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Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia
Thomas O. Carpenter, … , Karl L. Insogna, Munro Peacock
Thomas O. Carpenter, … , Karl L. Insogna, Munro Peacock
Published February 24, 2014
Citation Information: J Clin Invest. 2014. https://doi.org/10.1172/JCI72829.
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Article has an altmetric score of 40

Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia

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Abstract

Background. X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH.

Methods. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003–0.3 mg/kg i.v. or 0.1–1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days.

Results. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P < 0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8–15 days) compared with that seen with i.v. dosing (0.5–4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8–12 days after i.v. administration and 13–19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine.

Conclusion. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients.

Trial registration. Clinicaltrials.gov NCT00830674.

Funding. Kyowa Hakko Kirin Pharma, Inc.

Authors

Thomas O. Carpenter, Erik A. Imel, Mary D. Ruppe, Thomas J. Weber, Mark A. Klausner, Margaret M. Wooddell, Tetsuyoshi Kawakami, Takahiro Ito, Xiaoping Zhang, Jeffrey Humphrey, Karl L. Insogna, Munro Peacock

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Evaluation of teriparatide treatment in adults with osteogenesis imperfecta
Eric S. Orwoll, … , Sandesh C.S. Nagamani, Brendan Lee
Eric S. Orwoll, … , Sandesh C.S. Nagamani, Brendan Lee
Published January 27, 2014
Citation Information: J Clin Invest. 2014. https://doi.org/10.1172/JCI71101.
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Article has an altmetric score of 23

Evaluation of teriparatide treatment in adults with osteogenesis imperfecta

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Abstract

Background. Adults with osteogenesis imperfecta (OI) have a high risk of fracture. Currently, few treatment options are available, and bone anabolic therapies have not been tested in clinical trials for OI treatment.

Methods. 79 adults with OI were randomized to receive 20 μg recombinant human parathyroid hormone (teriparatide) or placebo for 18 months in a double-blind, placebo-controlled trial. The primary endpoint was the percent change in areal bone mineral density (aBMD) of the lumbar spine (LS), as determined by dual-energy X-ray absorptiometry. Secondary endpoints included percent change in bone remodeling markers and vertebral volumetric BMD (vBMD) by quantitative computed tomography, estimated vertebral strength by finite element analysis, and self-reported fractures.

Results. Compared with the placebo group, the teriparatide group showed increased LS aBMD (6.1% ± 1.0% vs. 2.8% ± 1.0% change from baseline; P < 0.05) and total hip aBMD (2.6% ± 1.0% vs. –2.4% ± 1.0% change; P < 0.001). Vertebral vBMD and strength improved with teriparatide therapy (18% ± 6% and 15% ± 3% change, respectively), but declined with placebo (–5.0% ± 6% and –2.0% ± 3% change; P < 0.05 for both comparisons). Serum procollagen type 1 N-terminal propeptide (P1NP) and urine collagen N-telopeptide (NTx) levels increased with teriparatide therapy (135% ± 14% and 64% ± 10% change, respectively). Teriparatide-induced elevation of P1NP levels was less pronounced in severe forms of OI (type III/IV) compared with the milder form (type I). Type I OI patients exhibited robust BMD increases with teriparatide; however, there was no observed benefit for those with type III/IV OI. There was no difference in self-reported fractures between the 2 groups.

Conclusions. Adults with OI, particularly those with less severe disease (type I), displayed a teriparatide-induced anabolic response, as well as increased hip and spine aBMD, vertebral vBMD, and estimated vertebral strength.

Trial registration. Clinicaltrials.gov NCT00131469.

Funding. The Osteoporosis Imperfecta Foundation, Eli Lilly and Co., the National Center for Advancing Translational Science (NCATS) at the NIH (grant no. UL1RR024140), and the Baylor College of Medicine General Clinical Research Center (grant no. RR00188).

Authors

Eric S. Orwoll, Jay Shapiro, Sandra Veith, Ying Wang, Jodi Lapidus, Chaim Vanek, Jan L. Reeder, Tony M. Keaveny, David C. Lee, Mary A. Mullins, Sandesh C.S. Nagamani, Brendan Lee

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Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
Ele Ferrannini, … , Uli C. Broedl, Hans-Juergen Woerle
Ele Ferrannini, … , Uli C. Broedl, Hans-Juergen Woerle
Published January 27, 2014
Citation Information: J Clin Invest. 2014. https://doi.org/10.1172/JCI72227.
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Article has an altmetric score of 52

Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients

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Abstract

Background. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes.

Methods. We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m2, HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry.

Results. Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol.min–1•m–2•mM–1 and 55 [IQR, 39] pmol.min–1•m–2•mM–1 vs. 44 [IQR, 32] pmol.min–1•m–2•mM–1, P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged.

Conclusions. In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid.

Trial registration. ClinicalTrial.Gov NCT01248364 (EudraCT no. 2010-018708-99).

Funding. This study was funded by Boehringer Ingelheim.

