Cooperative Research And Development Agreement Research Articles

A Phase I/II, Intra-Patient Dose-Escalation Study of Bitopertin, a Selective Inhibitor of GlyT1 and Heme Synthesis, for Steroid-Refractory Diamond-Blackfan Anemia

Background: Diamond-Blackfan anemia (DBA) is a heritable bone marrow failure disorder characterized by macrocytic anemia with reticulocytopenia and bone marrow erythroid hypoplasia, usually presenting within the first two years of life. Treatment consists of systemic corticosteroids. Treatment failure or steroid intolerance occurs in approximately half of all cases, necessitating chronic transfusions, which carry the risks of iron overload and infections. Hematopoietic cell transplant remains the sole curative therapy for DBA. In cases where a causative mutation can be identified, with rare exceptions, the affected genes encode ribosomal proteins (RPs), defining DBA as prototypic haploinsufficient ribosomopathy. Erythrocyte hemoglobinization requires balanced heme synthesis and globin translation. Various in vitro and animal models suggest that RP insufficiency results in reduced ribosomal biogenesis, disrupting this balance and leading to excess of heme, resulting in toxicity to developing erythroid cells and premature termination of erythroid differentiation. Bitopertin is an investigational, orally administered, inhibitor of the GlyT1 glycine transporter. Outside the central nervous system (CNS), GlyT1 is expressed almost exclusively on developing erythrocytes. By reducing intracellular glycine, a rate-limiting substrate for heme synthesis, bitopertin slows heme synthesis and thus we hypothesize rebalances hemoglobin synthesis. In preclinical DBA models, bitopertin rescues erythropoiesis. The drug was originally developed for CNS indications, and has been shown to exhibit a favorable safety profile in prior studies with cumulative enrollment of over 4,000 patients and healthy volunteers. It is currently under clinical investigation for the treatment of erythropoietic protoporphyria. Study Design and Methods: This is a phase I/II, intra-patient dose-escalation study of bitopertin for steroid-refractory DBA, conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland. Subjects visit the NIH for initial evaluation and eligibility assessment and at the primary endpoint, with interim follow-up conducted via telehealth and local laboratory assessments. Subjects must be 18 years of age or and older, diagnosed with DBA and with clinically significant anemia (hemoglobin < 9/dL and/or requiring 2 units PRBC per 8 weeks). They must have relapsed and/or steroid refractory disease or be intolerant of systemic steroids, and be without significant comorbidities. Ongoing transfusions and chelation therapy are allowed, but other DBA-directed therapy, most notably steroids and growth factors, are not. Each subject will take oral bitopertin daily, escalating the dose monthly (5 mg, 10 mg, 20 mg, 40mg, and 60 mg) until reaching either the study maximum dose of 60 mg, the minimum effective dose (MED), or the maximum tolerated dose (MTD). Subjects will be followed for 8 months (32 weeks), including a minimum of 4 months (16 weeks) at the final dose (MED, MTD or study maximum). Response will be assessed on an ongoing basis and will be defined as an increase in hemoglobin ≥by 1.5 g/dL and/or a reduction in the units of PRBC transfusions by ≥50% from baseline. Furthermore, a robust response will be defined as a hemoglobin ≥10 g/dL and transfusion independence for 8 weeks. Patients with response (robust or non) by the 8-month primary endpoint will be allowed to continue extended therapy for 3 additional years. The primary endpoint is erythroid response. Secondary endpoints include safety as defined by the toxicity profile over 8 months of therapy and on extended therapy, relapse, survival, clonal evolution, health-related quality of life, and ancillary laboratory studies including the impact of bitopertin upon erythroid cell dynamics. The study employs a minmax design. A minimum of 15 patients will be enrolled. If the minimum efficacy threshold is met or surpassed (≥13% response rate), an additional 10 patients will be enrolled. Status: This study has been granted an FDA IND (165778) and is open for enrollment. It is monitored under the NIH Institutional Review Board (001528-H) and is registered with the U.S. National Library of Medicine (NCT05828108). Funding: This study is supported by the NHLBI Division of Intramural Research and in part through a Cooperative Research and Development Agreement (CRADA) with Disc Medicine, Inc. (Watertown, MA).

The Pyruvate Kinase Activator Mitapivat Improves Red Blood Cell Deformability and Sickling Kinetics in Adult Patients with Sickle Cell Disease

