47 results on '"Linda Pan"'
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2. Rapid postglacial rebound amplifies global sea level rise following West Antarctic Ice Sheet collapse
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Linda Pan, Evelyn M. Powell, Konstantin Latychev, Jerry X. Mitrovica, Jessica R. Creveling, Natalya Gomez, Mark J. Hoggard, and Peter U. Clark
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- 2021
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Catalog
3. Data from Effect of Montanide and Poly-ICLC Adjuvant on Human Self/Tumor Antigen-Specific CD4+ T Cells in Phase I Overlapping Long Peptide Vaccine Trial
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Sacha Gnjatic, Andres M. Salazar, David Spriggs, Luis Ferran, Gerd Ritter, Linda Pan, Erika Ritter, Achim A. Jungbluth, Paul Sabbatini, and Takemasa Tsuji
- Abstract
Vaccination of patients with ovarian cancer with overlapping long peptides (OLP) from cancer-testis antigen NY-ESO-1 and poly-ICLC in Montanide-ISA-51 (Montanide) was found to consistently induce integrated immune responses (antibody, CD4+, and CD8+ T cells). Using detailed methods, we investigated the respective effects of poly-ICLC and Montanide adjuvant on pre- and postvaccine NY-ESO-1–specific CD4+ T cells, because of their central function for induction and maintenance of both antibody and CD8+ T cells. Polyclonal NY-ESO-1–specific CD4+ T-cell lines were generated from 12 patients using CD154-based selection of precursors before and after vaccination with (i) OLP alone, (ii) OLP in Montanide, or (iii) OLP and poly-ICLC in Montanide. Kinetics, quantification, fine specificity, avidity, and cytokine-producing pattern were analyzed in depth and compared between vaccine cohorts. Vaccination with OLP alone did not elicit CD4+ T-cell responses; it suppressed high-avidity CD4+ T-cell precursors that recognized naturally processed NY-ESO-1 protein before vaccination. Emulsification of OLP in Montanide was required for the expansion of high-avidity NY-ESO-1–specific CD4+ T-cell precursors. Poly-ICLC significantly enhanced CD4+ Th1 responses while suppressing the induction of interleukin (IL)-4–producing Th2 and IL-9–producing Th9 cells. In summary, Montanide and poly-ICLC had distinct and cooperative effects for the induction of NY-ESO-1–specific Th1 cells and integrated immune responses by OLP vaccination. These results support the use of admixing poly-ICLC in Montanide adjuvant to rapidly induce antitumor type I immune responses by OLP from self/tumor antigens in human cancer vaccines. Cancer Immunol Res; 1(5); 340–50. ©2013 AACR. more...
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- 2023
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4. Supplementary Figure 1 from Effect of Montanide and Poly-ICLC Adjuvant on Human Self/Tumor Antigen-Specific CD4+ T Cells in Phase I Overlapping Long Peptide Vaccine Trial
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Sacha Gnjatic, Andres M. Salazar, David Spriggs, Luis Ferran, Gerd Ritter, Linda Pan, Erika Ritter, Achim A. Jungbluth, Paul Sabbatini, and Takemasa Tsuji
- Abstract
PDF file - 13027K, Comparison of apparent avidities of NY-ESO-1-specific CD4+ T cells before and after vaccination. Apparent avidity (EC50) for recognition of the NY-ESO-1 assay OLP was determined for NY-ESO-1-specific CD4+ T cell lines before and after the vaccination. (A) Cohort 1 (OLP alone); (B) Cohort 2 (OLP in Montanide); and (C) Cohort 3 (OLP and poly-ICLC in Montanide). more...
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- 2023
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5. Supplementary Figure 2 from Effect of Montanide and Poly-ICLC Adjuvant on Human Self/Tumor Antigen-Specific CD4+ T Cells in Phase I Overlapping Long Peptide Vaccine Trial
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Sacha Gnjatic, Andres M. Salazar, David Spriggs, Luis Ferran, Gerd Ritter, Linda Pan, Erika Ritter, Achim A. Jungbluth, Paul Sabbatini, and Takemasa Tsuji
- Abstract
PDF file - 3271K, Comparison of NY-ESO-1-specific cytokine production between 3 cohorts before vaccination. Normalized cytokine production from NY-ESO-1-specific CD4+ T cells before vaccination is shown for statistical consideration. The shape of symbols indicates a single patient as shown in Fig. 1B. Bars indicate mean plus-minus SD. *: p=0.04 by Student's t-test. All other pairs show no statistically significant difference. more...
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- 2023
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6. Supplementary Figure Legend from Effect of Montanide and Poly-ICLC Adjuvant on Human Self/Tumor Antigen-Specific CD4+ T Cells in Phase I Overlapping Long Peptide Vaccine Trial
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Sacha Gnjatic, Andres M. Salazar, David Spriggs, Luis Ferran, Gerd Ritter, Linda Pan, Erika Ritter, Achim A. Jungbluth, Paul Sabbatini, and Takemasa Tsuji
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PDF file - 62K
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- 2023
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7. Supplementary Figure 3 from Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
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Sacha Gnjatic, Lloyd J. Old, Catherine Magid Diefenbach, Andres M. Salazar, Linda Pan, Ralph Venhaus, Eric W. Hoffman, David R. Spriggs, William Tew, Jason Konner, Martee L. Hensley, Katherine Bell-McGuinn, Carol Aghajanian, Gerd Ritter, Achim A. Jungbluth, Kevin Tuballes, Christine Sedrak, Erika Ritter, Luis Ferran, Takemasa Tsuji, and Paul Sabbatini more...
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PDF file - 1810K, Detection of NY-ESO-1-specific CD4+ T cells by intracellular cytokine staining. CD4+ T cells were stimulated once with T-cell depleted PBMC pulsed with NY-ESO-1 assay OLP and after 22-23 day culture, NY-ESO-1-specific IFN-γ and IL-5 production was evaluated by intracellular cytokine staining. Peptide-pulsed or unpulsed autologous EBV-B cells pulsed or unpulsed with 20-mer NY-ESO-1 peptides covering areas indicated were used as target cells. Responses shown at week 16 after vaccination in two patients (M09 and M19) representative of Cohort 2 and 3, respectively. more...
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- 2023
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8. Supplementary Figure Legend from Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
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Sacha Gnjatic, Lloyd J. Old, Catherine Magid Diefenbach, Andres M. Salazar, Linda Pan, Ralph Venhaus, Eric W. Hoffman, David R. Spriggs, William Tew, Jason Konner, Martee L. Hensley, Katherine Bell-McGuinn, Carol Aghajanian, Gerd Ritter, Achim A. Jungbluth, Kevin Tuballes, Christine Sedrak, Erika Ritter, Luis Ferran, Takemasa Tsuji, and Paul Sabbatini more...
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PDF file - 68K
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- 2023
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9. Supplementary Figure 1 from Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
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Sacha Gnjatic, Lloyd J. Old, Catherine Magid Diefenbach, Andres M. Salazar, Linda Pan, Ralph Venhaus, Eric W. Hoffman, David R. Spriggs, William Tew, Jason Konner, Martee L. Hensley, Katherine Bell-McGuinn, Carol Aghajanian, Gerd Ritter, Achim A. Jungbluth, Kevin Tuballes, Christine Sedrak, Erika Ritter, Luis Ferran, Takemasa Tsuji, and Paul Sabbatini more...
- Abstract
PDF file - 2015K, Injection site reaction in patient M21
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- 2023
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10. Supplementary Table 2 from Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
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Sacha Gnjatic, Lloyd J. Old, Catherine Magid Diefenbach, Andres M. Salazar, Linda Pan, Ralph Venhaus, Eric W. Hoffman, David R. Spriggs, William Tew, Jason Konner, Martee L. Hensley, Katherine Bell-McGuinn, Carol Aghajanian, Gerd Ritter, Achim A. Jungbluth, Kevin Tuballes, Christine Sedrak, Erika Ritter, Luis Ferran, Takemasa Tsuji, and Paul Sabbatini more...
- Abstract
PDF file - 70K, Incidence of treatment-related adverse events by maximum grade
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- 2023
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11. Data from Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
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Sacha Gnjatic, Lloyd J. Old, Catherine Magid Diefenbach, Andres M. Salazar, Linda Pan, Ralph Venhaus, Eric W. Hoffman, David R. Spriggs, William Tew, Jason Konner, Martee L. Hensley, Katherine Bell-McGuinn, Carol Aghajanian, Gerd Ritter, Achim A. Jungbluth, Kevin Tuballes, Christine Sedrak, Erika Ritter, Luis Ferran, Takemasa Tsuji, and Paul Sabbatini more...
- Abstract
Purpose: Long peptides are efficiently presented to both CD4+ and CD8+ T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.Experimental Design: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).Results: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1–specific antibody and CD8+ T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1–specific CD4+ T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1–specific immune responses.Conclusions: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8+ and CD4+) in nearly all vaccinated patients when given with appropriate adjuvants. Clin Cancer Res; 18(23); 6497–508. ©2012 AACR. more...
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- 2023
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12. Supplementary Figure 2 from Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
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Sacha Gnjatic, Lloyd J. Old, Catherine Magid Diefenbach, Andres M. Salazar, Linda Pan, Ralph Venhaus, Eric W. Hoffman, David R. Spriggs, William Tew, Jason Konner, Martee L. Hensley, Katherine Bell-McGuinn, Carol Aghajanian, Gerd Ritter, Achim A. Jungbluth, Kevin Tuballes, Christine Sedrak, Erika Ritter, Luis Ferran, Takemasa Tsuji, and Paul Sabbatini more...
- Abstract
PDF file - 196K, Humoral immune responses to NY-ESO-1 protein and peptides in individual patients throughout vaccination with NY-ESO-1 OLP. A) Reciprocal titers of plasma IgG antibodies were measured throughout vaccination by ELISA against NY-ESO-1 recombinant protein. Each patient was tested for all available time points, from prestudy (pre) up to week (w) 16. B) IgG plasma antibody responses were analyzed using 20-mer OLP in ELISA from samples at the time points where maximal titers had been achieved against NY-ESO-1 protein following vaccination. Peaks represent titers against 20-mer individual peptides centered around amino-acids from NY-ESO-1 shown along the X-axis. Reciprocal titers were considered significant if > 100. Assays representative of at least 2 repeats. more...
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- 2023
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13. Supplementary Table 1 from Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
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Sacha Gnjatic, Lloyd J. Old, Catherine Magid Diefenbach, Andres M. Salazar, Linda Pan, Ralph Venhaus, Eric W. Hoffman, David R. Spriggs, William Tew, Jason Konner, Martee L. Hensley, Katherine Bell-McGuinn, Carol Aghajanian, Gerd Ritter, Achim A. Jungbluth, Kevin Tuballes, Christine Sedrak, Erika Ritter, Luis Ferran, Takemasa Tsuji, and Paul Sabbatini more...
