+ T cell proliferation and cytokine production that persisted 18weeks after the last vaccination. CD4+ T cell expansion, IFN-γ production and multifunctional CD4+ Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50μg of H4 in combination with the 500nmol IC31 adjuvant dose. ConclusionsThe novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4+ T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50μg of H4 and 500nmol of IC31.Trial registration: ClinicalTrials.gov, NCT02066428 and NCT02074956.

Abstract P5-14-03: Adjuvant dose dense doxorubicin-cyclophosphamide (ddAC) or docetaxel-AC (TAC) for high-risk breast cancer: First results of the randomized MATADOR trial (BOOG-2004-04)

Abstract Background: Anthracycline-based adjuvant chemotherapy has substantially improved breast cancer survival. Both the addition of taxanes as well as using a dose dense treatment schedule can further ameliorate outcome, but inter-individual differences exist. Here we present the efficacy and toxicity of dose dense scheduled doxorubicin/cyclophosphamide (ddAC) versus docetaxel/doxorubicin/cyclophosphamide (TAC), which is, to our knowledge, the first direct comparison of these treatment regimens. Methods: In this Dutch, multicenter phase III trial (ISRCTN61893718), patients with pT1-3, pN0-3, M0 breast cancer were randomized between six cycles of either A60C600 every 2 weeks or T75A50C500 every 3 weeks. All patients received pegfilgrastim. Patients were evaluated for recurrence-free survival (RFS) and overall survival (OS). Survival was compared in a Cox regression analysis and adjusted for known prognostic factors. These factors include age, type of surgery, tumor size, histological grade, ER/PR status, HER2 status, and lymph node status. Adverse events were reported according to the common toxicity criteria (CTCAE version 3.0). Results: Between 2004 and 2012, 664 patients were enrolled of whom 531 (80%) had node positive disease. At a median follow up of 5 years, OS was 92% in the ddAC treated subgroup and 93% in the TAC treated subgroup (adjusted hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.42-1.34, intention to treat population). Forty-two breast-cancer specific deaths were equally divided over both treatment arms. Similarly, no significant difference in RFS was observed between both treatment groups (adjusted HR 0.85, 95% CI 0.55-1.32). Molecular subtypes were defined by St. Gallen criteria: 548 patients (83%) had estrogen receptor positive disease and 102 patients (15%) triple negative disease. No heterogeneity regarding treatment efficacy was observed in these subtypes. In particular, there was no survival benefit for ddAC or TAC in the triple negative subtype. Both treatment regimens were well tolerated. Whereas anemia was more frequent in ddAC treated patients (19% vs 4.7%; p&amp;lt;0.001), peripheral neuropathy occurred more frequently in TAC treated patients (4.6% vs 14.4%; p&amp;lt;0.001). The frequency of febrile neutropenia was not significantly different between the treatment arms (11% vs 12.5%; n.s.). Six patients developed congestive heart failure: 2 ddAC treated patients, 4 TAC treated patients. One ddAC treated patient and one TAC treated patient were diagnosed with acute myeloid leukemia after study treatment; another patient in the ddAC treatment group developed myelodysplastic syndrome. Conclusions: At a median follow up of 5 years no significant survival differences were observed between adjuvant ddAC and TAC, in all patients and in molecular subgroups, including triple negative. Our findings are in line with the Oxford overview, which reported no significant differences between taxane-based chemotherapy and more, non-taxane based chemotherapy given in a dose dense schedule. ddAC could be a reasonable alternative for patients with a contra-indication for TAC. Citation Format: van Rossum AGH, Oosterkamp HM, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok E, van Tinteren H, Kok M, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Rodenhuis S, Linn SC. Adjuvant dose dense doxorubicin-cyclophosphamide (ddAC) or docetaxel-AC (TAC) for high-risk breast cancer: First results of the randomized MATADOR trial (BOOG-2004-04) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-14-03.

Potent Immune Stimulation from Nanoparticle Carriers Relies on the Interplay of Adjuvant Surface Density and Adjuvant Mass Distribution.

Development of novel adjuvant delivery approaches which provide safe and effective immune stimulation are critical for prophylactic and therapeutic advances in a wide range of diseases. Toll-like receptor agonists (TLRas) have been identified as potent stimulators of antigen presenting cells (APCs) and are capable of inducing proinflammatory immune responses desirable for vaccine and immunostimulatory applications. Although TLRas have been successfully incorporated into nanoparticle platforms, minimal work has been done to evaluate the direct role of the adjuvant incorporation in these formulations in directing the immune response. Here, we developed a series of nanoparticle carriers with controlled surface densities of two TLRas, lipopolysaccharide (LPS), corresponding to TLR-4, and CpG oligodeoxynucleotide, corresponding to TLR-9. The proinflammatory cytokine production and expression of costimulatory molecules on APCs were evaluated following a 24 h particle incubation period in vitro using bone marrow derived macrophages and in vivo following particle instillation in the airway of mice. Results demonstrate that proinflammatory cytokine production is predominantly driven by the distribution of the adjuvant dose to a maximal number of cells, whereas the upregulation of costimulatory molecules needed to drive APC maturation and promote adaptive responses indicate the requirement of an optimal density of TLRa on the particle surface. These results indicate that adjuvant surface density is an important parameter for tight control of immune stimulation and provide a foundation for pathogen mimicking particle (PMP) vaccines and immunostimulatory therapeutics.