Background: A hallmark of sickle cell disease (SCD) is compromised red blood cell (RBC) deformability. Polymerization of hemoglobin S (HbS) underlies this "sickling" which results in altered biomechanical properties that impact rheology and hemodynamics (Barabino et al, 2010). There have been exciting clinical developments in anti-sickling therapies - including enhancement of red cell pyruvate kinase (PKR) modality. Importantly, deformability measurements of RBCs via ektacytometry are increasingly used to aid the assessment of their therapeutic efficacy. Here we employed the Laser assisted Optical Rotational Red Cell Analyzer (LORRCA, RR Mechatronics), which permits the evaluation of RBC deformability as a function of shear stress, osmotic pressure, and oxygen tension, to evaluate the changes in RBC deformability in subjects undergoing treatment with mitapivat (AG-348), a PKR activator under clinical development for sickle cell disease. We analyzed changes in deformability measurements of RBCs in HbSS subjects after 4 weeks and 12 weeks of mitapivat therapy and compared them to t50 - a single parameter measure of sickling kinetics (Dunkelberger et al, 2018). Methods: We studied subjects currently enrolled under IRB approved clinical trial NCT04610866 that evaluates the long-term safety and tolerability of mitapivat in SCD patients. Fifteen subjects (aged 25 - 57 years; 5 females, 10 males; African/African-American) were evaluated, though not all endpoints were available for every patient across all assays. Fresh whole blood (collected in EDTA tubes) was obtained at baseline (prior to drug initiation), after 4 weeks and after 12 weeks of therapy. Cells were counted and diluted in polyvinylpyrrolidone (PVP) solution before undergoing same-day LORRCA assays. The Elongation Index (EI) is a measure of the cells' ability to undergo deformation at different physiologically relevant conditions. EI was assessed at increasing shear stresses of .3 Pascals (Pa), .95 Pa, 3 Pa, 9.49 Pa, and 30 Pa (elongation assay). Parameters derived under continuous osmotic changes (0-600mOsm/kg - osmoscan) include O min which informs on RBC fragility, O Hyper which informs on hydration state and corresponds to 50% of the maximum deformability in the hypertonic region, EI max (osmo) which reveals maximum deformability and informs on RBC cytoskeletal mechanics, and O Max which gives the osmolality at which EI Max is achieved. Point of Sickling (POS) gives the oxygen tension at which the cells start to sickle during nitrogen facilitated deoxygenation of the sample (oxyscan). These parameters of deformability are generated by LORRCA software. For all assays, we analyzed the % change from baseline after 4 weeks and 12 weeks of therapy (Wilcoxon signed rank test, R v1.4.1106) and compared these changes to those in t50 (Spearman correlation test, Prism v9) (Figure 1). Results: Mitapivat therapy resulted in increased elongation indices across all shear stress levels, with significance reached at shears of .3 Pa, .95 Pa, and 3 Pa (respective mean % changes of 78.5, 181.8, and 23.0 (4 weeks) and 101.2, 212.9, and 30.1 (12 weeks)) suggesting improved deformability of RBCs. Likewise, significant increases in O hyper (mean % changes of 2.8 and 3.4) and osmo EI Max (mean % changes 7.9 and 9.5) respectively, indicate improvements in RBC hydration and cytoskeletal dynamics in response to changing osmotic pressures. Furthermore, a significant decrease in the average point of sickling was noted at both 4 weeks and 12 weeks (-20.15% and -16.8%, respectively), suggesting RBCs were susceptible to sickling at partial pressures of oxygen lower than those observed before therapy. Conclusion: Altogether, these findings indicate that mitapivat therapy results in improved ability of RBCs to withstand deformational changes in response to shear stress, osmotic pressure, and decreasing oxygen tension, likely via bolstered membrane integrity. Interestingly, when compared to t50 values, significant correlation was observed at all levels of shear stress and at the maximal deformability (EI max) achieved during both the osmoscan and oxyscan assays. Acknowledgement: This study is part of a Cooperative Research and Development Agreement (CRADA) with AGIOS Pharmaceuticals, Inc., Cambridge, MA, United States Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

582 Immune correlates from QuEST1 in men with castration-resistant prostate cancer

BackgroundImmune checkpoint inhibitors have limited efficacy in unselected metastatic castration-resistant prostate cancer (mCRPC) patients. Combination immunotherapy approaches to generate a tumor-directed immune response (vaccine) and facilitate the resulting anti-tumor immune activity (checkpoint inhibitors, cytokines) have shown synergy preclinically. In the phase I/II Quick Efficacy Seeking Trial (QuEST1, NCT03493945), combination of a brachyury-targeting vaccine (BN-brachyury), TGF-β/anti-PD-L1 blocking bifunctional fusion protein (bintrafusp alfa), and IL-15 superagonist (N-803) have produced preliminary evidence of efficacy in CRPC, with 5/12 patients having a sustained prostate-specific antigen (PSA) response that included 2 radiographic partial responses, compared to 1/13 patients who received BN-brachyury plus bintrafusp alfa. Here, we present immune correlates from patients enrolled in Arm 2.1A (BN-brachyury + bintrafusp alfa) and Arm 2.2A (BN-brachyury + bintrafusp alfa + N-803).MethodsPeripheral blood mononuclear cells (PBMC) and serum were obtained from 25 patients pre and multiple time points post treatment. PBMCs were assessed for antigen specific T cells targeting brachyury and MUC-1 by intracellular cytokine staining, 158 peripheral immune cell subsets by multicolor flow cytometry, and TCRVβ sequencing. Patients were also evaluated for complete blood counts, and serum cytokines/soluble factors using ELISA assays and OLINK’s immuno-oncology panel. Immune parameters were compared between Arm 2.1A and Arm 2.2A and evaluated for associations with clinical response in Arm 2.2A.ResultsBrachyury and MUC-1 specific T cells were increased in most patients post treatment in both arms. A greater increase in total NK cells, refined NK subsets expressing markers of activation/adhesion, and TCR diversity was observed after 2 weeks of therapy in Arm 2.2A than Arm 2.1A. Absolute lymphocyte counts and serum levels of granzyme B, sCD27, and sCD40L were also increased after 2 weeks in Arm 2.2A compared to Arm 2.1A. Serum proteomic analyses revealed a greater increase in analytes related to NK cell signaling in Arm 2.2A than Arm 2.1A. Specific immune parameters at baseline associated with development of clinical response in patients treated in Arm 2.2A; responders had trends of higher frequencies of CD4+ and CD8+ T cells, lower frequencies of MDSCs and monocytes, and lower levels of serum IL-6 and sCD40 than non-responders.ConclusionsThese findings demonstrate enhanced immune activation of both NK and T cells with the addition of N-803 in Arm 2.2A, where more clinical activity was observed than in Arm 2.1A. These findings support the continued evaluation of the combination of BN-brachyury, bintrafusp alfa, and N-803 in patients with mCRPC.AcknowledgementsThis research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health, and via Cooperative Research and Development Agreements (CRADAs) between the NCI and EMD Serono, the NCI and Bavarian Nordic, and the NCI and ImmunityBio.Trial RegistrationNCT03493945Ethics ApprovalThe trial was approved by the Institutional Review Board of the Center for Cancer Research, National Cancer Institute (ClinicalTrials.gov identifier: NCT03493945).