- Abstract
PDF file - 65K, Immunohistochemical analysis of NY-ESO-1 expression (mAb E978) in tumor tissue and vaccine regimen
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- 2023
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14. Female permanent contraception policies and occurrence at a sample of U.S. prisons and jails
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Y. Linda Pan, Carolyn Sufrin, Kareen Espino, and Lauren Beal
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medicine.medical_specialty ,Descriptive statistics ,business.industry ,media_common.quotation_subject ,Obstetrics and Gynecology ,Correctional Facilities ,Convenience sample ,Sample (statistics) ,Prison ,social sciences ,Article ,Unmet needs ,Contraception ,Policy ,Reproductive Medicine ,Sterilization (medicine) ,Prisons ,Family medicine ,medicine ,Humans ,Female ,business ,Jails ,Autonomy ,media_common - Abstract
OBJECTIVE(S): Incarcerated individuals have an unmet need for contraception, yet have also been subject to coercive permanent contraception practices. Data do not exist on prison and jail policies around access to permanent contraception or how often it occurs among women in custody. We sought to describe permanent and reversible contraception policies at U.S carceral institutions and the frequency of these procedures. STUDY DESIGN: We surveyed a convenience sample of 22 state prison systems and 6 county jails from 2016 to 2017 about female permanent contraception and reversible contraception policies. In addition, 10 prisons and 4 jails reported 6 months of monthly data on the number of postpartum permanent contraception procedures performed on women who gave birth in custody. We analyzed results for descriptive statistics. RESULTS: Eleven prisons (50%) and 5 jails (83%) permitted female permanent contraception; 7 of these prisons and 3 of these jails allowing permanent contraception did not have a written policy about it. Six prisons and no jails provided access to permanent but not reversible contraception. Over 6 months, 3 women from 2 prisons and 4 women at 2 jails received postpartum permanent contraception. CONCLUSION(S): The majority of prisons and jails in our study allowed incarcerated women to have permanent contraception in custody, often without formalized policies in place. Postpartum permanent contraception occurred during the study period. Given the inherent lack of autonomy of incarceration and history of sterilization abuses in this marginalized group, policy-makers should advance policies that avoid coercive permanent contraception and increase access to reversible contraception in carceral settings. IMPLICATIONS: Many carceral institutions permit women to undergo permanent contraception but provide no access to reversible contraception; this practice raises concern for compromised autonomy and further reproductive marginalization of a group with limited access to quality reproductive health care. more...
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- 2021
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15. A detection of the sea level fingerprint of Greenland Ice Sheet melt
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Sophie Coulson, Sönke Dangendorf, Jerry X. Mitrovica, Mark E. Tamisiea, Linda Pan, and David T. Sandwell
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Multidisciplinary - Abstract
Rapid melting of ice sheets and glaciers drives a unique geometry, or fingerprint, of sea-level change, including a sea-level fall in the vicinity of the ice sheet that is an order of magnitude greater than the associated global mean sea-level rise of the melt event. The detection of individual fingerprints has been challenging due to sparse sea surface height measurements at high latitudes and the difficulty of disentangling ocean dynamic variability from the signal. Efforts to date have analyzed sea level records outside the zone of major sea-level fall, where the gradients and amplitudes of the fingerprint signal are significantly lower. We predict the fingerprint of Greenland Ice Sheet (GrIS) melt using new ice mass loss estimates from radar altimetry data and model reconstructions of nearby glaciers, and compare this prediction to an independent, altimetry-derived sea surface height trend corrected for ocean dynamic variability in the region adjacent to the ice sheet. The two fields show consistent gradients across the region, with the expected strong drawdown of the sea surface toward GrIS. A statistically significant correlation between the two fields (p < 0.001) provides the first unambiguous observational detection of the near-field sea level fingerprint of recent GrIS melting in our warming world. This detection provides a robust map of the impact of ice mass flux on global oceans since the early 1990s, and validates theoretical and numerical developments in the sea level modelling community. more...
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- 2022
16. The influence of lateral Earth structure on inferences of global ice volume during the Last Glacial Maximum
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Linda Pan, Glenn A. Milne, Konstantin Latychev, Samuel L. Goldberg, Jacqueline Austermann, Mark J. Hoggard, and Jerry X. Mitrovica
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Archeology ,Global and Planetary Change ,Geology ,Ecology, Evolution, Behavior and Systematics - Published
- 2022
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17. Reassessing the Contribution of West Antarctica to Last Interglacial Sea Level in Light of 3D Mantle Viscosity Structure
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E. M. Powell, Natalya Gomez, Linda Pan, Mark Hoggard, Konstantin Latychev, Jerry X. Mitrovica, Jessica R. Creveling, and Peter U. Clark
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Viscosity ,Interglacial ,Geochemistry ,Geology ,Mantle (geology) ,Sea level - Abstract
Studies of peak global mean sea level (GMSL) during the Last Interglacial (LIG; 130-116 ka) commonly cite values ranging from ~2-5 m for the maximum contribution from grounded, marine-based sectors of the West Antarctic Ice Sheet (WAIS). However, this estimate neglects viscoelastic crustal uplift and the associated meltwater flux out of marine sectors as they are exposed, a contribution considered to be small and slowly-accumulating. This assumption should be revisited, as a range of evidence indicates that West Antarctica is underlain by shallow mantle of anomalously low viscosity. By incorporating this complex structure into a gravitationally self-consistent sea-level calculation, we find that GMSL differs substantially from previous estimates. Our results indicate that these estimates thus require a reassessment of the contribution to GMSL rise from WAIS collapse, as will ice sheet models that do not account for the uplift mechanism. This conclusion has important implications for the sea level budget not only during the LIG, but also for all previous interglacials and projections of GMSL change in the future warming world. more...
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- 2021
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18. The influence of the solid Earth on the contribution of marine sections of the Antarctic ice sheet to future sea level change
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Natalya Gomez, Jeannette Wang, Jerry X. Mitrovica, Maryam Yousefi, David Pollard, Linda Pan, and Konstantin Latychev
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Oceanography ,Antarctic ice sheet ,Future sea level ,Solid earth ,Geology - Abstract
The future retreat of marine-based sectors of the Antarctic Ice Sheet (AIS) and its consequent global mean sea level (GMSL) rise is driven by various climatic and non-climatic feedbacks between ice, ocean, atmosphere, and solid Earth. The primary mode of ice loss in marine sectors of the AIS is dynamic flow of ice across the grounding line into the ocean. The flux of ice across the grounding line is strongly sensitive to the thickness of ice there, which is in turn proportional to the water depth (sea level) such that sea level rise enhances ice loss and grounding line retreat while sea level fall acts to slow or stop migration of the grounding line. In response to the unloading from removal of ice mass, the underlying bedrock deforms isostatically leading to lower local sea surface which promotes stabilization of the grounding line. In addition to its effect on AIS evolution, solid Earth deformation also alters the shape and size of the ocean basin areas that are exposed as marine areas of ice retreat and influences the amount of meltwater that leaves Antarctica and contributes to global sea-level rise. The solid Earth deformational response to surface loading changes, in terms of both magnitude and timescales, depends on Earth rheology. Seismic tomography models indicate that the interior structure of the Earth is highly variable over the Antarctica with anomalously low shallow mantle viscosities across the western section of the AIS. An improved projection of the contribution from AIS to sea level change requires a consideration of this complexity in Earth structure. Here we adopt a state-of-the-art seismic velocity model to build a high-resolution 3D viscoelastic structure model beneath Antarctica. We incorporate this structure into a high spatiotemporal resolution sea-level model to simulate the influence of solid Earth deformation on contributions of the AIS evolution to future sea-level change. Our sea-level model is coupled with the dynamics of PSU ice sheet model and our calculations are based on a range of future climate forcings. We show that the influence of applying a spatially variable Earth structure is significant, particularly in the regions of West Antarctica where upper mantle viscosities are lower and the elastic lithosphere is thinned. more...
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- 2021
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19. Evolution and genetics of precocious burrowing behavior in Peromyscus mice
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Hillery C. Metz, Yangshu Linda Pan, Hopi E. Hoekstra, and Nicole L. Bedford
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Peromyscus ,biology ,fungi ,Zoology ,Single gene ,Peromyscus polionotus ,musculoskeletal system ,Burrow ,biology.organism_classification ,Life stage ,parasitic diseases ,Juvenile ,Allele ,Hybrid - Abstract
A central challenge in biology is to understand how innate behaviors evolve between closely related species. One way to elucidate how differences arise is to compare the development of behavior in species with distinct adult traits. Here, we report that Peromyscus polionotus is strikingly precocious with regard to burrowing behavior, but not other behaviors, compared to its sister species P. maniculatus . In P. polionotus , burrows were excavated as early as 17 days of age, while P. maniculatus did not build burrows until 10 days later. Moreover, the well-known differences in burrow architecture between adults of these species -- P. polionotus adults excavate long burrows with an escape tunnel, while P. maniculatus dig short, single-tunnel burrows -- were intact in juvenile burrowers. To test whether this juvenile behavior is influenced by early-life environment, pups of both species were reciprocally cross-fostered. Fostering did not alter the characteristic burrowing behavior of either species, suggesting these differences are genetic. In backcross F2 hybrids, we show that precocious burrowing and adult tunnel length are genetically correlated, and that a single P. polionotus allele in a genomic region linked to adult tunnel length is predictive of precocious burrow construction. The co-inheritance of developmental and adult traits indicates the same genetic region -- either a single gene with pleiotropic effects, or closely linked genes -- acts on distinct aspects of the same behavior across life stages. Such genetic variants likely affect behavioral drive (i.e. motivation) to burrow, and thereby affect both the development and adult expression of burrowing behavior. more...
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- 2017
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20. NY-ESO-1 Protein Cancer Vaccine With Poly-ICLC and OK-432: Rapid and Strong Induction of NY-ESO-1-specific Immune Responses by Poly-ICLC
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Koji Kurose, Yoshihiro Ohue, Shuji Takiguchi, Hisashi Wada, Hiroyoshi Nishikawa, Akiko Morimoto-Okazawa, Eiichi Sato, Hirotsugu Nagase, Ralph Venhaus, Makoto Yamasaki, Tomohira Takeoka, Eiichi Nakayama, Midori Isobe, Atsunari Kawashima, Linda Pan, Masaki Mori, Yuichiro Doki, Kota Iwahori, Mikio Oka, Mitsunobu Matsumoto, and Takayuki Kanazawa more...
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0301 basic medicine ,Pharmacology ,Cancer Research ,biology ,business.industry ,medicine.medical_treatment ,Immunology ,Vaccination ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Immunization ,030220 oncology & carcinogenesis ,Poly ICLC ,medicine ,biology.protein ,Immunology and Allergy ,Cancer vaccine ,Antibody ,Seroconversion ,business ,Adjuvant ,medicine.drug - Abstract
We conducted a clinical trial of a cancer vaccine using NY-ESO-1 protein with polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) and/or OK-432 against solid tumors. A total of 15 patients were sequentially enrolled in 4 cohorts. Patients in cohort 1 received NY-ESO-1 protein; cohort 2a received NY-ESO-1 protein+OK-432; cohort 2b received NY-ESO-1 protein+poly-ICLC; cohort 3 received NY-ESO-1 protein+OK-432+poly-ICLC with Montanide ISA-51. The endpoints of this trial were safety, NY-ESO-1 immune responses, and clinical response. Vaccine-related adverse events observed were fever and injection-site reaction (grade 1). Two patients showed stable disease after vaccination. NY-ESO-1 antibodies were observed in 4 patients at the baseline (sero-positive) and augmented in all patients after vaccination. Eleven patients showed a conversion of negative antibody responses at baseline to positive after vaccination (seroconversion). The seroconversions were observed in all 11 sero-negative patients by the fourth immunization; in particular, it was observed by the second immunization in patients with poly-ICLC, and these induced antibody responses were stronger than those in patients immunized without poly-ICLC. The number of NY-ESO-1-specific interferon (IFN)γ-producing T cells was increased in patients immunized with poly-ICLC and/or OK-432, and furthermore, the increase of IFNγ-producing CD8 T cells in patients immunized with poly-ICLC was significantly higher than that in patients without poly-ICLC. Nonspecific activations of T-cell or antigen presenting cells were not observed. Our present study showed that poly-ICLC is a promising adjuvant for cancer vaccines. more...