Abstract P4-21-23: A retrospective evaluation of cardiovascular recovery and oncologic outcomes associated with interrupted and continuous adjuvant trastuzumab in the setting of mild left ventricular dysfunction

Abstract Background: Trastuzumab is a monoclonal antibody that targets the HER2 receptor. In the adjuvant setting, 12 months of trastuzumab therapy has been shown to significantly reduce the risk of cancer recurrence. However, treatment with trastuzumab may also be associated with a decline in left ventricular (LV) function that, in most cases, will recover after trastuzumab therapy is stopped. When severe or symptomatic left ventricular dysfunction (LVD) occurs, trastuzumab is generally held with the intention of restoring cardiac function. It is less clear how to manage trastuzumab to optimize both cancer therapy and cardiovascular care when mild, asymptomatic drops in LV function are observed. The intention of this study was to assess how trastuzumab was managed immediately after the development of mild LVD in a non-trial setting and evaluate these outcomes. Methods: Patients who received adjuvant trastuzumab therapy for breast cancer between September 2005 and September 2010 in British Columbia were identified. Heart function imaging data for these patients were subsequently reviewed to identify those who experienced either a drop in LV ejection fraction (LVEF) to 40-49% or a greater than 15% drop in LVEF relative to their pre-chemotherapy baseline to a final LVEF ≥50%. The charts of patients who met these inclusion criteria were then reviewed for demographic information, comorbidities, trastuzumab dosing regime, subsequent cardiac events, and breast cancer outcomes. Results: A total of 171 patients were included in this study. 121 (70.8%) patients had an immediate hold in their trastuzumab therapy while the remaining 50 (29.2%) continued with their next scheduled dose. The number of patients who experienced a cancer relapse event in the therapy interruption and continuation groups were 21 (17.4%) and 5 (10.0%), respectively (P = 0.25). Cardiovascular events in the therapy interruption group included a subsequent drop in LVEF to &amp;lt;40% in 11 (9.1%) patients, long-term congestive heart failure (CHF) in 2 (1.7%) patients, and 1 (0.9%) death related to CHF. Cardiovascular events in the therapy continuation group included a subsequent drop in LVEF to &amp;lt;40% in 3 (6.0%) patients and long-term CHF in 1 (2.0%) patient. 24 (19.8%) patients in the therapy interruption group had a final LV function measurement that had fallen more than 10% below their baseline value while 12 (24.0%) patients in the therapy continuation group met this criterion (P=0.54). The mean numbers of adjuvant trastuzumab doses administered in the therapy interruption and continuation groups were 11.3 and 14.3, respectively. Finally, mean follow up times for the therapy interruption and continuation groups were 5.6 and 5.8 years, respectively. Conclusions: Continuing trastuzumab immediately after the development of mild LVD did not appear to be associated with an increased risk of long-term cardiovascular events. However, holding trastuzumab immediately after the development of mild LVD appeared to be associated with a 7.4% absolute risk increase in breast cancer recurrence. While these results are not statistically significant, they are concerning and warrant further investigation. Citation Format: Gibson JD, Yao RJR, Davis MK, Simmons CE. A retrospective evaluation of cardiovascular recovery and oncologic outcomes associated with interrupted and continuous adjuvant trastuzumab in the setting of mild left ventricular dysfunction [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-23.

NEW POSSIBILITIES FOR THE DEVELOPMENT OF A COMBINED VACCINE AGAINST ETEC AND SHIGELLA

BackgroundTogether, enterotoxigenic Escherichia coli (ETEC) and Shigella contribute greatly to the mortality and the morbidity due to diarrhoeal diseases, including a number of negative lifetime health impacts. Vaccines represent a...

The treatment of acute and late vaginal toxicity after adjuvant high dose rate [HDR] vaginal brachytherapy in patients with intermediate risk endometrial cancer: Is local therapy with hyaluronic acid of clinical benefit?

The treatment of acute and late vaginal toxicity after adjuvant high dose rate [HDR] vaginal brachytherapy in patients with intermediate risk endometrial cancer: Is local therapy with hyaluronic acid of clinical benefit?