(Invited) H-Mat: Enhancing the Durability and Affordability of Metals and Polymers in Hydrogen Service

The H-Mat national laboratory consortium is conducting cross-cutting, foundational R&D to enhance the durability of key polymers and metals in hydrogen service. Technologies utilized in hydrogen service commonly face stresses that influence materials compatibility, such as cryogenic temperatures, fatigue loading, and corrosive environments. Industries in which hydrogen compatibility can heavily influence materials selection are diverse, and include fuel cell electric vehicles (FCEVs), nuclear energy technologies, oil & gas sectors, and vehicle lightweighting applications. H-Mat R&D aims to enhance fundamental understanding of materials’ behavior in hydrogen, with a current focus on materials used onboard FCEVs and at fueling stations. Key research thrusts include: 1) development of novel experimental polymers with enhanced durability in hydrogen pressure cycles, 2) microstructural engineering to enhance the fracture toughness of high-strength steels in hydrogen, 3) development of higher-fidelity predictions of crack initiation in steels in hydrogen service, and 4) evaluation of the effects of moisture on hydrogen induced degradation in aluminum alloys. These R&D thrusts are targeted to enhance durability of hydrogen seals by 50%, fracture resistance of pressure vessel steels by 50%, and life of pressure vessels by 50%. H-Mat is led by Sandia National Laboratories and Pacific Northwest National Laboratory, with participation from Oak Ridge National Laboratory, Savannah River National Laboratory, and Argonne National Laboratory. Members of industry and academia are encouraged to engage with the consortium through cooperative research and development agreements (CRADAs) and funding opportunity announcement (FOA) awards. For more information, please see: https://www.energy.gov/eere/fuelcells/h-mat-hydrogen-materials-consortium

Benchmarking Ultrawideband Phased Antenna Arrays: Striving for Clearer and More Informative Reporting Practices

This article presents embedded element design and measurement data for an ultrawideband (UWB) flared-notch (Vivaldi) array. The U.S. Naval Research Laboratory (NRL) built this all-metal dual-polarized phased array specifically as a benchmarking reference for other planar phased-array apertures in the 2-21.2-GHz frequency range. It is suitable for comparative reporting of new array radiator performance, a practice favored by the Navy for effective technology readiness level (TRL) assessment. The 256-port (16 t 16, 7-mm array lattice spacing) slant-linear array is precision machined to ensure consistent agreement between measured performance results and predictions from simulated full-wave models, making the array desirable for benchmarking new array hardware as well as validating computational modeling tools. The optimally sampled aperture has excellent matching and zero scan blindness out to 80d in all scan planes, for grating-lobe-free scans over roughly 2-21.2 GHz. Benchmarking is tailored to highlight cross-polarization (cross-pol) performance in all scan planes, an important metric that should be tested during array radiator design. This data can be made available to design engineers for comparative evaluation of new UWB radiator performance under a cooperative research and development agreement (CRADA). NRL provides this and similar benchmarking data sets (and related measurement services) in the 0.8-75-GHz range.

U.S. federal laboratories and their research partners: a quantitative case study

The Stevenson–Wydler Technology Innovation Act of 1980 made explicit the technology transfer responsibilities of U.S. Federal laboratories. The Federal Technology Transfer Act of 1986 and the National Competitiveness Technology Transfer Act of 1989 further enhanced the technology transfer activities of laboratories by permitting Cooperative Research and Development Agreements (CRADAs). However, very little is known about the characteristics of CRADA activity in Federal laboratories. Using a new, robust dataset of CRADA activity at the National Institute of Standards and Technology (NIST), we describe research partnerships over the years 1978 through 2014, and we explore several research questions. When did the Federal Technology Transfer Act have an impact on CRADA activity at NIST? Is CRADA activity at NIST a cyclical phenomenon? At what frequency do private sector establishments engage in CRADA activity with NIST? We find suggestive evidence that the Federal Technology Transfer Act began to influence NIST’s CRADA activity within 2–3 years after its passage, and we find that CRADA activity moves with the business cycle. We also find that most establishments that were engaged in CRADA activity were engaged only once over this time period; it was only the larger establishments that continued to engage in CRADAs with NIST. We speculate about the implications of these findings, and we suggest a broader research agenda into CRADA activity in Federal laboratories.