- Published
- 2017
21. NY-ESO-1 specific antibody and cellular responses in melanoma patients primed with NY-ESO-1 protein in ISCOMATRIX and boosted with recombinant NY-ESO-1 fowlpox virus
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Linda Pan, Lloyd L. Old, Vincenzo Cerundolo, Paul Nathan, Abdelouahid Tajar, Mark R. Middleton, Christian H. Ottensmeier, Judy Browning, Christian Verfaille, Jonathan Cebon, Sacha Gnjatic, Ji-Li Chen, Douglas G. Altman, Sarah Pratap, Ioannis Karydis, Andrea Tarlton, Amina Dawoodji, and Ralph Venhaus more...
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Fowlpox ,Cancer Research ,Melanoma ,T cell ,Heterologous ,Biology ,medicine.disease ,Virology ,Fowlpox virus ,Vaccination ,medicine.anatomical_structure ,Oncology ,Immunology ,medicine ,NY-ESO-1 ,CD8 - Abstract
Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8(+) or CD4(+) T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4(+) T cell and antibody response, which was maintained by both regiments at similar levels. However, CD8(+) T cell responses were significantly boosted in 3 out of 18 patients in Arm A after the first rF-NY-ESO-1 injection and such responses were maintained until the end of the trial, while no patients in Arm B showed similar CD8(+) T cell responses. In addition, our results clearly identified immunodominant regions in the NY-ESO-1 protein: NY-ESO-179-102 and NY-ESO-1115-138 for CD4+ T cells and NY-ESO-185-108 for CD8+ T cells in a large proportion of vaccinated patients. These regions of NY-ESO-1 protein should be considered in future clinical trials as immunodominant epitopes. more...
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- 2014
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22. Vaccination With NY-ESO-1 Overlapping Peptides Mixed With Picibanil OK-432 and Montanide ISA-51 in Patients With Cancers Expressing the NY-ESO-1 Antigen
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Kazuhiro Kakimi, Yuichiro Doki, Hirokazu Matsushita, Yasuyuki Seto, Kazuhiro Yamada, Katsuyuki Kiura, Makoto Yamasaki, Heiichiro Udono, Eiichi Nakayama, Hisashi Wada, Keiji Iwatsuki, Shingo Eikawa, Yu Mizote, Mikio Oka, Ralph Venhaus, Midori Isobe, Linda Pan, Eiichi Sato, Hiroshi Miyata, Kazuhide Tsuji, Hiroyoshi Nishikawa, and Nagio Takigawa more...
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CD4-Positive T-Lymphocytes ,Male ,Cancer Research ,Esophageal Neoplasms ,Immunology ,Epitopes, T-Lymphocyte ,Oleic Acids ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Cancer Vaccines ,Epitope ,Picibanil ,Immune system ,Antigen ,Antigens, Neoplasm ,Humans ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,Mannitol ,Amino Acid Sequence ,Cells, Cultured ,Aged ,Pharmacology ,biology ,business.industry ,Vaccination ,Membrane Proteins ,Middle Aged ,Virology ,Peptide Fragments ,Immunity, Humoral ,Treatment Outcome ,Vaccines, Subunit ,biology.protein ,Cytokines ,Female ,Cancer vaccine ,NY-ESO-1 ,Antibody ,business - Abstract
We conducted a clinical trial of an NY-ESO-1 cancer vaccine using 4 synthetic overlapping long peptides (OLP; peptides #1, 79-108; #2, 100-129; #3, 121-150; and #4, 142-173) that include a highly immunogenic region of the NY-ESO-1 molecule. Nine patients were immunized with 0.25 mg each of three 30-mer and a 32-mer long NY-ESO-1 OLP mixed with 0.2 KE Picibanil OK-432 and 1.25 mL Montanide ISA-51. The primary endpoints of this study were safety and NY-ESO-1 immune responses. Five to 18 injections of the NY-ESO-1 OLP vaccine were well tolerated. Vaccine-related adverse events observed were fever and injection site reaction (grade 1 and 2). Two patients showed stable disease after vaccination. An NY-ESO-1-specific humoral immune response was observed in all patients and an antibody against peptide #3 (121-150) was detected firstly and strongly after vaccination. NY-ESO-1 CD4 and CD8 T-cell responses were elicited in these patients and their epitopes were identified. Using a multifunctional cytokine assay, the number of single or double cytokine-producing cells was increased in NY-ESO-1-specific CD4 and CD8 T cells after vaccination. Multiple cytokine-producing cells were observed in PD-1 (-) and PD-1 (+) CD4 T cells. In conclusion, our study indicated that the NY-ESO-1 OLP vaccine mixed with Picibanil OK-432 and Montanide ISA-51 was well tolerated and elicited NY-ESO-1-specific humoral and CD4 and CD8 T-cell responses in immunized patients. more...
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- 2014
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23. Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma
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Patrick A. Ott, Anna C. Pavlick, Bor-Wen Wu, Richard D. Carvajal, Lloyd J. Old, Ralph Venhaus, Eric W. Hoffman, Linda Pan, Neeta Pandit-Taskar, Achim A. Jungbluth, John S. Bomalaski, and Jedd D. Wolchok more...
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Adult ,Male ,Uveal Neoplasms ,medicine.medical_specialty ,Pathology ,Skin Neoplasms ,Maximum Tolerated Dose ,Arginine ,Hydrolases ,Argininosuccinate synthase ,Gastroenterology ,Article ,Polyethylene Glycols ,Cohort Studies ,Immunoenzyme Techniques ,Internal medicine ,medicine ,Humans ,Tissue Distribution ,Pharmacology (medical) ,Melanoma ,Survival rate ,Arginine deiminase ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Pharmacology ,Dose-Response Relationship, Drug ,biology ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Survival Rate ,Oncology ,Pharmacodynamics ,Toxicity ,biology.protein ,Immunohistochemistry ,Female ,business ,Follow-Up Studies - Abstract
Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup. more...
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- 2012
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24. Immunoediting and persistence of antigen-specific immunity in patients who have previously been vaccinated with NY-ESO-1 protein formulated in ISCOMATRIX™
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Ian D. Davis, W. Hopkins, Weisan Chen, Catherine Barrow, Lloyd J. Old, Duncan MacGregor, Eric W. Hoffman, Heather Jackson, Judy Browning, Ralph Venhaus, Eugene Maraskovsky, Linda Pan, Nektaria Dimopoulos, David S. Williams, Jonathan Cebon, and Theo Nicholaou more...
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Adult ,Male ,Cancer Research ,medicine.medical_treatment ,Molecular Sequence Data ,Immunology ,Down-Regulation ,Breast Neoplasms ,Cancer Vaccines ,Disease-Free Survival ,Drug Hypersensitivity ,Immune system ,Adjuvants, Immunologic ,Antigen ,Antigens, Neoplasm ,Immunity ,medicine ,Humans ,Immunology and Allergy ,Amino Acid Sequence ,Prospective Studies ,Melanoma ,Phospholipids ,Aged ,Skin ,biology ,business.industry ,Membrane Proteins ,Middle Aged ,Saponins ,Immunohistochemistry ,Vaccination ,Drug Combinations ,Cholesterol ,Oncology ,Immunoediting ,biology.protein ,Female ,Antibody ,business ,Adjuvant ,CD8 - Abstract
NY-ESO-1 protein formulated in ISCOMATRIX™ results in CD4+, CD8+ T cell and antibody-mediated immunity. We evaluated persistence of immunity, relapse-free survival and tumour antigen expression upon relapse in patients vaccinated in an earlier trial. Immunity was measured in 28 patients with resected NY-ESO-1-expressing tumours (melanoma 25, breast 3) 252–1,155 days (median = 681) after vaccination. In the earlier vaccination, trial patients received NY-ESO-1 with ISCOMATRIX™ adjuvant at three protein doses 10 μg, 30 μg or 100 μg (n = 14); 100 μg NY-ESO-1 protein (n = 8) or placebo (n = 6), together with 1 μg of intradermal (ID) NY-ESO-1 protein twice for DTH skin testing. Immune responses assessed in the current study included antibody titres, circulating NY-ESO-1-specific T cells and DTH reactivity 2 days after DTH skin testing with NY-ESO-1 protein (1 μg) or peptides (10 μg). Relapse-free survival was determined for 42 melanoma patients. On relapse NY-ESO-1 and HLA, class I was assessed by immunohistochemistry in 17. Persisting anti-NY-ESO-1 immunity was detected in 10/14 recipients who had previously received vaccine with ISCOMATRIX™ adjuvant. In contrast, immunity only persisted in 3/14 who received 100 μg un-adjuvanted NY-ESO-1 protein (3/8) or 2 μg DTH protein (0/6) P = 0.02. Hence, persisting NY-ESO-1 immunity was associated with prior adjuvant. Tumour NY-ESO-1 or HLA class I was downregulated in participants who relapsed suggesting immunoediting had occurred. Immunoediting suggests that a signal of anti-tumour activity was observed in high-risk resected melanoma patients vaccinated with NY-ESO-1/ISCOMATRIX™. This was associated with measurable persisting immunity in the majority of vaccinated subjects tested. A prospective randomised trial has been undertaken to confirm these results. more...
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- 2011
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25. Heteroclitic serological response in esophageal and prostate cancer patients after NY-ESO-1 protein vaccination
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Nami Okazaki, Lloyd J. Old, Hiroshi Miyata, Sacha Gnjatic, Hiroyoshi Nishikawa, Yurika Nakamura, Makoto Yamasaki, Naoaki Mizuno, Shinichi Fujiwara, Gerd Ritter, Eiichi Nakayama, Junji Kawada, Erika Ritter, Midori Isobe, Achim A. Jungbluth, Hisashi Wada, Roger Murphy, Yuichiro Doki, Linda Pan, Akiko Uenaka, Takashi Saika, and Ralph Venhaus more...
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Male ,Cancer Research ,Esophageal Neoplasms ,Antibodies, Neoplasm ,Cancer Vaccines ,Mice ,Immune system ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,Mice, Inbred BALB C ,biology ,business.industry ,Membrane Proteins ,Prostatic Neoplasms ,Virology ,Vaccination ,Oncology ,Immunology ,biology.protein ,Cancer/testis antigens ,Immunohistochemistry ,Cancer vaccine ,NY-ESO-1 ,Antibody ,business - Abstract
NY-ESO-1 is a prototypic cancer/testis antigen. In a recent phase I clinical trial, we vaccinated 13 patients bearing NY-ESO-1-expressing tumors with a complex of cholesterol-bearing hydrophobized pullulan (CHP) and NY-ESO-1 protein (CHP-NY-ESO-1) and showed efficient induction of NY-ESO-1 antibody, and CD4 and CD8 T cell responses using peripheral blood from the patients. In our study, we analyzed heteroclitic serological responses in those patients after vaccination. Serological response against 11 tumor antigens including MAGE-A1, MAGE-A3, MAGE-A4, CT7/MAGEC1, CT10/MAGEC2, CT45, CT46/HORMAD1, SOX2, SSX2, XAGE1B and p53 was examined by enzyme-linked immunosorbent assay (ELISA) using sera from ten vaccinated patients. Expression of tumor antigens was determined by reverse transcription-polymerase chain reaction or immunohistochemistry. Eight of nine patients who showed antibody responses against NY-ESO-1 also showed an antibody response against at least 1 of these 11 tumor antigens after vaccination. In one patient, seven tumor antigens were recognized. Specificity analysis of the antibody response by ELISA using control recombinant proteins and synthetic peptides and by Western blot showed that the response was not against His6-tag and/or bacterial products included in a preparation of CHP-NY-ESO-1 used for vaccination. Thus, heteroclitic serological responses appear to be indicative of the overall immune response against the tumor, and their analysis could be useful for immune monitoring in cancer vaccine. more...