A novel vaccinological evaluation of intranasal vaccine and adjuvant safety for preclinical tests

Vaccines are administered to healthy humans, including infants, so the safety and efficacy must be very high. Therefore, evaluating vaccine safety in preclinical and clinical studies, according to World Health Organization guidelines, is crucial for vaccine development and clinical use. A change in the route of administration is considered to alter a vaccine’s immunogenicity. Several adjuvants have also been developed and approved for use in vaccines. However, the addition of adjuvants to vaccines may cause unwanted immune responses, including facial nerve paralysis and narcolepsy. Therefore, a more accurate and comprehensive strategy must be used to develope next-generation vaccines for ensuring vaccine safety. Previously, we have developed a system with which to evaluate vaccine safety in rats using a systematic vaccinological approach and 20 marker genes. In this study, we developed a safety evaluation system for nasally administered influenza vaccines and adjuvanted influenza vaccines using these marker genes. Expression of these genes increased dose-dependent manner when mice were intranasally administered the toxicity reference vaccine. When the adjuvant CpG K3 or a CpG-K3-combined influenza vaccine was administered intranasally, marker gene expression increased in a CpG-K3-dose-dependent way. A histopathological analysis indicated that marker gene expression correlated with vaccine- or adjuvant-induced phenotypic changes in the lung and nasal mucosa. We believe that the marker genes expression analyses will be useful in preclinical testing, adjuvant development, and selecting the appropriate dose of adjuvant in nasal administration vaccines.

Enhanced Potency and Durability of Antibody Response to Seasonal Trivalent Inactivated Influenza Vaccine (TIV) Combined with a Novel Water-in-Oil Adjuvant System at Reduced Hemagglutinin (HA) Doses

BackgroundNew influenza vaccines are needed to increase vaccine efficacy against infection and illness. Adjuvants may allow HA dose-sparing while increasing the antibody response. MAS-1 is an investigational low viscosity, free-flowing, water-in-oil emulsion-based adjuvant delivery system with stable nanoglobular droplets whether manufactured in bulk or at point-of-use (POU). MAS-1 oily vehicle is stable for at least 5 years at room temperature, in bulk or POU vials.MethodsA phase 1, double-blind, single-center, safety and immunogenicity, HA dose escalation trial was conducted. 1, 3, 5 or 9 µg per HA from the licensed 2014/15 seasonal TIV prepared POU with a fixed dose of MAS-1 adjuvant in 0.3 mL emulsion compared with standard dose (SD, 15 µg per HA) TIV in 0.5 mL was injected IM on day 1. Safety was measured by reactogenicity, adverse events, and safety labs. Serum hemagglutination inhibition (HAI) antibody titers were measured at 5 time points post-vaccination.Results72 subjects, age 18–47 years, were randomly assigned to either adjuvanted vaccine or TIV in a 2:1 ratio. The 1 and 3 µg per HA cohorts were enrolled together, then the 5 µg follo wed by the 9 µg per HA cohorts. Common injection site reactions were mild tenderness (74%) and pain (54%), resolving by 5 days post-vaccination. Common systemic reactions were mild headache (36%), myalgia (19%), malaise (18%) and fatigue (18%) through day 14 post-vaccination. Safety labs were not concerning. Geometric mean antibody titers against component strains were higher, of longer duration and peaked later in the adjuvanted vaccine groups than with SD TIV (Figures 1 – 3). Seroconversion rates (%) had a similar pattern:VaccineSubjects (N)Days Post-VaccinationA/H1 (%)A/H3 (%)B (%)1µg HA+MAS-112142533.3252833.341.741.7845060403µg HA+MAS-1121433.325252833.35033.38433.35016.75µg HA+MAS-1121441.741.750285058.350845058.358.39µg HA+MAS-1121466.75066.72866.75066.784757566.715µg HA SD TIV241429.245.825282533.320.8841326.18.7ConclusionMAS-1 adjuvant provided HA dose-sparing without significant systemic or local safety concerns, higher HAI antibody titers and seroconversion rates for a longer duration than SD TIV, and could conceivably contribute to greater vaccine efficacy.Disclosures G. J. Gorse, Nova Immunotherapeutics Limited: Principal Investigator at Saint Louis University, Funding to Saint Louis University for the clinical study; S. Grimes, Mercia Pharma, Inc.: Employee and Principal Scientist, Salary; H. Buck, Nova Immunotherapeutics Limited: Consultant, Consulting fee; H. Mulla, Nova Immunotherapeutics Limited: Employee, Salary; P. White, Nova Immunotherapeutics Limited: Employee, Salary; Mercia Pharma, Inc.: Shareholder, Licensing agreement or royalty; P. Blackburn, Mercia Pharma, Inc.: President and CSO, Salary