Cyclophosphamide and Fludarabine Conditioning Chemotherapy Induces a Key Homeostatic Cytokine Profile in Patients Prior to CAR T Cell Therapy

This study is supported in part by funding from the Cooperative Research and Development Agreement (CRADA) between the National Cancer Institute and Kite PharmaIntroduction: CAR-engineered autologous T-cell therapy has shown promising activity in relapsed/refractory B-cell malignancies in an ongoing phase 1 study (Kochenderfer et al. J Clin Oncol 2014). Lymphodepleting conditioning chemotherapy is critical for optimal CAR T-cell activity in animal models. We evaluated the effects of conditioning chemotherapy on cytokine and chemokine levels in patients dosed with anti-CD19 CAR T cells.Methods: In this National Cancer Institute clinical trial (NCT00924326), patients with relapsed/refractory B-cell malignancies received conditioning with cyclophosphamide and fludarabine daily for 3 days starting on day -5; followed by anti-CD19 CAR T cells engineered with a CAR comprising CD28 and CD3-zeta signaling domains. Forty one cytokines, chemokines and immune response related markers were measured in the blood of patients pre (day -5) and post conditioning (day 0) by using EMD Millipore Luminex® xMAP® multiplex assays. Data acquisition and analysis were performed using a Luminex 200™ instrument and xPONENT® 3.1 data analysis software. Increases in cytokine and chemokine levels were analyzed pre- and post- conditioning, and the fold-changes in cytokine and chemokine levels were analyzed relative to clinical outcome subsequent to infusion with anti-CD19 CAR T cells. Analyses were performed with the Wilcoxon rank sum test adjusted for multiplicity with a Bonferroni correction, using a nominal level of 0.006 for significance.Results: Samples from 15patients have been evaluated. There were significant increases pre- to post-conditioning in the levels of interleukin 15 (IL-15; p=0.001), interleukin 7 (IL-7; p=0.0002), and monocyte chemoattractant protein-1 (MCP-1; p<0.0025) in blood, five days after the initiation of conditioning chemotherapy. Levels of interferon-gamma induced protein 10 (IP-10) were elevated post-conditioning, but did not meet the threshold for significance (p=0.048). Compared with baseline, levels of IL-15 increased on average 13 fold and levels of IL-7, IP-10 and MCP-1, about 2 fold. Comparison of the fold-increases in IL-15 upon conditioning between responders and non-responders approached significance (p=0.01), but did not meet the threshold after multiplicity adjustment. Larger fold-change increases for responders versus non-responders were also observed with placental growth factor (PLGF) (median fold increase 2.6 v. 1.6, average fold increase 32 v 4.2), C-reactive protein (CRP) (median fold increase 3.5 v 2.4, average fold increase 6.6 v. 2.0), IP-10 (median fold increase 2.1 v. 0.7, average fold increase 2.6 v. 2.8), and interleukin 10 (IL-10) (median fold increase 1.8 v. 0.4, average fold increase 3.1 v. 2.0), but did not meet the threshold for significance. In addition to ongoing analysis of conditioning-mediated cytokine induction and clinical response, we are evaluating the impact of conditioning chemotherapy dose on cytokine levels, as well as the relationship between conditioning-related cytokines and CAR T-cell expansion and persistence.Conclusions: The data obtained to date support the hypothesis that cytokines such as IL-15 play a key role in the clinical outcomes to anti-CD19 CAR T-cell therapy. Our results demonstrate that conditioning chemotherapy significantly increases the levels of homeostatic cytokines known to regulate T-cell expansion, as well as specific pro-inflammatory cytokines and chemokines. Optimization of conditioning chemotherapy is critical to the activity of CAR T-cell therapies. DisclosuresBot:Kite Pharma: Employment, Equity Ownership. Rossi:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Navale:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Shen:Kite Pharma: Employment, Equity Ownership. Sherman:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Mardiros:Kite Pharma: Employment, Equity Ownership. Yoder:Kite Pharma: Employment, Equity Ownership. Go:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Rosenberg:Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Chang:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Roberts:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma.

Pharmacodynamic Profile and Clinical Response in Patients with B-Cell Malignancies of Anti-CD19 CAR T-Cell Therapy