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- 2011
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26. Regulatory T-Cell–Mediated Attenuation of T-Cell Responses to the NY-ESO-1 ISCOMATRIX Vaccine in Patients with Advanced Malignant Melanoma
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Ralph Venhaus, Ian D. Davis, Eric W. Hoffman, Wendie Hopkins, Nektaria Dimopoulos, Lena Miloradovic, Theo Nicholaou, Weisan Chen, Lisa M. Ebert, Bee Shin Tan, Linda Pan, Jonathan Cebon, Grant A. McArthur, Eugene Maraskovsky, and Heather Jackson more...
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Adult ,Male ,Cancer Research ,Regulatory T cell ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Cancer Vaccines ,T-Lymphocytes, Regulatory ,Immune system ,Adjuvants, Immunologic ,Antigen ,Antigens, Neoplasm ,medicine ,Humans ,Hypersensitivity, Delayed ,IL-2 receptor ,Melanoma ,Phospholipids ,Aged ,Aged, 80 and over ,business.industry ,Vaccination ,Membrane Proteins ,FOXP3 ,Immunotherapy ,Middle Aged ,Saponins ,Drug Combinations ,Cholesterol ,medicine.anatomical_structure ,Oncology ,Immunology ,Female ,Cancer vaccine ,business - Abstract
Purpose: NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. We recently developed a vaccine consisting of full-length recombinant NY-ESO-1 protein formulated with ISCOMATRIX adjuvant, which generated strong humoral and T-cell–mediated immune responses and seemed to reduce the risk of disease relapse in patients with fully resected melanoma. This study examines the clinical and immunologic efficacy of the same vaccine in patients with advanced metastatic melanoma. Experimental Design: Delayed-type hypersensitivity responses, circulating NY-ESO-1–specific CD4+ and CD8+ T cells, and proportions of regulatory T cells (Treg) were assessed in patients. Results: In contrast to patients with minimal residual disease, advanced melanoma patients showed no clinical responses to vaccination. Although strong antibody responses were mounted, the generation of delayed-type hypersensitivity responses was significantly impaired. The proportion of patients with circulating NY-ESO-1–specific CD4+ T cells was also reduced, and although many patients had CD8+ T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting. Tregs were enumerated in the blood by flow cytometric detection of cells with a CD4+CD25+FoxP3+ and CD4+CD25+CD127− phenotype. Patients with advanced melanoma had a significantly higher proportion of circulating Treg compared with those with minimal residual disease. Conclusions: Our results point to a tumor-induced systemic immune suppression, showing a clear association between the stage of melanoma progression, the number of Treg in the blood, and the clinical and immunologic efficacy of the NY-ESO-1 ISCOMATRIX cancer vaccine. more...
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- 2009
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27. Immunization of Malignant Melanoma Patients with Full-Length NY-ESO-1 Protein Using TLR7 Agonist Imiquimod as Vaccine Adjuvant
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Ralph Venhaus, Lloyd Old, Crystal M. Cruz, Nina Bhardwaj, Francesca Angiulli, Sacha Gnjatic, Rose Marie Holman, Erika Ritter, Russell S. Berman, Sylvia Adams, Richard L. Shapiro, Yongzhao Shao, Elizabeth Hardin, Achim A. Jungbluth, Angelica Angiulli, Anna C. Pavlick, David O'Neill, Eric W. Hoffman, Daisuke Nonaka, Linda Pan, Kimberly Siu, Luis Chiriboga, Olivier Manches, and Natalie Berner more...
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Adult ,Male ,Biopsy ,medicine.medical_treatment ,Immunology ,Pilot Projects ,Imiquimod ,Cancer Vaccines ,Article ,Immune system ,Adjuvants, Immunologic ,Antigen ,Antigens, Neoplasm ,medicine ,Humans ,Immunology and Allergy ,Melanoma ,Aged ,business.industry ,Immunogenicity ,Membrane Proteins ,TLR7 ,Middle Aged ,medicine.disease ,Toll-Like Receptor 7 ,Erythema ,Antibody Formation ,Aminoquinolines ,Female ,Immunization ,NY-ESO-1 ,business ,Adjuvant ,Epitope Mapping ,medicine.drug - Abstract
T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via TLRs. In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations against the cancer/testis Ag NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod preconditioned sites followed by additional topical applications of imiquimod. The regimen was very well tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod’s in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs, NK cells, and, to a lesser extent, plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist used as a vaccine adjuvant in cancer patients. Imiquimod’s adjuvant effects require further evaluation and likely need optimization of parameters such as formulation, dose, and timing relative to Ag exposure for maximal immunogenicity. more...
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- 2008
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28. Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015
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Erik Wennerberg, Gabriele Madonna, Gennaro Ciliberto, Michele Minopoli, Caroline Dutriaux, Matthew Wongchenko, Elisabetta Gambale, David F. Stroncek, Céleste Lebbé, Ani S. Balmanoukian, Gianluca Di Monta, Vincenzo Ingangi, Soldano Ferrone, Ivan Marquez-Rodas, Giuseppe Masucci, Janis M. Taube, Simona Mastroeni, Gerardo Bott, Franck Pagès, Jonathan M. Pitt, Judit Olasz, Elisabetta Panza, Paola Michelozzi, Daniil Stoyakovskiy, Stéphane Dalle, Mario Sznol, John M. Kirkwood, Keith T. Flaherty, Maria Capuano, Amalia Azzariti, Edward Cha, Peter Boasberg, Maria Godeny, Angela Gismondi, Ornella Franzese, Giusy Gentilcore, Jean-Jacques Grob, Olivier Michielin, Adina Elena Stanciu, Giuseppe Cirino, Julien Fourcade, Nelofer Syed, Giuseppe Ercolano, Caroline Robert, Ascierto Paolo Antonio, Christine K. Gause, Silviu Voinea, Adeeb Rahman, Anne Caignard, Camila Flores, Cristina Fortes, Yuya Yoshimoto, Angela Sandru, Andras Szollar, Monica Cantile, Frederic Lehmann, Maria Libera Ascierto, Sacha Gnjatic, Marco Tucci, Rosa Russo, Giuseppina Liguori, Valeria De Biasio, David Ross Kaufman, Mary Ruisi, Ewa Kalinka-Warzocha, Phillip Wong, Rosaria Falcon, Vincenzo Faiola, Nicole Richie, Lars Ny, Miri Blank, Paola De Cicco, Anna Passarelli, Jean-François Baurain, Guido Kroemer, Claudio Jommi, Francesca Capone, Maria Teresa Fierro, Tracee L. McMiller, Lev V. Demidov, Alessandro Testori, Omid Hamid, Marone Ugo, Annamaria Anniciello, Andrew J. Park, Fara De Murtas, RuthAnn Gordan, Emil Farkas, David Hogg, Alessandra Di Paolo, Mark Maurer, Yangyang Wang, Mario Mandalà, Rodabe N. Amaria, Massimiliano Di Marzo, Stefania Guida, Luigi Fattore, Veronica Huber, Ludmila Danilova, Luigi Aurisicchio, Gabriella Aquino, Domenico Mallardo, Catriona M. McNeil, Stephanie Anne Kronenberg, Consiglia Carella, Theresa S. Pritchard, Katia Bifulco, Michaela Semeraro, Carlo M. Croce, David P. Enot, Laurence Zitvogel, Marcella Occelli, Benjamin Weide, Magdalena Thurin, Margherita Cerrone, Naiyer A. Rizvi, Blessing Agunwamba, Stella D'Oronzo, Sarah Jegou, Stucci Stefania, Drew M. Pardoll, Vito Michele Garrisi, Haidong Tang, Szabolcs Horvath, Hong Wang, Benjamin Brady, Antonio Doronzo, Claudia Marino, Xian He, Michael A. Davies, Hexiao Wang, Isabelle Rooney, Orsolya Csuka, Maurizio Nudo, Lance Leopold, Jeffrey S. Wasser, Sabino Strippoli, Silvia Ch Formenti, MariaLaura Foddai, Michael A. Postow, Robert H.I. Andtbacka, Paul Lorigan, Tommy Andersson, Naoko Imai, Ari VanderWalde, Mariaelena Capone, Ilsung Chang, Laura Lattanzio, Carmen Loquai, Arantxa Sancho, Christine Horak, Federica Sallusto, Timea Balatoni, Maha Ayyoub, Angela Santoni, Alessio Caggiati, Anna Lisa De Presbiteris, Henrik Schmidt, Paola Savoia, Pontus Berglund, Igor Puzanov, Aurélien Marabelle, Ana Carrizossa Anderson, Hassane M. Zarour, Maria Wolodarski, Patrick Hwu, Joel Jiang, Pio Zeppa, Jeffrey A. Sosman, Eugenio Fernandez, Susan Costantini, Marcus Ballinger, Luc Thomas, Leslie Cope, Rolf Kiessling, Christophe Borg, Francesca Platini, Florian Stratica, Tilman T. Rau, Craig L. Slingluff, Paolo A. Ascierto, Angela Ianaro, Harriet M. Kluger, Stephen Hodi, Tara C. Gangadhar, Claire Vanpouille-Box, Caroline Flament, Hearn J. Cho, Mannavola Francesco, Takahiro Yamazaki, Charles G. Drake, Jason J. Luke, Miklos Kasler, Linda Pan, Caracò Corrado, Alfonso Berrocal, Angel Rivera, Vera Hirsh, Eduardo J. Patriarca, Giovanni Di Giulio, Antonello Pessi, Helena Stabile, Helene Hardy, Tucci Marco, Ralph Venhaus, Maria Luisa Di Cecilia, Catherine A. Harwood, Jonathan Cebon, Anna Maria Anniciello, Grant A. McArthur, Carlo Baldi, Ahmad A. Tarhini, Shelley Coleman, Gil Bar-Sela, Axel Hauschild, Byoung S. Kwon, Maria Paula Roberti, Sabin Cinca, Tiziana Cocco, Valeria Sorrentino, Jeffrey Wallin, Rosa Camerlingo, Sandra Demaria, Jedd D. Wolchok, Isabel Poschke, Alessandro Lugli, Michael B. Atkins, Andrea Cavalcanti, Laura Marra, Rosamaria Pinto, Adam D. Cohen, Michele Maio, Weiyi Peng, Rosario Guarrasi, David Enot, Antoni Ribas, Oscar Alabiso, Chiara Armogida, Silvestris Franco, Jessica C. Hassel, Rita Mancini, Michele Guida, Silvia C. Formenti, Andrea P. Sponghini, Imma Maida, Alba Zappalà, Charlotte M. Proby, Alan J. Korman, Yibing Yan, Matias Chacon, Haiying Xu, Carolin Blattner, Maria-Paula Roberti, Lisa Chen, James Larkin, Ryan J. Sullivan, Madonna Gabriele, Nadege Vimond, Cosmo Di Donna, Farnaz Moradi, Manish R. Patel, Sylvie Rusakiewicz, Francesca Passarelli, Luis de la Cruz-Merino, Nicolas Jacquelot, Roberta Miceli, Viktor Umansky, Akos Savolt, David Rondonotti, Gabriella Liszkay, Jianda