Authors

Ele Ferrannini, Elza Muscelli, Silvia Frascerra, Simona Baldi, Andrea Mari, Tim Heise, Uli C. Broedl, Hans-Juergen Woerle

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Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir
Romain Coriat, … , François Goldwasser, Frédéric Batteux
Romain Coriat, … , François Goldwasser, Frédéric Batteux
Published December 20, 2013
Citation Information: J Clin Invest. 2013. https://doi.org/10.1172/JCI68730.
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Article has an altmetric score of 33

Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

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Abstract

Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer.

Methods. The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir.

Results. Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders.

Conclusion. Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients.

Trial registration. Clinicaltrials.gov NCT00727922.

Funding. Université Paris Descartes, Ministère de la Recherche et de l’Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris.

Authors

Romain Coriat, Jérôme Alexandre, Carole Nicco, Laurent Quinquis, Evelyne Benoit, Christiane Chéreau, Hervé Lemaréchal, Olivier Mir, Didier Borderie, Jean-Marc Tréluyer, Bernard Weill, Joel Coste, François Goldwasser, Frédéric Batteux

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Essential amino acid supplementation in patients following total knee arthroplasty
Hans C. Dreyer, … , Steven N. Shah, Brian A. Jewett
Hans C. Dreyer, … , Steven N. Shah, Brian A. Jewett
Published October 25, 2013
Citation Information: J Clin Invest. 2013. https://doi.org/10.1172/JCI70160.
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Article has an altmetric score of 105

Essential amino acid supplementation in patients following total knee arthroplasty

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Abstract

Background. By the year 2030, 3.48 million older U.S. adults are projected to undergo total knee arthroplasty (TKA). Following this surgery, considerable muscle atrophy occurs, resulting in decreased strength and impaired functional mobility. Essential amino acids (EAAs) have been shown to attenuate muscle loss during periods of reduced activity and may be beneficial for TKA patients.

Methods. We used a double-blind, placebo-controlled, randomized clinical trial with 28 older adults undergoing TKA. Patients were randomized to ingest either 20 g of EAAs (n = 16) or placebo (n = 12) twice daily between meals for 1 week before and 2 weeks after TKA. At baseline, 2 weeks, and 6 weeks after TKA, an MRI was performed to determine mid-thigh muscle and adipose tissue volume. Muscle strength and functional mobility were also measured at these times.

Results. TKA patients receiving placebo exhibited greater quadriceps muscle atrophy, with a –14.3 ± 3.6% change from baseline to 2 weeks after surgery compared with –3.4 ± 3.1% for the EAA group (F = 5.16, P = 0.036) and a –18.4 ± 2.3% change from baseline to 6 weeks after surgery for placebo versus –6.2 ± 2.2% for the EAA group (F = 14.14, P = 0.001). EAAs also attenuated atrophy in the nonoperated quadriceps and in the hamstring and adductor muscles of both extremities. The EAA group performed better at 2 and 6 weeks after surgery on functional mobility tests (all P < 0.05). Change in quadriceps muscle atrophy was significantly associated with change in functional mobility (F = 5.78, P = 0.021).

Conclusion. EAA treatment attenuated muscle atrophy and accelerated the return of functional mobility in older adults following TKA.

Trial registration. Clinicaltrials.gov NCT00760383.

Funding. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Office of the Director (OD), and the National Institutes of Health Office of Dietary Supplements (ODS), NIH grant K01HD057332, and the Medical Research Foundation, Oregon Health and Science University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the funders.

Authors

Hans C. Dreyer, Lisa A. Strycker, Hilary A. Senesac, Austin D. Hocker, Keith Smolkowski, Steven N. Shah, Brian A. Jewett

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Metabolic network as a progression biomarker of premanifest Huntington’s disease
Chris C. Tang, … , Vijay Dhawan, David Eidelberg
Chris C. Tang, … , Vijay Dhawan, David Eidelberg
Published August 29, 2013
Citation Information: J Clin Invest. 2013. https://doi.org/10.1172/JCI69411.
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Article has an altmetric score of 51

Metabolic network as a progression biomarker of premanifest Huntington’s disease

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Abstract

Background. The evaluation of effective disease-modifying therapies for neurodegenerative disorders relies on objective and accurate measures of progression in at-risk individuals. Here we used a computational approach to identify a functional brain network associated with the progression of preclinical Huntington’s disease (HD).

Methods. Twelve premanifest HD mutation carriers were scanned with [18F]-fluorodeoxyglucose PET to measure cerebral metabolic activity at baseline and again at 1.5, 4, and 7 years. At each time point, the subjects were also scanned with [11C]-raclopride PET and structural MRI to measure concurrent declines in caudate/putamen D2 neuroreceptor binding and tissue volume. The rate of metabolic network progression in this cohort was compared with the corresponding estimate obtained in a separate group of 21 premanifest HD carriers who were scanned twice over a 2-year period.

Results. In the original premanifest cohort, network analysis disclosed a significant spatial covariance pattern characterized by progressive changes in striato-thalamic and cortical metabolic activity. In these subjects, network activity increased linearly over 7 years and was not influenced by intercurrent phenoconversion. The rate of network progression was nearly identical when measured in the validation sample. Network activity progressed at approximately twice the rate of single region measurements from the same subjects.