This study is supported in part by funding from the CooperativeResearch and Development Agreement (CRADA) between the National Cancer Institute and Kite PharmaIntroduction: Chimeric antigen receptor (CAR) engineered autologous T-cell therapy has shown promising efficacy in B-cell malignancies in an ongoing phase 1 study (Kochenderfer et al. J Clin Oncol 2014). Anti-CD19 CAR T-cell product characteristics and potential pharmacodynamic markers from patients in this study were evaluated together with updated clinical responses.Methods: In this National Cancer Institute (NCI) clinical trial (NCT00924326), patients with relapsed/refractory B-cell malignancies received conditioning with cyclophosphamide and fludarabine daily for 3 days starting on day -5; followed by 1-2 x 106/kg anti-CD19 CAR T cells engineered with a CAR expressing CD28 and CD3-zeta signaling domains. Forty one cytokines, chemokines and immune response related markers were measured in the serum of patients prior to conditioning and CAR T-cell infusion, and during an interval of 4 weeks post-CAR T-cell infusion. EMD Millipore Luminex® xMAP® multiplex assays were used to measure all analytes. A Luminex 200™ instrument and xPONENT® 3.1 software were used for data acquisition and analysis. Major T-cell phenotypic markers including CD4, CD8, CD45RA and CCR7 were evaluated by multicolor flow cytometry on CAR-expressing T cells prior to and post-infusion, using a BD FACSCanto II. FlowJo software was used for data analysis. T-cell marker expression, as well as cytokine and chemokine levels were analyzed together with the clinical response to anti-CD19 CAR T cells. Maximum fold increase (MFI) was defined as the maximum fold change of measured analytes above baseline (pre-conditioning, day -5) across sampling timepoints.Results: Anti-CD19 CAR T-cell products, PBMCs from 12 patients, and serum samples from 15 patients have been evaluated. In 12 patient lots evaluated to date, the median CD4+/CD8+ CAR T-cell ratio was 0.48 (range 0.02-6.12). In addition, the median ratio between naïve (TN) plus central memory T cells (TCM), and more differentiated effector memory (TEM) plus effector cells (TE), was 0.48 (range 0.1-16.8). Post-hoc analyses adjusted for multiple comparisons showed that the frequency of CD4+ TN and TCM cells in the 6-8 day T-cell lots was significantly greater than that of CD4+ TN and TCM cells in the 10 day T-cell lots. The corresponding frequencies of CD8+ TN and TCM cells in the 6-8 day T-cell lots compared to 10 day T-cell lots approached significance, but did not meet the threshold after multiplicity adjustment. Clinical responses were seen across broad ranges of CD4+/CD8+ and (TN+TCM)/(TEM+TE) ratios in the CAR T-cell product.CAR T cells upregulated T-cell activation and immune modulating markers, as well as released measurable levels of cytokines and chemokines in response to CAR engagement of CD19 in vitro, or post-infusion. Cytokine and chemokine levels achieved their peak 3-10 days post T-cell infusion and returned to baseline generally within 3 weeks. Key pro-inflammatory cytokines and markers were upregulated: IL-6 median fold increase (MFI) at peak of 66 (interquartile range 5-152), IFN-g MFI 57 (13-126), C-reactive protein MFI 6 (4-42); immune homeostatic cytokines IL-15 MFI 19 (7-54), IL-2 MFI 20 (4-22), IL-10 MFI 10 (4-15); chemokines monocyte chemotactic protein (MCP)-1 MFI 7 (5-9), MCP-4 MFI 4 (2-5); and the immune effector molecules granzyme A MFI 7 (6-17) and granzyme B MFI 5 (3-9). Further analyses are ongoing.Conclusion: Clinical responses were observed irrespective of the CD4+/CD8+ ratio in the CAR T cell product. Cytokines and immune effector mediators peaked and cleared within 3 weeks. This pharmacodynamic profile reveals a rapid and coordinated sequence of T cell activation underlying durable responses in patients with B-cell malignancies. DisclosuresPerez:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Shen:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Sherman:Amgen: Equity Ownership; Kite Pharma: Employment, Equity Ownership. Mardiros:Kite Pharma: Employment, Equity Ownership. Yoder:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership; Amgen: Equity Ownership. Rosenberg:Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma. Wiezorek:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Roberts:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Chang:Kite Pharma: Employment, Equity Ownership, Other: Officer of Kite Pharma. Bot:Kite Pharma: Employment, Equity Ownership.

Supporting Remote Sensing Research with Small Unmanned Aerial Systems

Abstract. We describe several remote sensing research projects supported with small Unmanned Aerial Systems (sUAS) operated by the NGA Basic and Applied Research Office. These sUAS collections provide data supporting Small Business Innovative Research (SBIR), NGA University Research Initiative (NURI), and Cooperative Research And Development Agreements (CRADA) efforts in addition to inhouse research. Some preliminary results related to 3D electro-optical point clouds are presented, and some research goals discussed. Additional details related to the autonomous operational mode of both our multi-rotor and fixed wing small Unmanned Aerial System (sUAS) platforms are presented.

Increased Transpulmonary Gradient Predicts Functional Class, Mortality, and RV Dysfunction by MRI in Patients with Sickle Cell Associated Pulmonary Hypertension