Yuan, Stefani Spranger, Yufan Zhao, Yehuda Shoenfeld, Todd M. Bauer, Claus Garbe, Joe-Marc Chauvin, Achim A. Jungbluth, Cristiana Lo Nigro, Alexander M. Lesokhin, Gabriella Guida, Brigitte Dréno, Cindy Sanders, Jeffrey S. Weber, Janet Maleski, Chris Cheadle, Romain Daillère, Isabella Sperduti, Michaele Maio, Claudia Felici, Parneet K. Cheema, Concetta Ragone, Johan Hansson, Klara Eles, Victoria Atkinson, Speiser Daniel, Daniel O. Koralek, Zhaojun Sun, Debora Malpicci, Elena Marra, Rickard Linnskog, Jeffrey Chou, Yang Wang, Eugenia Panaitescu, F. Stephen Hodi, Anthony J. Olszanski, Chiara Botti, Nicola Mozzillo, Anna Ferretta, Paul B. Chapman, Michaë la Semeraro, Belinda Palermo, Francesco Sabbatino, Neil H. Segal, Yago Pico de Coaña, Tseng-hui Timothy Chen, Ornella Pagliano, John B. A. G. Haanen, Huibin Yue, Emilia Caputo, Alan E. Berger, Simona De Summa, Nikoletta Lendvai, Paola Queirolo, Francesco Mannavola, Thomas F. Gajewski, Michele De Tursi, Paola Nisticò, Karen Briscoe, Karmele Mujika Eizmendi, Maria Vincenza Carrier, Passarelli Anna, Laurent Mortier, Crescenzo D'Alterio, Jorge Camarero, Licia Rivoltini, Pietro Quaglino, Davide Quaresmini, Marie Vétizou, Anna Maria Di Giacomo, Chandra Prakash Prasad, Riccardo Bono, Vichnou Poirier-Colame, David Smith, Capone Mariaelena, Giosuè Scognamiglio, Margaret K. Callahan, Vashisht Gopal Yennu Nanda, Fabiola Gilda Cordaro, George J. Netto, Madalina Bolovan, Federica Fratangelo, Josep Malvehy, Robert A. Anders, Karsten A. Pilones, Vincenzo C. Battarra, Karin Leandersson, Maria Letizia Motti, Yang Xin Fu, Tim Crook, Sarah Nataraj, Alastair M. Thompson, Franco Silvestris, Carolina Cauchi, Georgina V. Long, Holbrook E Kohrt, Giuseppe Pirozzi, Celeste Fusciello, Marco Carlo Merlano, François Aubin, Mozzillo Nicola, Giuseppe Cirin, Stefania Scala, Suzanne L. Topalian, Alexander M.M. Eggermont, Antonio Marra, Jinshui Fan, Reinhard Dummer, Federica Zito Marino, Amanda Ralabate, Matthew M. Burke, Piotr Rutkowski, Gerardo Botti, Stefano Pepe, Ivor Caro, and Stefania Tommasi more...
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0301 basic medicine ,business.industry ,MEDLINE ,General Medicine ,medicine.disease ,Bridge (interpersonal) ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Medicine ,Medical emergency ,business - Published
- 2016
29. Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer
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Kunle Odunsi, Paulette Mhawech-Fauceglia, Jeannine A. Villella, Chris Andrews, Junko Matsuzaki, Sacha Gnjatic, Bridget Thomas, Gerd Ritter, Shashikant Lele, Eric W. Hoffman, Protul Shrikant, Kerry J. Rodabaugh, Linda Pan, Feng Qian, and Lloyd J. Old more...
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T-Lymphocytes ,medicine.medical_treatment ,T cell ,Freund's Adjuvant ,Biology ,Cancer Vaccines ,Antibodies ,Epitope ,Interleukin 21 ,Antigen ,medicine ,Humans ,Cytotoxic T cell ,Antigen-presenting cell ,Ovarian Neoplasms ,Multidisciplinary ,Histocompatibility Antigens Class I ,Histocompatibility Antigens Class II ,Immunotherapy ,Biological Sciences ,Peptide Fragments ,Neoplasm Proteins ,medicine.anatomical_structure ,Antibody Formation ,Immunology ,Female ,CD8 - Abstract
NY-ESO-1 is a “cancer-testis” antigen expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. The NY-ESO-1 peptide epitope, ESO 157–170 , is recognized by HLA-DP4-restricted CD4 + T cells and HLA-A2- and A24-restricted CD8 + T cells. To test whether providing cognate helper CD4 + T cells would enhance the antitumor immune response, we conducted a phase I clinical trial of immunization with ESO 157–170 mixed with incomplete Freund's adjuvant (Montanide ISA51) in 18 HLA-DP4 + EOC patients with minimal disease burden. NY-ESO-1-specific Ab responses and/or specific HLA-A2-restricted CD8 + and HLA-DP4-restricted CD4 + T cell responses were induced by a course of at least five vaccinations at three weekly intervals in a high proportion of patients. There were no serious vaccine-related adverse events. Vaccine-induced CD8 + and CD4 + T cell clones were shown to recognize NY-ESO-1-expressing tumor targets. T cell receptor analysis indicated that tumor-recognizing CD4 + T cell clones were structurally distinct from non-tumor-recognizing clones. Long-lived and functional vaccine-elicited CD8 + and CD4 + T cells were detectable in some patients up to 12 months after immunization. These results confirm the paradigm that the provision of cognate CD4 + T cell help is important for cancer vaccine design and provides the rationale for a phase II study design using ESO 157–170 epitope or the full-length NY-ESO-1 protein for immunotherapy in patients with EOC. more...
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- 2007
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30. Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients
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Dennis Panicali, Armin Bender, Linda Pan, Danila Valmori, Julia Karbach, Lloyd J. Old, Erika Ritter, Sacha Gnjatic, Antje Neumann, Maha Ayyoub, Gerd Ritter, Herbert F. Oettgen, Dirk Jäger, Alexander Knuth, Eric A. Hoffman, and Elke Jager more...
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Cytotoxicity, Immunologic ,Fowlpox ,Vaccinia virus ,CD8-Positive T-Lymphocytes ,Biology ,Cancer Vaccines ,Antibodies ,Epitope ,Cohort Studies ,Epitopes ,Immune system ,Antigen ,Neoplasms ,medicine ,Humans ,Cytotoxic T cell ,Immunity, Cellular ,Vaccines, Synthetic ,Fowlpox virus ,Multidisciplinary ,Immunogenicity ,Vaccination ,Membrane Proteins ,Biological Sciences ,medicine.disease ,Virology ,Peptide Fragments ,Clone Cells ,Neoplasm Proteins ,Antibody Formation ,Immunology ,NY-ESO-1 - Abstract
NY-ESO-1 is a cancer/testis antigen expressed in a range of human malignancies, and a number of vaccine strategies targeting NY-ESO-1 are being developed. In the present study, the safety and immunogenicity of recombinant vaccinia-NY-ESO-1 and recombinant fowlpox-NY-ESO-1 were analyzed in a series of 36 patients with a range of different tumor types. Each construct was first tested individually at two different dose levels and then in a prime-boost setting with recombinant vaccinia-NY-ESO-1 followed by recombinant fowlpox-NY-ESO-1. The vaccines were well tolerated either individually or together. NY-ESO-1-specific antibody responses and/or specific CD8 and CD4 T cell responses directed against a broad range of NY-ESO-1 epitopes were induced by a course of at least four vaccinations at monthly intervals in a high proportion of patients. CD8 T cell clones derived from five vaccinated patients were shown to lyse NY-ESO-1-expressing melanoma target cells. In several patients with melanoma, there was a strong impression that the natural course of the disease was favorably influenced by vaccination. more...
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- 2006
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31. Resiquimod as an immunologic adjuvant for NY-ESO-1 protein vaccination in patients with high-risk melanoma
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Rachel Lubong Sabado, Linda Rolnitzsky, Judith D. Goldberg, Caroline Muren, Luis Chiriboga, Nina Bhardwaj, Ethel Yepes, Dunbar Sharpe, Farbod Darvishian, Ralph Venhaus, John P. Vasilakos, Rose Marie Holman, J. Escalon, Crystal Escano, John Mandeli, Achim A. Jungbluth, Sylvia Adams, Anna C. Pavlick, Isabelita Vengco, Patrick A. Ott, Sacha Gnjatic, Meredith Spadaccia, Farah Hasan, Crystal M. Cruz, and Linda Pan more...
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Adult ,CD4-Positive T-Lymphocytes ,Male ,Cancer Research ,Antibodies, Neoplasm ,Immunology ,Oleic Acids ,Immunopotentiator ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Article ,chemistry.chemical_compound ,Antigen ,Adjuvants, Immunologic ,Antigens, Neoplasm ,Medicine ,Humans ,Mannitol ,Melanoma ,Aged ,Aged, 80 and over ,Immunity, Cellular ,biology ,business.industry ,Immunogenicity ,Vaccination ,Imidazoles ,Membrane Proteins ,Middle Aged ,Peptide Fragments ,chemistry ,Immunologic adjuvant ,Antibody Formation ,biology.protein ,Female ,NY-ESO-1 ,Antibody ,Resiquimod ,business - Abstract
The Toll-like receptor (TLR) 7/8 agonist resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide (Seppic) with or without resiquimod in patients with high-risk melanoma. In part I of the study, patients received 100 μg of full-length NY-ESO-1 protein emulsified in 1.25 mL of Montanide (day 1) followed by topical application of 1,000 mg of 0.2% resiquimod gel on days 1 and 3 (cohort 1) versus days 1, 3, and 5 (cohort 2) of a 21-day cycle. In part II, patients were randomized to receive 100-μg NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel [(arm A; n = 8) or 1,000 mg of 0.2% resiquimod gel (arm B; n = 12)] using the dosing regimen established in part I. The vaccine regimens were generally well tolerated. NY-ESO-1–specific humoral responses were induced or boosted in all patients, many of whom had high titer antibodies. In part II, 16 of 20 patients in both arms had NY-ESO-1–specific CD4+ T-cell responses. CD8+ T-cell responses were only seen in 3 of 12 patients in arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1–specific CD8+ responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical resiquimod is safe and induces both antibody and CD4+ T-cell responses in the majority of patients; the small proportion of CD8+ T-cell responses suggests that the addition of topical resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1–specific CD8+ T-cell responses. Cancer Immunol Res; 3(3); 278–87. ©2015 AACR. more...
