Therapeutic monoclonal antibodies continue to achieve clinical success for the treatment of many different diseases, particularly cancer. However, the production and purification of antibodies continues to be a time and labor-intensive process with considerable technical challenges. Gene-based delivery of antibodies may address this, via direct production within the host that achieves therapeutic levels. In this report, we validate the feasibility that gene-based delivery is a viable approach for efficacious delivery of antibodies in the preclinical and, presumably, clinical setting. We demonstrate high and sustained in vivo expression of the murine antihuman epidermal growth factor receptor antibody 14E1 following intramuscular delivery by adeno-associated virus (AAV) 2/1. Incorporating the Furin/2A technology for monocistronic expression of both heavy and light chains, we achieved sustained serum levels of full-length 14E1 peaking over 1 mg ml À1 in athymic nude mice. In the A431 xenograft tumor model, 14E1was capable of significantly inhibiting tumor growth and prolonging survival when AAV was administered prior to tumor challenge. Furthermore, 14E1 demonstrated significant antitumor efficacy against well-established tumors (B400 mm 3 ) when AAV was administered up to 20 days after tumor challenge. Here we demonstrate for the first time growth inhibition of a well-established tumor by a full-length antibody following delivery by AAV.
Induced 10T1/2 cell microsomes were independently reconstituted with [3H]benzo[a]pyrene (BP) and glutathione (GSH) or purified GSH-transferases. Levels of the primary BP anti 7,8-dihydrodiol 9,10-epoxide (r-7,t-8 dihydroxy-t-9,10-oxy-7,8,9,10 tetrahydrobenzo[a]pyrene) hydrolysis product, 7,10/8,9-tetrol, were measured in incubation extracts, enabling us to monitor the level of free anti diol-epoxide in incubations and to determine the independent effects of GSH or GSH-transferases upon it. GSH alone had no effect on anti diol-epoxide levels over the concentration range tested (0-4.0 mM), however, the addition of purified GSH-transferase from rat liver resulted in a dose-dependent conjugation of anti diol-epoxide as well as 9,10-epoxide and 7,8-epoxide with 50% conjugation occurring at 0.036, 0.039 and 0.17 units GSH-transferase/ml, respectively. Free anti diol-epoxide was reduced by greater than 95% when we reconstituted with the GSH-transferase concentration which we measured in 10T1/2 cells (0.15-0.27 units/ml cell cytosol); this GSH-transferase concentration represents only 6% of that found in rat liver. The results suggest that in both 10T1/2 cells and rat hepatocytes GSH-transferase catalyzed GSH conjugation is quantitatively significant in determining the intracellular level of anti diol-epoxide.
9555 Background: Ipilimumab was approved by FDA in March 2011 for the treatment of Metastatic Melanoma. We conducted this study to compare survival outcome in patients with Metastatic Melanoma in pre- (1973-2010) and post- (2011-2013) ipilimumab era in the United States using U.S. Surveillance, Epidemiology, and End Result (SEER) registry database. Methods: We selected patients with metastatic melanoma age ≥ 20 years from the SEER database. We used SEER 18 registry database to evaluate relative survival (RS) rate during 1973-2010 and 2011-2013. The RS rate at 1year and 2 year were analyzed for cohorts by age (20-49 years, 50-74 and ≥75 years), race [White, African American (AA), and others] and gender. The RS rates (%) accompany standard error (SE). We used SEER Stat software for statistical analysis. Results: There were a total of 129,362 (106,516 and 22,846 in pre and post ipilimumab era) metastatic melanoma patients, male (n = 71,220), female (n = 58,142), white (n = 121,843), AA (n = 854) other (n = 1,315) reported in the registry. RS in pre vs post-ipilimumab era for age group 20-49 was: 96.50 ± 0.1% vs 97.20 ±0.3%, P = 0.013; and 94.10 ± 0.1% to 95.60 ±0.40, P = 0.0009; for age group 50-74 was: 94.10 ± 0.1% vs 95.30 ± 0.2%, P = 0.0001; and 90.70 ± 0.1%vs 92.90 ± 0.3%, P = 0.0001; and for age group ≥75 was 90.80 ± 0.3% vs 91.40 ± 0.7%, P = 0.23; and 85.0 ± 0.4% vs 88.10 ± 1.0%, P = 0.011 at 1 and 2 years respectively. Overall RS in pre and post ipilimumab era for white population was: 93.83 ± 0.16% vs 94.567 ± 0.4%, P = 0.017; and 90.0 ± 0.2% vs 92.033 ± 0.6%, P = 0.0008 at 1 and 2 years respectively. Similarly RS for AA was: 78.07 ± 2.93% vs 73.33 ± 8.23%, P = 0.37; and 65.87 ± 3.47% vs 65.33 ± 9.73%, P = 0.94; and for other race was: 85.2 ± 2.13% vs 77.97 ± 5.6%, P = 0.04; and 74.43 ± 5.2% vs 69.67 ± 6.7%, P = 0.1 at 1 year and 2 years. Conclusions: Our study showed that younger (20-74 years) patients with metastatic melanoma have improvement in 1 and 2-year RS rates in post ipilimumab era. Subgroup analysis by race showed no improvement in RS in AA and other races patients during this period. There was also no significant survival benefit seen in older (≥ 75 years) patients of all races and gender in post ipilimumab era.