AbstractAbstract 89▪▪This icon denotes a clinically relevant abstract Background:Patients with sickle cell disease (SCD) and pulmonary hypertension (PH) have increased mortality. Whether SCD-associated PH (SCD-PH) is predominantly a pulmonary pre-capillary (PAH) vs. post-capillary (PVH) process is an area of ongoing investigation. SCD-PH is often complicated by high cardiac output (CO) related to anemia.The transpulmonary gradient (TPG) represents a pressure differential across the pulmonary vascular bed that the right ventricle (RV) has to overcome regardless of the total volume being ejected and has been employed to determine eligibility for cardiac transplantation because it eliminates the confounding effect of CO (PVR=TPG/CO). Typically, a TPG ≥ 12 mmHg indicates significant PAH with increased risk of acute RV failure post-transplantation.With significant PAH, there is often morphologic adaptation by the RV. MRI enables accurate quantification of RV function and structure. In idiopathic PAH, RV dilation and decreased function have been correlated with poor prognosis. Thus, we hypothesize that patients with SCD and a TPG ≥ 12 mmHg would have lower functional capacity, increased mortality, and MRI evidence of RV dysfunction. Materials & Methods:Five hundred and thirty one consecutive patients (age 35.6 ± 12.6, 54% (n=284) female, 73% (n=387) HbSS phenotype) with SCD were prospectively screened for PH using echocardiography (tricuspid regurgitant jet ≥ 2.5 m/s) without any exclusion criteria. Eighty four patients (age 41 ± 13, 55% (n=46) female, 82% (n=69) HbSS phenotype, mean Hb 8.8 ± 1.7) underwent RHC, and forty-one patients (age 42 ± 15, 54% (n=22) female, 80% (n=33) HbSS phenotype, mean Hb 8.9 ± 1.8) underwent cardiac MRI (CMR) within one week of RHC. CMR sequences consisted of cine imaging and late gadolinium enhancement imaging. Results:Of the 84 catheterized patients, forty-six had a TPG ≥ 12 mmHg and 38 had a TPG < 12 mmHg. Of the 41 patients who had both RHC and CMR, twenty-one had a TPG ≥ 12 mmHg and 20 had a TPG < 12 mmHg. Those with a TPG ≥ 12 mmHg had higher mortality (median years from enrollment to death were 4.0 vs. 4.7 years with 21 (46%) deaths in the high TPG group vs. 6 (16%) deaths in the lower TPG group, p=0.008), poorer functional class (p=0.007), shorter 6-minute walk distance (p=0.003), higher pulmonary vascular resistance index (p<0.001), and lower cardiac index (p=0.001). High TPG patients demonstrated significantly more abnormal CMR markers of RV dysfunction, including lower tricuspid annular plane excursion (p=0.001) and RV ejection fraction (p=0.002). High TPG patients also showed a non-significant trend for other markers of RV dysfunction, including higher RV end-diastolic volume index (EDVI) and RV mass index (MI), and lower RV stroke volume index (SVI). Recently validated CMR markers of pulmonary hypertension including septal-to-LV-free-wall curvature ratio (p=0.013), septomarginal trabeculae mass index (p=0.002), and ventricular mass index ratio (p=0.016) were significantly different in the high TPG group. CMR eccentricity index (EI) at end-systole (ES) was significantly greater in the high TPG group (p=0.026) without a significant change between ES and ED (end-diastole), which is consistent with the finding that there is a greater degree of RV pressure overload. In the low TPG group, the EIED was greater than EIES(p=0.001), which supports anemia-related RV volume overload rather than pressure overload. Although the left ventricular (LV) ejection fraction was similar in both groups, parameters indicative of LV dilation such as LV ESVI (p=NS) and EDVI (p=0.006) were more elevated in the low TPG group. Late gadolinium enhancement (LGE) at the RV insertion points indicative of myocardial fibrosis also occurred more frequently in the higher TPG group (p=0.030). Conclusions:A TPG ≥ 12 mmHg effectively identified patients with a lower functional capacity, MRI evidence of RV dysfunction, and overall worse prognosis. The MRI pattern of RV dysfunction in the TPG ≥ 12 mmHg is consistent with RV pressure overload. The TPG, being less subject to the confounding effects of CO, further demonstrates the functional severity of pulmonary arterial disease in SCD using objective thresholds established in the cardiac transplant literature. Disclosures:Off Label Use: Gadolinium contrast is used for late gadolinium enhancement imaging. Arai:Siemens: Dr. Arai is a principal investigator on a US Government Cooperative Research and Development Agreement (CRADA). Other.

Technology transfer contracts between R&amp;D labs and commercial partners: choose your words wisely

Our study is motivated by the problems encountered by external collaborators, particularly those between research and development laboratories and commercial partners, when writing technology transfer contracts. Kruskal–Wallis one-way nonparametric Analyses of Variance are used to analyze Cooperative Research and Development Agreements (CRADAs) from a national, Department of Defense laboratory in the United States of America. The CRADA information elements serve as the independent variables for the study. Benefits accrued by the laboratory serve as the dependent variable. The results highlight the link between information asymmetry and technology transfer and the connection between benefits obtained and contract specificity. Quantifying royalty streams in the CRADA increases the likelihood of achieving of these royalty payments. Too much contract detail may boomerang: limiting laboratory image enhancement, harming employee morale, and impeding efficient and effective laboratory management. Always, technology transfer involves a bargain: a contract where tacit knowledge must be nurtured and the amount of specificity managed.

Hyperspectral Confocal Fluorescence Microscope: A New Look into the Cell

Confocal microscopy is widely used in cell biology. Like other filter-based systems, traditional confocal microscopes are limited by the spectral bands established by each optical filter. As a result, emission spectra from labels and/or autofluorescence can be overlapped leading to spectral crosstalk and inability to quantify the amount of signal originating from each individual fluorescent species. The need for accurate quantification of in vivo cellular processes and in-depth knowledge of organelle development and microstructure led Monsanto to search for non-commercial microscopes that could achieve those goals. Through a cooperative research and development agreement (CRADA) established between Monsanto and Sandia Corporation in August 2006, we built a new 3D-hyperspectral confocal fluorescence imaging system, specifically designed to meet the analytical requirements of plant specimens.