- Published
- 2015
32. Effect of Montanide and poly-ICLC adjuvant on human self/tumor antigen-specific CD4+ T cells in phase I overlapping long peptide vaccine trial
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Achim A. Jungbluth, Gerd Ritter, Andres M. Salazar, David R. Spriggs, Paul Sabbatini, Sacha Gnjatic, Luis Ferran, Erika Ritter, Takemasa Tsuji, and Linda Pan
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CD4-Positive T-Lymphocytes ,Cancer Research ,medicine.medical_treatment ,Immunology ,CD40 Ligand ,Epitopes, T-Lymphocyte ,Oleic Acids ,Cancer Vaccines ,Immune system ,Antigen ,Antigens, Neoplasm ,Poly ICLC ,medicine ,Humans ,Mannitol ,Polylysine ,CD154 ,biology ,Chemistry ,Membrane Proteins ,Tumor antigen ,Poly I-C ,Carboxymethylcellulose Sodium ,Peptide vaccine ,biology.protein ,Antibody ,Peptides ,Adjuvant ,medicine.drug - Abstract
Vaccination of patients with ovarian cancer with overlapping long peptides (OLP) from cancer-testis antigen NY-ESO-1 and poly-ICLC in Montanide-ISA-51 (Montanide) was found to consistently induce integrated immune responses (antibody, CD4+, and CD8+ T cells). Using detailed methods, we investigated the respective effects of poly-ICLC and Montanide adjuvant on pre- and postvaccine NY-ESO-1–specific CD4+ T cells, because of their central function for induction and maintenance of both antibody and CD8+ T cells. Polyclonal NY-ESO-1–specific CD4+ T-cell lines were generated from 12 patients using CD154-based selection of precursors before and after vaccination with (i) OLP alone, (ii) OLP in Montanide, or (iii) OLP and poly-ICLC in Montanide. Kinetics, quantification, fine specificity, avidity, and cytokine-producing pattern were analyzed in depth and compared between vaccine cohorts. Vaccination with OLP alone did not elicit CD4+ T-cell responses; it suppressed high-avidity CD4+ T-cell precursors that recognized naturally processed NY-ESO-1 protein before vaccination. Emulsification of OLP in Montanide was required for the expansion of high-avidity NY-ESO-1–specific CD4+ T-cell precursors. Poly-ICLC significantly enhanced CD4+ Th1 responses while suppressing the induction of interleukin (IL)-4–producing Th2 and IL-9–producing Th9 cells. In summary, Montanide and poly-ICLC had distinct and cooperative effects for the induction of NY-ESO-1–specific Th1 cells and integrated immune responses by OLP vaccination. These results support the use of admixing poly-ICLC in Montanide adjuvant to rapidly induce antitumor type I immune responses by OLP from self/tumor antigens in human cancer vaccines. Cancer Immunol Res; 1(5); 340–50. ©2013 AACR. more...
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- 2014
33. Use of an in Silico Approach to Define the Gene Structure of Eukaryotic Adenylyl Cyclases
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Paul A. Insel, Linda Pan, and Brinda K. Rana
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Genetics ,Gene isoform ,DNA, Complementary ,Base Sequence ,Protein family ,In silico ,Biophysics ,Intron ,Cell Biology ,Biology ,Adenylyl Cyclases ,Biochemistry ,Exon ,Animals ,Humans ,Human genome ,Amino Acid Sequence ,Molecular Biology ,Gene - Abstract
The limited information available regarding the gene structure of adenylyl cyclases (AC), which catalyze the synthesis of cAMP, suggests a complex arrangement with many exons and large introns such that molecular techniques to define these gene structures are time- and labor-intensive. We report here the use of a computer-based approach involving the assembly of fragmented sequence data generated by the Human Genome Project and nucleic acid analysis software to decipher the gene structure of human and murine AC 6 and other human AC isoforms (ACs 3, 7, and 8). The results, which document 21 exons in human and murine AC 6, human AC 3, 18 exons in AC 8, and 24 exons in AC 7, show substantial conservation of exon organization in the AC family and in particular regions of the AC protein. Application of such in silico methods should prove useful to characterize genes for other ACs and protein families and data provided here should facilitate studies of polymorphisms in AC genes. more...
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- 2001
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34. Phase I/II study of Resiquimod as an immunologic adjuvant for NY-ESO-1 protein vaccination in patients with melanoma
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Rachel Lubong Sabado, Patrick A. Ott, Farah Hasan, Isabelita Vengco, Sacha Gnjatic, Anna C. Pavlick, Caroline Muren, Achim A. Jungbluth, Crystal M. Cruz, Luis Chiriboga, Farbod Darvishian, Dunbar Sharpe, Ethel Yepes, Ralph Venhaus, Linda Pan, Crystal Escano, Sylvia Adams, Nina Bhardwaj, Rose Marie Holman, and J. Escalon more...
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Agonist ,Cancer Research ,medicine.drug_class ,Immunology ,Bioinformatics ,chemistry.chemical_compound ,Immune system ,medicine ,Immunology and Allergy ,In patient ,Pharmacology ,business.industry ,Immunogenicity ,Melanoma ,medicine.disease ,Vaccination ,Oncology ,chemistry ,Immunologic adjuvant ,Poster Presentation ,Molecular Medicine ,Cancer vaccine ,Resiquimod ,NY-ESO-1 ,business - Abstract
2589 Background: The TLR 7/8 agonist, Resiquimod has been shown to induce local activation of immune cells, production of cytokines, and antigen-presentation by dendritic cells, features desirable for cancer vaccine adjuvants. In this study, we evaluated the safety and immunogenicity of vaccination with NY-ESO-1 protein emulsified in Montanide ISA-51 VG when given with or without Resiquimod in patients with surgically resected stage IIB-IV melanoma patients. Methods: This is a two-part study design. Part I represents an open-label dose-escalation with Resiquimod using 2 cohorts treated with 100ug NY-ESO-1 protein emulsified in 1.25mL Montanide (day1) followed by topical application of 1000mg of the 0.2% Resiquimod gel on days 1 and 3 for cohort-1 (N=3) or days 1, 3, and 5 for cohort-2 (N=3). The cycles were repeated every 3 weeks, total of 4 cycles. Part II of the study is blinded. Patients were randomized to receive 100ug NY-ESO-1 protein emulsified in 1.25mL Montanide (day1) followed by topical application of placebo gel (Arm-A; N=8) or 1000mg of 0.2% Resiquimod gel (Arm-B; N=12) using the dosing regimen established in Part I. Blood samples were collected at baseline, one week after each cycle of vaccination, and at follow-up visit for the assessment of NY-ESO-1-specific humoral and cellular immune responses. Results: Enrollment has been completed. 25/26 patients received all 4 vaccinations. The treatment was generally well-tolerated, with no grade 4 adverse events or study-related deaths. The most common toxicities were mild to moderate and included local injection site reactions (granuloma, pruritus, induration) and systemic flu-like symptoms. One patient experienced a grade 3 syncopal episode that was deemed unrelated to the drug. Another patient experienced a grade 3 injection site necrosis that was possibly related to the study drug and was removed from the study prior to receiving the 4th vaccine. Conclusions: This study demonstrates the safety of Resiquimod as an adjuvant for NY-ESO-1 protein vaccination. The study will remain blinded until all immune monitoring assays have been completed. An updated abstract will be submitted once the study is unblinded. more...
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- 2013
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35. Phase I trial of overlapping long peptides from a tumor self-antigen and poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients
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Martee L. Hensley, Takemasa Tsuji, Linda Pan, Katherine M. Bell-McGuinn, Lloyd J. Old, Ralph Venhaus, Luis Ferran, Achim A. Jungbluth, Andres M. Salazar, Jason A. Konner, Paul Sabbatini, Sacha Gnjatic, Carol Aghajanian, Gerd Ritter, Catherine M. Diefenbach, Christine Sedrak, Erika Ritter, William P. Tew, David R. Spriggs, Kevin Tuballes, and Eric W. Hoffman more...
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Adult ,CD4-Positive T-Lymphocytes ,Cancer Research ,medicine.medical_treatment ,CD8-Positive T-Lymphocytes ,Autoantigens ,Cancer Vaccines ,T-Lymphocytes, Regulatory ,Antibodies ,Immune system ,Antigen ,Antigens, Neoplasm ,Poly ICLC ,medicine ,Humans ,Polylysine ,Aged ,Neoplasm Staging ,Ovarian Neoplasms ,biology ,business.industry ,ELISPOT ,Immunogenicity ,Middle Aged ,Immunity, Humoral ,Vaccination ,Poly I-C ,Treatment Outcome ,Oncology ,Carboxymethylcellulose Sodium ,Immunology ,Vaccines, Subunit ,biology.protein ,Female ,Antibody ,business ,Peptides ,Adjuvant ,medicine.drug ,Follow-Up Studies - Abstract
Purpose: Long peptides are efficiently presented to both CD4+ and CD8+ T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations. Experimental Design: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining). Results: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1–specific antibody and CD8+ T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1–specific CD4+ T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1–specific immune responses. Conclusions: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8+ and CD4+) in nearly all vaccinated patients when given with appropriate adjuvants. Clin Cancer Res; 18(23); 6497–508. ©2012 AACR. more...
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- 2012
36. A phase I study of vaccination with NY-ESO-1f peptide mixed with Picibanil OK-432 and Montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen
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Tomoki Yamatsuji, Eric W. Hoffman, Keiji Iwatsuki, Kenshiro Shiraishi, Lloyd J. Old, Jun Nakajima, Yoshio Naomoto, Midori Isobe, Kazuhiro Kakimi, Yuichiro Doki, Nagio Takigawa, Yasuyuki Seto, Linda Pan, Mikio Oka, Eiichi Sato, Kazuhide Tsuji, Eiichi Nakayama, Akiko Uenaka, Hisashi Wada, and Katsuyuki Kiura more...
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Adult ,CD4-Positive T-Lymphocytes ,Male ,Cancer Research ,Oleic Acids ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Epitope ,Picibanil ,Immune system ,Antigen ,Antigens, Neoplasm ,Neoplasms ,Medicine ,Cytotoxic T cell ,Humans ,Mannitol ,Antigens ,Aged ,biology ,business.industry ,Membrane Proteins ,Middle Aged ,Virology ,Peptide Fragments ,Immunity, Humoral ,Treatment Outcome ,Oncology ,Immunology ,Vaccines, Subunit ,biology.protein ,Peptide vaccine ,Female ,Cancer vaccine ,NY-ESO-1 ,Antibody ,business - Abstract
We conducted a phase I clinical trial of a cancer vaccine using a 20-mer NY-ESO-1f peptide (NY-ESO-1 91–110) that includes multiple epitopes recognized by antibodies, and CD4 and CD8 T cells. Ten patients were immunized with 600 μg of NY-ESO-1f peptide mixed with 0.2 KE Picibanil OK-432 and 1.25 ml Montanide ISA-51. Primary end points of the study were safety and immune response. Subcutaneous injection of the NY-ESO-1f peptide vaccine was well tolerated. Vaccine-related adverse events observed were fever (Grade 1), injection-site reaction (Grade 1 or 2) and induration (Grade 2). Vaccination with the NY-ESO-1f peptide resulted in an increase or induction of NY-ESO-1 antibody responses in nine of ten patients. The sera reacted with recombinant NY-ESO-1 whole protein as well as the NY-ESO-1f peptide. An increase in CD4 and CD8 T cell responses was observed in nine of ten patients. Vaccine-induced CD4 and CD8 T cells responded to NY-ESO-1 91–108 in all patients with various HLA types with a less frequent response to neighboring peptides. The findings indicate that the 20-mer NY-ESO-1f peptide includes multiple epitopes recognized by CD4 and CD8 T cells with distinct specificity. Of ten patients, two with lung cancer and one with esophageal cancer showed stable disease. Our study shows that the NY-ESO-1f peptide vaccine was well tolerated and elicited humoral, CD4 and CD8 T cell responses in immunized patients. more...