TPS493 Background: Mucin 1 (MUC1) is a tumor associated membrane-bound glycoprotein that promotes oncogenesis through promotion of epithelial cell polarity loss, anti-apoptosis, and hypoxia driven angiogenesis. MUC1 overexpression is associated with aggressive behavior and poor outcomes in pancreatic ductal adenocarcinoma (PDAC), and increased resistance to gemcitabine (G) in vitro. BTH1704 (BTH) is a humanized monoclonal antibody (MAb) targeting aberrantly glycosylated MUC1. Imprime PGG (PGG) is a soluble yeast-derived b 1,3/1,6 glucan that binds complement receptor 3 (CR3) on innate immune cells priming them to exert anti-tumor activity against complement (iC3b) opsonized tumor cells. Following incubation of PGG with whole blood from healthy subjects, variability in PGG binding to neutrophils and monocytes has been observed, with higher binding and functional changes correlating with higher levels of endogenous anti-b glucan antibodies. BTH binds to antigens (MUC1), leading to iC3b opsonization of tumor cells thus, allowing PGG-primed leukocytes to kill the iC3b-opsonized tumor cells. This forms the rationale for testing BTH1704 combined with G + PGG. Methods: This is a single institution Phase 1b dose escalation study with a standard 3x3 design to determine the maximal administered dose (MAD) of BTH combined with G + PGG in patients with previously treated advanced PDAC.Each dose cohort includes at least one subject with high and one low PGG binding capability. Primary objectives: establish MAD of BTH combined with G + PGG. Secondary objectives: characterize adverse effects, clinical response, time to progression, progression free and overall survival. Correlative objectives: quantify PGG binding, MDSC phenotyping of PBMC, anti b glucan antibody levels, MUC1 IHC. Inclusion criteria: confirmed advanced PDAC, ECOG PS 0-2, rest period 2-6 weeks from prior first- or second-line treatment. Exclusion criteria: uncontrolled chronic illness. Administration and design: BTH and PGG are administered on days 1, 8, 15, and 22 of a 28-day cycle; G is administered on days 1, 8, and 15. The study is currently enrolling patients. Clinical trial information: NCT02132403. Clinical trial information: NCT02132403.
Background: Development of second primary malignancies (SPM) in Peripheral T-cell lymphoma, not otherwise specified (PTCL- NOS) patients is not well studied. This study was conducted to evaluate SPM in PTCL- NOS patients using data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER*Stat) 18 database. We compared secondary cancer rate among adult PTCL-NOS patients ≥ 20 years of age during the period of 2000 - 2015. We used SEER MP-SIR session and Graph pad scientific software to calculate p value and Observed/Expected (O/E) ratio and excess risk per 10,000 compared to general population. Results: The total number of adult PTCL-NOS patients reported was 3,321. Among them 211 patients developed ≥1 SPM, 75% of SPM occurred ≤ 5 yrs from the diagnosis of PTCL-NOS. All site secondary cancer (n=224) incidence was significantly higher among PTCL-NOS patients compared to general population with O/E: 1.73, p value < 0.05 with excess risk of 93.94 per 10,000. Most common SPMs were Non-Hodgkin's lymphoma (NHL) with O/E: 9.53, P-value <0.05, excess risk 46.28; all leukemia O/E: 5.0, P value <0.05, excess risk 14.31; melanoma O/E: 2.29, p value<0.05, excess risk 7.27. The risk of all SPMs was increased within 5 yrs from the diagnosis of PTCL-NOS. However, risk of NHL as SPM continues after 5 yrs of diagnosis of PTCL-NOS. Sub group analysis by age and sex showed the similar pattern in the incidence of SPM. Conclusions: This study showed that overall risk of second malignancies among PTCL- NOS patients is higher compared to general population. The risk of leukemia, lymphoma and melanoma is significantly increased during the first five years of diagnosis of PTCL-NOS. Disclosures No relevant conflicts of interest to declare.
110 Background: At the University of Illinois Hospital and Health Sciences System (UIC), inpatient IV chemotherapy administration occurs in the setting of specific protocols and multidisciplinary safety assessments while oral chemotherapy agent (OCA) inpatient administration occurs less formally. Baseline 8 week review of 174 admissions to the oncology service revealed that of 16 patients (9.2%) on outpatient OCA, 50% received OCAs while inpatient, with 12. 55% having a formal chemotherapy note in place. We aimed to increase the percentage of administered OCAs with associated provider generated chemotherapy notes from 12.5% to 75% over 16 weeks. Methods: A multidisciplinary task force comprised of oncology providers, clinical pharmacy, nursing leadership, and information technology was assembled. An actual and ideal process map was created, and using tools such as affinity sorting and root cause analysis, interventions were implemented focusing on residents (knowledge of OCA), nurses (documentation and policy adherence), pharmacists (education, policy adherence) and IT team (order modification). A standardized multidisciplinary hospital wide process was implemented for OCA ordering, administration, documentation, and patient education. A novel REDCap (research electronic data capture) auditing procedure was designed by which a weekly pharmacy report of every oral chemotherapy order at UI Health is automatically generated. Results: Between June and September 2015, a total of 67 OCA administration reports were audited. OCA notes were associated with OCA administration in 58% of cases in June, 100% in July, 78% in August and 93% in September. Furthermore, OCA notes were entered within 4 hours of OCA ordering in 58% of cases in June, 54% in July and 78% of the cases in August and September. No adverse events were reported. Conclusions: At the University of Illinois Hospital and Health Sciences System, a multidisciplinary team designed and implemented a standardized OCA administration, ordering, and documentation process focused on safe, appropriate and timely inpatient OCA administration. A novel REDCap auditing process assisted the team to identify the areas in need of optimization.
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