Evaluating the Return on Investment for Department of Defense to private sector technology transfer

The United States Government policy indicates maximising Return On Investment (ROI) on R&D as a fundamental reason for technology transfer. Under public laws, federal agencies, are required to spend 0.5/ of their overall budget on technology transfer. Since no models exist to evaluate transfer ROI, this paper presents a framework for such a model. Individual Cooperative Research and Development Agreements (CRDAs) between the Air Force Research Laboratory (AFRL) and private firms are analysed using the model proposed, using objective and subjective measures. Sensitivity analysis is used to identify the best CRDA choice over a range of parameter values.

Updated Announcement - AAPS and FDA Agreement to Build Quantitative Alzheimer’s Disease Model

American Association of Pharmaceutical Scientists (AAPS) and Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration (FDA) have a Cooperative Research and Development Agreement (CRADA) to build a quantitative Alzheimer’s Disease Model. AAPS is seeking fellows who are interested in applying quantitative ‘learning’ approaches for solving drug development and regulatory challenges. Specifically, the incumbent will work with the FDA Pharmacometrics group (Silver Spring, MD) to develop and apply Alzheimer’s Disease Model to drug development. The fellowship is for 2 years.

Updated Announcement—AAPS and FDA Agreement to Build Quantitative Alzheimer’s Disease Model

American Association of Pharmaceutical Scientists (AAPS) and Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration (FDA) have a Cooperative Research and Development Agreement (CRADA) to build a quantitative Alzheimer’s Disease Model. AAPS is seeking fellows who are interested in applying quantitative ‘learning’ approaches for solving drug development and regulatory challenges. Specifically, the incumbent will work with the FDA Pharmacometrics group (Silver Spring, MD) to develop and apply Alzheimer’s Disease Model to drug development. The fellowship is for 2 years.

Announcing AAPS and FDA Agreement to Build Quantitative Alzheimer’s Disease Model

American Association of Pharmaceutical Scientists (AAPS) and Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration (FDA) have a Cooperative Research and Development Agreement (CRADA) to build a quantitative Alzheimer’s Disease Model. AAPS is seeking fellows who are interested in applying quantitative ‘learning’ approaches for solving drug development and regulatory challenges. Specifically, the incumbent will work with the FDA Pharmacometrics group (Silver Spring, MD, USA) to develop and apply Alzheimer’s Disease Model to drug development. The fellowship is for 2 years. Requirements include an earned Pharm.D., Ph.D., M.D. or other professional doctorate related to pharmaceutical sciences or statistics. Clinical and pharmaceutical scientists with a good knowledge of pharmacokinetic and pharmacodynamic principles, an experience in mixed effects modeling including software skills (SAS, Splus, NONMEM, etc) or a statistician with a good knowledge of trial design and analyses principles with an interest in advanced innovative methods to explore clinical trial data are eligible for this fellowship. Proficiency with standard software (NONMEM, SAS or SPlus/R) is a must. This fellowship could also be a good opportunity for academicians who are willing to take 2 years of sabbatical leave. Good communication and writing skills are critical. Opportunities to learn and contribute in a dynamic team, to gain first-hand experience with regulatory aspects of Pharmacometrics, and to conduct and publish research in related areas are abundant. Candidates will need to be US permanent residents or citizens. Please forward your resume to: AAPS Attention: CRADA—Alzheimer’s Disease Model 2107 Wilson Boulevard, Suite 700 Arlington, VA 22201 crada@aaps.org www.aapspharmaceutica.com/crada Deadline for submissions: June 30, 2008

Aircraft Passenger Cabin ECS-Generated Ventilation Velocity and Mass Transport CFD Simulation: Mass Transport Validation Exercise

A collaborative research project established between the University of Tennessee (UT) computational fluid dynamics (CFD) lab and the Federal Aviation Administration (FAA) Civil Aerospace Medical Institute (CAMI) sought to validate CFD prediction of the environmental control system (ECS)-generated ventilation velocity vector field with induced mass transport. The results of the velocity field validation exercise were published previously. An FAA Cooperative Research and Development Agreement (CRADA) project generated an experimental database of time-dependent inserted mass distributions in the CAMI Aircraft Environmental Research Facility (AERF). The companion CFD mass transport simulations were conducted at the UT CFD Lab using both commercial and proprietary computer codes. This paper reports the qualified results of the mass transport validation exercise.