- Published
- 2010
37. Abstract A046: Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM)
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Domenic W. Lai, Gavin P. Dunn, Jennifer Clarke, Rajesh Narwal, Thomas Kaley, Hui K Gan, Jorg Dietrich, Michael Lim, Timothy F. Cloughesy, David A. Reardon, Joyson Joseph Karakunnel, Paul B. Robbins, Ralph Venhaus, Andrew J. Park, and Linda Pan more...
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,Bevacizumab ,business.industry ,medicine.medical_treatment ,Immunology ,Phases of clinical research ,Immunosuppression ,Surgery ,Radiation therapy ,Tolerability ,Internal medicine ,Cohort ,medicine ,biology.protein ,PTEN ,Progression-free survival ,business ,medicine.drug - Abstract
Background: Programmed cell death ligand-1 (PD-L1) is widely expressed on antigen presenting cells (APC) and other immune cells. PD-L1 binds two important regulatory receptors on T-cells: programmed cell death-1 (PD-1) and CD80/B7. Targeting Programmed Death-1 (PD-1) and its ligand, PD-L1, have demonstrated promising anti-tumor activity among other challenging solid tumors and growing data implicates PD-1/PD-L1 signaling as a significant contributor to immunosuppression in glioblastoma (GBM). PD-1 is expressed by many GBM infiltrating lymphocytes while PD-L1 is expressed by 61-100% of GBM tumors. Furthermore, loss of the PTEN tumor suppressor gene, which occurs in 40-50% of GBM tumors, leads to increased transcription and expression of PD-L1 in GBM. These findings indicate that PD-L1 is an attractive and important therapeutic target in GBM. MEDI4736 (M), a human IgG1κ blocking monoclonal antibody against PD-L1, represents a compelling immune-mediated anti-tumor treatment for GBM. Methods: Phase 2, multicenter, open-label study (NCT02336165) is evaluating the clinical efficacy and safety of M in GBM patients. Eligible patients include those who are newly diagnosed with unmethylated MGMT GBM scheduled for standard radiotherapy (Cohort A); Bevacizumab-naïve patients with recurrent GBM (Cohort B); and Bevacizumab-refractory patients with recurrent GBM (Cohort C). Cohort A patients will receive M at 10 mg/kg i.v. Q2W for up to 12 months beginning with standard radiotherapy. Cohort B will receive M at 10 mg/kg i.v. Q2W for up to 12 months as monotherapy. Cohort C will receive M at 10 mg/kg i.v. Q2W for up to 12 months in combination with continued bevacizumab at 10 mg/kg Q2W. Primary endpoints include overall survival (OS) at 12 months (cohort A), progression free survival rate at 6 months (PFS-6) (cohort B) and OS-6 (cohort C). Secondary endpoints are safety/tolerability, PFS, median OS, radiographic response, and quality of life (QoL) by EORTC QLQ-C30/BN20. Exploratory endpoints are patient neurologic function using the Neurologic Assessment in Neuro-Oncology (NANO) scale, as well as immuno-correlative biomarkers and pharmacokinetics. Cohort A represents the first time MEDI4736 is being given in combination with radiation, so a 3+3 subject safety run-in is required by protocol. Subjects must clear a 10 week DLT observation period before enrollment opens to the remainder of the cohort. If 2 or more DLTs are noted within the first 6 patients, then the MEDI4736 dose will be de-escalated. Cohort C represents the first time MEDI4736 is being given in combination with bevacizumab, so a 3+3 subject safety run-in period similar to that for Cohort A is also required, but with a 6 week DLT observation period. Study Status: All cohorts opened to enrollment in March 2015 with Cohorts A and C currently limited by the subject safety run-in period. As of 10 June 2015, the numbers of subjects enrolled by cohort are: Cohort A = 2, Cohort B = 26, Cohort C = 3. No DLTs have been reported, and clinical efficacy and safety data collection are ongoing. Citation Format: David A. Reardon, Jorg Dietrich, Thomas Kaley, Hui Gan, Gavin P. Dunn, Timothy Cloughesy, Michael Lim, Jennifer Clarke, Andrew Park, Linda Pan, Domenic W. Lai, Joyson Karakunnel, Paul Robbins, Rajesh Narwal, Ralph Venhaus. Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A046. more...
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- 2016
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38. LUD 00-009: phase 1 study of intensive course immunization with NY-ESO-1 peptides in HLA-A2 positive patients with NY-ESO-1-expressing cancer
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Armin, Bender, Julia, Karbach, Antje, Neumann, Dirk, Jäger, Salah E, Al-Batran, Akin, Atmaca, Eckhart, Weidmann, Melina, Biskamp, Sacha, Gnjatic, Linda, Pan, Eric, Hoffman, Lloyd J, Old, Alexander, Knuth, and Elke, Jäger more...
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Adult ,Male ,Adolescent ,Granulocyte-Macrophage Colony-Stimulating Factor ,Membrane Proteins ,CD8-Positive T-Lymphocytes ,Middle Aged ,Cancer Vaccines ,Peptide Fragments ,Article ,Neoplasm Proteins ,Cohort Studies ,Treatment Outcome ,Antigens, Neoplasm ,Lymphatic Metastasis ,Neoplasms ,HLA-A2 Antigen ,Humans ,Female ,Hypersensitivity, Delayed ,Immunization ,Immunotherapy ,Aged ,T-Lymphocytes, Cytotoxic - Abstract
NY-ESO-1 is a cancer-testis antigen and an attractive target for immunotherapy in patients with different malignancies. Here we report the results of a phase I clinical study of intensive course NY-ESO-1 peptide vaccination, evaluating the safety, immunogenicity and clinical response in HLA-A2 positive patients with NY-ESO-1 expressing cancers. Of 20 patients enrolled in the trial, 14 completed at least 2 cycles of immunization and were evaluable for clinical and immunological response. Five of these evaluable patients were treated in cohort 1 (baseline seropositive) and 9 patients were treated in cohort 2 (baseline seronegative). During vaccination, NY-ESO-1-specific CD8+ T-cells were induced in 3 of 9 baseline seronegative patients. In patients with pre-existing antigen-specific CD8+ T-cells, their number increased or remained stable. In contrast to previous immunization protocols with less intensive immunization schedules, we observed a rapid induction of high magnitude NY-ESO-1 peptide-specific T-cell responses detectable already on day 15-22 of immunization. A specific immune response of high magnitude and early onset may be more effective in eliminating minimal residual disease in adjuvant treatment situations and in preventing tumor progression due to immune escape mechanisms. more...
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- 2007
39. Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming
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Eric Hoffmann, Lloyd J. Old, Linda Pan, Angelica Angiulli, David O'Neill, Maha Ayyoub, Valeria Tosello, Anna C. Pavlick, Gerd Ritter, Crystal M. Cruz, Ralph Venhaus, Gregory Mears, Danila Valmori, Francesca Angiulli, Susan M. Vogel, Achim A. Jungbluth, Nina Bhardwaj, Naira E. Souleimanian, Sylvia Adams, and J. Escalon more...
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T cell ,Oleic Acids ,Biology ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Epitope ,Antibodies ,Interleukin 21 ,Cross-Priming ,Antigen ,Antigens, Neoplasm ,Neoplasms ,medicine ,Cytotoxic T cell ,Humans ,Mannitol ,Antigen-presenting cell ,Multidisciplinary ,Vaccination ,Membrane Proteins ,Biological Sciences ,Th1 Cells ,Tumor antigen ,Recombinant Proteins ,medicine.anatomical_structure ,Oligodeoxyribonucleotides ,Immunology ,Epitopes, B-Lymphocyte ,Immunotherapy ,CD8 - Abstract
The use of recombinant tumor antigen proteins is a realistic approach for the development of generic cancer vaccines, but the potential of this type of vaccines to induce specific CD8 + T cell responses, through in vivo cross-priming, has remained unclear. In this article, we report that repeated vaccination of cancer patients with recombinant NY-ESO-1 protein, Montanide ISA-51, and CpG ODN 7909, a potent stimulator of B cells and T helper type 1 (Th1)-type immunity, resulted in the early induction of specific integrated CD4 + Th cells and antibody responses in most vaccinated patients, followed by the development of later CD8 + T cell responses in a fraction of them. The correlation between antibody and T cell responses, together with the ability of vaccine-induced antibodies to promote in vitro cross-presentation of NY-ESO-1 by dendritic cells to vaccine-induced CD8 + T cells, indicated that elicitation of NY-ESO-1-specific CD8 + T cell responses by cross-priming in vivo was associated with the induction of adequate levels of specific antibodies. Together, our data provide clear evidence of in vivo cross-priming of specific cytotoxic T lymphocytes by a recombinant tumor antigen vaccine, underline the importance of specific antibody induction for the cross-priming to occur, and support the use of this type of formulation for the further development of efficient cancer vaccines. more...
