The effects of different types of acute bouts of resistance exercise on autonomic modulation in individuals that are resistance-trained compared to untrained individuals are unknown. Seventeen untrained and 17 resistance-trained participants were assessed for autonomic modulation after various acute resistance exercise bouts. Electrocardiogram readings were collected at rest and 25 min after a control period, whole-, lower-, or upper-body acute bouts of resistance exercise. Heart rate variability and heart rate complexity were used to assess autonomic modulation. Participants were similar for age, height, weight and measures of body composition (p>0.05) and were different for measures of maximal strength (p<0.05). There were no differences (p>0.05) in autonomic modulation at rest between groups. Significant decreases (p<0.05) in parasympathetic modulation after the acute bouts of resistance exercise were noted. Sample entropy was not affected in the untrained group, but was significantly decreased after whole- (-17.5%) and upper-body exercise (-13.5%) in the resistance training group. The changes in sample entropy after lower-body resistance exercise were not significant (-15.7%; p=0.06). These data suggest that resistance exercise training further attenuates the parasympathetic responses to an acute bout of resistance training regardless of the modality compared to the untrained state.

# These authors contributed equally to this work. AbstractPurpose-We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201 binding peptide CAP-1 from carcinoembryonic antigen ) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin.Experimental Design-Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (Arm-I) and 12 patients without radiological evidence of disease (Arm-II). Six intramuscular vaccinations of naked DNA (1mg/dose) were administered up to week 12. Clinical and immunological follow-up was to week 64 or clinical/ radiological disease.Results-DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared to 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8 + T-cells, respectively. CAP-1-specific T-cells were only detectable in the blood post-vaccination, but could also be identified in previously resected cancer tissue. The gastrointestinal adverse event diarrhea was reported by 48% of patients and linked to more frequent decreases in CEA (p<0.001) and improved global immunological responses (anti-DOM responses of greater magnitude (p<0.001), frequency (p=0.004) and duration) compared to patients without diarrhea. In advanced disease patients, decreases in CEA were associated with better overall survival (HR=0.14, p=0.017). CAP-1 peptide was detectable on MHC class I of normal bowel mucosa and primary colorectal cancer tissue by mass-spectrometry, offering a mechanistic explanation for diarrhea through CD8 + T-cell attack.Conclusions-Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody.

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2525 Background: GSK1070916A is a potent and selective inhibitor of Aurora B and C. This phase I study in collaboration with GlaxoSmithKline was part of the Cancer Research UK Clinical Development Programme. Methods: Patients (pts) with advanced/metastatic solid cancers for whom there was no standard therapy, with adequate performance status and organ function were eligible for GSK1070916A (1 hour i.v. infusion days 1 – 5, every 21 days). The primary objectives were to determine the safety profile, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of GSK1070916A. The starting dose was 5mg/m2/day, with initial single pt cohorts, followed by “3 + 3” cohorts and expansion at the MTD. DLTs included prolonged (> 5 days) or complicated grade 4 neutropenia; the MTD was the highest dose at which < 1 of 3 - 6 pts experienced DLT. Cycle 1 blood and healthy skin biopsies were obtained for PK and PD assays. The expanded cohort included 6 pts having pre- and post-treatment functional imaging studies (FDG PET-CT and MRI), and a further 6 having paired tumour biopsies for PD studies. Results: Nine single pt cohorts received up to 73mg/m2/day of GSK1070916A with no grade 3 or 4 related adverse events. At 102.2mg/m2/day, 1 pt had a DLT (febrile neutropenia) and 2 pts non-DLT grade 4 neutropenia; this dose was considered unacceptably toxic and 23 pts received a lower dose of 85mg/m2/day; 7/23 pts had prolonged/complicated grade 4 neutropenia, 5 of whom continued GSK1070916A with dose reduction +/- delay. There were no treatment related deaths. A pt with ovarian cancer (102.2mg/m2/day) had a RECIST PR; 19 pts had stable disease for < 223 days. GSK1070916A PK were linear with a strong correlation between exposure (AUC) and reduction in neutrophils (r2 0.91). At the 85 mg/m2 dose, mean day 1 t1/2 was 8.98 hours and Cl 9.2 l/h; AUCinf was 10% higher on day 5 than day 1. PD results in healthy skin (phosphoHistone-H3, Ki 67 and cleaved caspase-3) were inconsistent. Conclusions: The MTD of GSK1070916A as a 1 hour i.v. infusion on days 1 – 5, every 21 days is 85mg/m2/day, with predictable and manageable neutropenia as the DLT and evidence of clinical activity. Serum levels of cytokeratin-18, tumour PD and functional imaging data will be presented. Clinical trial information: NCT01118611.

<p>Supplementary Figure S1: Detection of CAP-1-specific T-cells Supplementary Figure S2: Effect of CAP-1-specific responses on OS Supplementary Figure S3: Effect of tumor load on vaccine-induced responses Supplementary Figure S4: Discovery of CAP-1-specific TCRs Supplementary Figure S5: Effect of diarrhea on OS Supplementary Figure S6: Effect of diarrhea and CEA drops on OS Supplementary Table S1: MIATA Supplementary Table S2: CAP-1-specific TCRs</p>