Announcing AAPS and FDA Agreement to Build Quantitative Alzheimer's Disease Model

American Association of Pharmaceutical Scientists (AAPS) and Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration (FDA) have a Cooperative Research and Development Agreement (CRADA) to build a quantitative Alzheimer’s Disease Model. AAPS is seeking fellows who are interested in applying quantitative ‘learning’ approaches for solving drug development and regulatory challenges. Specifically, the incumbent will work with the FDA Pharmacometrics group (Silver Spring, MD, USA) to develop and apply Alzheimer’s Disease Model to drug development. The fellowship is for 2 years. Requirements include an earned Pharm.D., Ph.D., M.D. or other professional doctorate related to pharmaceutical sciences or statistics. Clinical and pharmaceutical scientists with a good knowledge of pharmacokinetic and pharmacodynamic principles, an experience in mixed effects modeling including software skills (SAS, Splus, NONMEM, etc) or a statistician with a good knowledge of trial design and analyses principles with an interest in advanced innovative methods to explore clinical trial data are eligible for this fellowship. Proficiency with standard software (NONMEM, SAS or SPlus/R) is a must. This fellowship could also be a good opportunity for academicians who are willing to take 2 years of sabbatical leave. Good communication and writing skills are critical. Opportunities to learn and contribute in a dynamic team, to gain first-hand experience with regulatory aspects of Pharmacometrics, and to conduct and publish research in related areas are abundant. Candidates will need to be US permanent residents or citizens. Please forward your resume to: AAPS Attention: CRADA—Alzheimer’s Disease Model 2107 Wilson Boulevard, Suite 700 Arlington, VA 22201 crada@aaps.org http://www.aapspharmaceutica.com/crada Deadline for submissions: June 30, 2008

Announcing AAPS and FDA Agreement to Build Quantitative Alzheimer's Disease Model

American Association of Pharmaceutical Scientists (AAPS) and Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration (FDA) have a Cooperative Research and Development Agreement (CRADA) to build a quantitative Alzheimer’s Disease Model. AAPS is seeking fellows who are interested in applying quantitative ‘learning’ approaches for solving drug development and regulatory challenges. Specifically, the incumbent will work with the FDA Pharmacometrics group (Silver Spring, MD, USA) to develop and apply Alzheimer’s Disease Model to drug development. The fellowship is for 2 years. Requirements include an earned Pharm.D., Ph.D., M.D. or other professional doctorate related to pharmaceutical sciences or statistics. Clinical and pharmaceutical scientists with a good knowledge of pharmacokinetic and pharmacodynamic principles, an experience in mixed effects modeling including software skills (SAS, Splus, NONMEM, etc) or a statistician with a good knowledge of trial design and analyses principles with an interest in advanced innovative methods to explore clinical trial data are eligible for this fellowship. Proficiency with standard software (NONMEM, SAS or SPlus/R) is a must. This fellowship could also be a good opportunity for academicians who are willing to take 2 years of sabbatical leave. Good communication and writing skills are critical. Opportunities to learn and contribute in a dynamic team, to gain first-hand experience with regulatory aspects of Pharmacometrics, and to conduct and publish research in related areas are abundant. Candidates will need to be US permanent residents or citizens. Please forward your resume to: AAPS Attention: CRADA—Alzheimer’s Disease Model 2107 Wilson Boulevard, Suite 700 Arlington, VA 22201 crada@aaps.org http://www.aapspharmaceutica.com/crada Deadline for submissions: June 30, 2008

Prediction of rodent carcinogenic potential of naturally occurring chemicals in the human diet using high-throughput QSAR predictive modeling

Consistent with the U.S. Food and Drug Administration (FDA) Critical Path Initiative, predictive toxicology software programs employing quantitative structure–activity relationship (QSAR) models are currently under evaluation for regulatory risk assessment and scientific decision support for highly sensitive endpoints such as carcinogenicity, mutagenicity and reproductive toxicity. At the FDA's Center for Food Safety and Applied Nutrition's Office of Food Additive Safety and the Center for Drug Evaluation and Research's Informatics and Computational Safety Analysis Staff (ICSAS), the use of computational SAR tools for both qualitative and quantitative risk assessment applications are being developed and evaluated. One tool of current interest is MDL-QSAR predictive discriminant analysis modeling of rodent carcinogenicity, which has been previously evaluated for pharmaceutical applications by the FDA ICSAS. The study described in this paper aims to evaluate the utility of this software to estimate the carcinogenic potential of small, organic, naturally occurring chemicals found in the human diet. In addition, a group of 19 known synthetic dietary constituents that were positive in rodent carcinogenicity studies served as a control group. In the test group of naturally occurring chemicals, 101 were found to be suitable for predictive modeling using this software's discriminant analysis modeling approach. Predictions performed on these compounds were compared to published experimental evidence of each compound's carcinogenic potential. Experimental evidence included relevant toxicological studies such as rodent cancer bioassays, rodent anti-carcinogenicity studies, genotoxic studies, and the presence of chemical structural alerts. Statistical indices of predictive performance were calculated to assess the utility of the predictive modeling method. Results revealed good predictive performance using this software's rodent carcinogenicity module of over 1200 chemicals, comprised primarily of pharmaceutical, industrial and some natural products developed under an FDA-MDL cooperative research and development agreement (CRADA). The predictive performance for this group of dietary natural products and the control group was 97% sensitivity and 80% concordance. Specificity was marginal at 53%. This study finds that the in silico QSAR analysis employing this software's rodent carcinogenicity database is capable of identifying the rodent carcinogenic potential of naturally occurring organic molecules found in the human diet with a high degree of sensitivity. It is the first study to demonstrate successful QSAR predictive modeling of naturally occurring carcinogens found in the human diet using an external validation test. Further test validation of this software and expansion of the training data set for dietary chemicals will help to support the future use of such QSAR methods for screening and prioritizing the risk of dietary chemicals when actual animal data are inadequate, equivocal, or absent.