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- 2007
40. Recombinant (rec) MAGE-A3 Protein Immunotherapy and Peripheral Blood Lymphocyte (PBL) Reconstitution Induce Strong Antigen-Specific Humoral and Cellular Immune Responses in Patients Undergoing Autologous Stem Cell Transplantation (ASCT) for Consolidation of Multiple Myeloma (MM)
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Adam D. Cohen, Nikoletta Lendvai, Sacha Gnjatic, Achim A Jungbluth, Stephane Bertolini, Linda Pan, Ralph Venhaus, Ioanna Tsakos, Katarzyna Garcia, Linda Thibodeau, Katherine Alpaugh, Nailah Cummings, Rafik Fellague-Chebra, Olivier Gruselle, and Hearn J. Cho more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
BACKGROUND: MAGE-A3 is an immunogenic tumor-associated antigen detected in 1/3 of newly diagnosed MM patients, and confers a poor prognosis, making it a rational target for immunotherapy. We previously reported (Cohen et al, ASH 2013, #154) that pre- and post-ASCT administration of recMAGE-A3 + AS15 adjuvant (containing MPL, QS21, and CpG7909) and infusion of vaccine-primed autologous peripheral blood lymphocytes (PBL) in the early post-ASCT period had an acceptable safety profile and induced robust antibody responses against MAGE-A3. We now report our initial cellular immune response data, and update the humoral response and clinical outcome data. METHODS: The composition of recMAGE-A3 +AS15 and the immunization schedule (Fig. 1) for this pilot study have been described (ASH 2013, #154). Antibody responses were assessed by ELISA. CD4 and CD8 T cell responses were assessed by ELISpot and intracellular cytokine release assays after in vitro re-stimulation with MAGE-A3 overlapping peptide pools or controls and autologous antigen-presenting cells. Clinical responses were determined by IMWG criteria. M3H67 mAb (specific for MAGE-A3 and homologous MAGE-A family members) was used for assessing expression in MM cells by immunohistochemistry (IHC). RESULTS: Thirteen patients enrolled (med. age 56; 45% high-risk cytogenetics; 42% ISS II/III). All had MAGE-A+ myeloma cells and had achieved at least VGPR following induction. Twelve of 12 (100%) subjects tested to date developed high-titer (1:104-106) antibodies against MAGE-A3 that persisted to at least 1 year post-SCT. These titers were 10-100-fold higher than those seen in a prior study in lung cancer patients with recMAGE-A3 + AS02b, an older adjuvant lacking CpG7909 (PNAS 2008; 105:1650). Epitope mapping identified at least 7 distinct MAGE-A3 epitopes clustering in the hydrophobic regions from aa. 1-100 and 220-300. Isotyping and IgG subclass analysis demonstrated IgG class switching in all patients, with IgG1 and IgG3 subclasses most prevalent. Peripheral blood T cell responses have been evaluated in 3 subjects to date. All had MAGE-A3-specific CD4 responses by IFNγ ELISpot starting as early as d+31 after ASCT, with significant expansion after booster vaccinations and persistence through 1 year post-ASCT. Intracellular cytokine staining confirmed a polyfunctional, Th1-biased CD4 T cell response (IFNγ+, TNFα+, IL5-) in all 3 patients. No CD8 responses against MAGE-A3 have been detected to date. Clinical response assessments were as follows: there were 12 VGPR and 1 CR at enrollment, 7 VGPR and 6 CR (3 stringent CR) at 3 months (mos.) post-ASCT, and 3 VGPR and 5 CR (4 sCR) at 1 year post-ASCT, with 4 patients relapsing at or before 1 year, and 1 not yet evaluable. With a median follow-up of 19 mos. (range 6-32), 6 patients have relapsed (estimated median PFS is 24 mos.) and 1 died of progressive MM. There was no difference between progressors and non-progressors with regard to cytogenetics, baseline MAGE-A expression, antibody titers, hematologic response, or use of lenalidomide maintenance (n=4). MAGE-A expression was assessed by IHC in 3 relapse bone marrow biopsies, and all were negative. CONCLUSIONS: RecMAGE-A3 immunotherapy and PBL reconstitution is well-tolerated, feasible, and induces antibody and Th1-biased CD4 T cell responses, but not CD8 responses, in the setting of ASCT for MM. Cellular immune assessments are ongoing. The magnitudes of antibody and CD4 responses appear greater than those seen historically with older formulations of recMAGE-A3 in other cancers, despite significant immune compromise after ASCT, suggesting a benefit from the new AS15 adjuvant formulation, or from immunization and autologous PBL transfer in the peri-ASCT setting, or both. The loss of MAGE-A3 expression in relapsing patients implies antigen-specific immune selective pressure even in the absence of CD8 T cell responses, and also suggests that combination strategies aimed at limiting immune escape (eg multi-antigen vaccines) should be investigated. Clinical outcomes are promising for this high-risk patient population. These results support advanced phase clinical trials to investigate clinical efficacy of recMAGE-A3 vaccine immunotherapy in MM. Figure 1 Figure 1. Disclosures Cohen: Onyx Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other; Celgene: Member, Independent Response Adjudication Committee Other. Bertolini:Ludwig Institute for Cancer Research: Employment. Pan:Ludwig Institute for Cancer Research: Employment. Venhaus:Ludwig Institute for Cancer Research: Employment. Fellague-Chebra:GlaxoSmithKline: Employment. Gruselle:GlaxoSmithKline: Employment. more...
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- 2014
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41. The TIME Questionnaire: A tool for eliciting personhood and enhancing dignity in nursing homes.
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Jingyan (Linda) Pan, Chochinov, Harvey, Thompson, Genevieve, and McClement, Susan
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This study aimed at evaluating the effectiveness of the TIME (This Is ME) Questionnaire in eliciting personhood and enhancing dignity; specifically investigating the residents' and health care providers' perspectives in the nursing home setting. Residents (n = 41) from six nursing homes in a Canadian urban center completed both the TIME Questionnaire and a feedback response questionnaire; health care providers (n = 22) offered feedback both through a questionnaire or participation in a focus group. 100% of the residents indicated the summary was accurate. 94% stated that they wanted to receive a copy of the summary, 92% indicated they would recommend the questionnaire to others, 72% wanted a copy of the summary to be placed into their medical chart. Overall HCPs' agreed that they have learned something new from TIME, and that TIME influenced their attitude, care, respect, empathy/compassion, sense of connectedness, as well as personal satisfaction in providing care. [ABSTRACT FROM AUTHOR] more...
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- 2016
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42. Genes for anti-Müllerian hormone and androgen receptor are underexpressed in human cumulus cells surrounding morphologically highly graded oocytes
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Sanja Dević Pavlić, Tamara Tramišak Milaković, Linda Panić Horvat, Kristina Čavlović, Hrvoje Vlašić, Miljenko Manestar, Neda Smiljan Severinski, and Anđelka Radojčić Badovinac
- Subjects
Medicine (General) ,R5-920 - Abstract
Objectives: The aim of this study was to investigate the expression of genes crucial for the quality of the oocyte and whether expression levels of these genes in cumulus cells can be biological markers for the quality of the oocyte, zygote or embryo, or even for achievement of pregnancy after the assisted reproductive technology procedure. We examined the expression profile of the anti-Müllerian hormone (AMH) gene and its respective receptors: anti-Müllerian hormone receptor type 2 (AMHR2), follicle-stimulating hormone receptor (FSHR) and androgen receptor (AR) in cumulus cells (CCs) surrounding the oocyte, as well as AMH concentrations in follicular fluid of the associated follicle. The obtained gene expression levels were correlated with the morphological quality of the associated oocyte, zygote and embryo as well as with assisted reproductive technology outcome following the intracytoplasmic sperm injection procedure. Methods: This study involved 129 cumulus cells and 35 follicular fluid samples, taken from 58 patients undergoing the intracytoplasmic sperm injection procedure. Oocytes, zygotes and embryos were assessed for morphological quality. The relative gene expression of AMH, AMHR2, FSHR and AR was calculated using the delta–delta Ct method. Anti-Müllerian hormone concentrations in follicular fluids were measured by enzyme-linked immunosorbent assay. Results: The results yielded suggest a relationship between AMH, AR and oocyte morphology: AMH and AR gene expression levels in CCs surrounding morphologically optimal oocytes were significantly lower than in CCs surrounding oocytes with suboptimal morphology (p = 0.011 and p = 0.008, respectively). Statistically significant positive correlation was found between mRNA expression levels of AMH and FSHR (p more...
- Published
- 2019
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43. Central Venous Catheter Intravascular Malpositioning: Causes, Prevention, Diagnosis, and Correction
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Carlos J. Roldan and Linda Paniagua
- Subjects
Medicine ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Despite the level of skill of the operator and the use of ultrasound guidance, central venous catheter (CVC) placement can result in CVC malpositioning, an unintended placement of the catheter tip in an inadequate vessel. CVC malpositioning is not a complication of central line insertion; however, undiagnosed CVC malpositioning can be associated with significant morbidity and mortality. The objectives of this review were to describe factors associated with intravascular malpositioning of CVCs inserted via the neck and chest and to offer ways of preventing, identifying, and correcting such malpositioning. A literature search of PubMed, Cochrane Library, and MD Consult was performed in June 2014. By searching for “Central line malposition” and then for “Central venous catheters intravascular malposition,” we found 178 articles written in English. Of those, we found that 39 were relevant to our objectives and included them in our review. According to those articles, intravascular CVC malpositioning is associated with the presence of congenital and acquired anatomical variants, catheter insertion in left thoracic venous system, inappropriate bevel orientation upon needle insertion, and patient’s body habitus variants. Although plain chest radiography is the standard imaging modality for confirming catheter tip location, signs and symptoms of CVC malpositioning even in presence of normal or inconclusive conventional radiography findings should prompt the use of additional diagnostic methods to confirm or rule out CVC malpositioning. With very few exceptions, the recommendation in cases of intravascular CVC malpositioning is to remove and relocate the catheter. Knowing the mechanisms of CVC malpositioning and how to prevent, identify, and correct CVC malpositioning could decrease harm to patients with this condition. more...
- Published
- 2015
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44. Practical steps and collegiality in the building of podiatry curricula to meet accreditation and health sector employability demands.
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Anita Raspovic and Linda Pannan
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embedding course learning outcomes ,graduate outcomes ,curriculum design ,curriculum mapping ,podiatry competency standards ,professional accreditation ,Special aspects of education ,LC8-6691 - Abstract
Historically, mixed arrangements have been in place between educational institutions and podiatrist registration bodies to evaluate the capacity of programs to adequately prepare new graduates for clinical practice. The national scheme for the registration of health practitioners introduced in 2010, followed by a national system for accreditation of respective programs, has however seen significant legislative and policy change to requirements for evidencing effectiveness of podiatry programs. In addition, there has been a local and international change in emphasis by stakeholders in higher education, government, professional regulation, quality assurance and employment, towards measureable, explicit student learning outcomes. Curricula initiatives at La Trobe University, including large scale systematic review and redesign of all courses within the Faculty of Health Sciences commencing in 2005, and a subsequent university wide ‘Design for Learning’ project (La Trobe University, 2009), provided a timely platform for podiatry staff to respond to critical emerging imperatives for increased program transparency and accountability. The case study presented in this paper provides a practical, in-context explanation of an approach adopted to develop and embed Podiatry Course Learning Outcomes (CLOs). It draws on the podiatry profession’s competency standards and produces aligned curricula (Biggs & Tang, 2007) where fine grain subject Intended Learning Outcomes (ILOs), underpinned by related learning and assessment activities, cumulatively address student development of the CLOs. Systematic and comprehensive documented evidence demonstrates when and how key podiatry competencies are developed, attained and assessed in these podiatry curricula. more...
- Published
- 2013
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45. A Nosocomial Outbreak of Community-Associated Methicillin-Resistant Staphylococcus aureus among Healthy Newborns and Postpartum Mothers
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Andrea Saunders, Linda Panaro, Allison McGeer, Alana Rosenthal, Diane White, Barbara M Willey, Denise Gravel, Erika Bontovics, Barbara Yaffe, and Kevin Katz
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Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has increasingly been isolated from individuals with no predisposing risk factors; however, such strains have rarely been linked to outbreaks in the hospital setting. The present study describes the investigation of an outbreak of CA-MRSA that occurred in the maternal-newborn unit of a large community teaching hospital in Toronto, Ontario. more...
- Published
- 2007
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46. HIV Testing among Canadian Tuberculosis Cases from 1997 to 1998
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Tara Harris, Linda Panaro, Melissa Phypers, Yogesh Choudhri, and Chris P Archibald
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Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
BACKGROUND: Recent evidence suggests a global rise in adult tuberculosis (TB) cases associated with HIV/AIDS. The World Health Organization, the United States Centers for Disease Control and Prevention, and the Public Health Agency of Canada advocate universal screening of all TB cases for HIV. The contribution of HIV to the TB burden in Canada remains unclear. more...
- Published
- 2006
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47. Tuberculosis drug resistance in Canada, 1998 to 2000
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Melissa D Phypers, Linda Panaro, and Penny Nault
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Infectious and parasitic diseases ,RC109-216 - Abstract
The emergence of drug-resistant strains of tuberculosis (TB) is a global threat to TB prevention and control efforts. A recent study conducted by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease found strains of TB resistant to first-line anti-TB drugs in all countries surveyed (1). The WHO estimates that 50 million people are infected with strains of drug-resistant TB (2). more...
- Published
- 2001
- Full Text
- View/download PDF
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