Conclusion. Metabolic network measurements provide a sensitive means of quantitatively evaluating disease progression in premanifest individuals. This approach may be incorporated into clinical trials to assess disease-modifying agents.

Trial registration. Registration is not required for observational studies.

Funding. NIH (National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering) and CHDI Foundation Inc.

Authors

Chris C. Tang, Andrew Feigin, Yilong Ma, Christian Habeck, Jane S. Paulsen, Klaus L. Leenders, Laura K. Teune, Joost C.H. van Oostrom, Mark Guttman, Vijay Dhawan, David Eidelberg

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Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells
Ute E. Burkhardt, … , Edwin P. Alyea, Catherine J. Wu
Ute E. Burkhardt, … , Edwin P. Alyea, Catherine J. Wu
Published August 5, 2013
Citation Information: J Clin Invest. 2013. https://doi.org/10.1172/JCI69098.
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Article has an altmetric score of 59

Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells

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Abstract

Background: Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity.

Methods: We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF–secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated.

Results: At a median follow-up of 2.9 (range, 1–4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%–94%) and 88% (95% CI, 59%–97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8+ T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%–33%) of CD8+ T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens.

Conclusion: Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control following allo-HSCT.

Trial registration: Clinicaltrials.gov NCT00442130.

Funding: NCI (5R21CA115043-2), NHLBI (5R01HL103532-03), and Leukemia and Lymphoma Society Translational Research Program.

Authors

Ute E. Burkhardt, Ursula Hainz, Kristen Stevenson, Natalie R. Goldstein, Mildred Pasek, Masayasu Naito, Di Wu, Vincent T. Ho, Anselmo Alonso, Naa Norkor Hammond, Jessica Wong, Quinlan L. Sievers, Ana Brusic, Sean M. McDonough, Wanyong Zeng, Ann Perrin, Jennifer R. Brown, Christine M. Canning, John Koreth, Corey Cutler, Philippe Armand, Donna Neuberg, Jeng-Shin Lee, Joseph H. Antin, Richard C. Mulligan, Tetsuro Sasada, Jerome Ritz, Robert J. Soiffer, Glenn Dranoff, Edwin P. Alyea, Catherine J. Wu

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IL-12p70–producing patient DC vaccine elicits Tc1-polarized immunity
Beatriz M. Carreno, … , Kathryn M. Trinkaus, Gerald P. Linette
Beatriz M. Carreno, … , Kathryn M. Trinkaus, Gerald P. Linette
Published July 11, 2013
Citation Information: J Clin Invest. 2013. https://doi.org/10.1172/JCI68395.
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Article has an altmetric score of 58

IL-12p70–producing patient DC vaccine elicits Tc1-polarized immunity

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Abstract

Background. Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but dose-limiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ–matured, IL-12p70–producing DCs.

Methods. 7 HLA-A*0201+ newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ–matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST.

Results. 6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen–derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine–derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients.

Conclusion. These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen–specific CD8+ T cell immunity in humans with cancer.

Trial registration. Clinicaltrials.gov NCT00683670.

Funding. Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Washington University/JNJ Translational Medicine Award, and NCI (P30 CA91842).

Authors

Beatriz M. Carreno, Michelle Becker-Hapak, Alexander Huang, Megan Chan, Amer Alyasiry, Wen-Rong Lie, Rebecca L. Aft, Lynn A. Cornelius, Kathryn M. Trinkaus, Gerald P. Linette

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Melanoma immunotherapy using mature DCs expressing the constitutive proteasome
Jens Dannull, … , Douglas S. Tyler, Scott K. Pruitt
Jens Dannull, … , Douglas S. Tyler, Scott K. Pruitt
Published June 24, 2013
Citation Information: J Clin Invest. 2013. https://doi.org/10.1172/JCI67544.
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Article has an altmetric score of 52

Melanoma immunotherapy using mature DCs expressing the constitutive proteasome

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Abstract

Background. Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen–loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo.

Methods. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5).

Results. Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3–4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2+ subjects, CD8+ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response.

Conclusion. These results suggest that the efficacy of melanoma DC–based immunotherapy is enhanced when tumor antigen–loaded DCs used for vaccination express cPs.

Trial registration. Clinicaltrials.gov NCT00672542.

Funding. Duke Clinical Research Institute/Duke Translational Medicine Institute, Duke Melanoma Consortium, and Duke University Department of Surgery.

Authors

Jens Dannull, N. Rebecca Haley, Gary Archer, Smita Nair, David Boczkowski, Mark Harper, Nicole De Rosa, Nancy Pickett, Paul J. Mosca, James Burchette, Maria A. Selim, Duane A. Mitchell, John Sampson, Douglas S. Tyler, Scott K. Pruitt

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Exenatide and the treatment of patients with Parkinson’s disease
Iciar Aviles-Olmos, … , Patricia Limousin, Thomas Foltynie
Iciar Aviles-Olmos, … , Patricia Limousin, Thomas Foltynie
Published May 20, 2013
Citation Information: J Clin Invest. 2013. https://doi.org/10.1172/JCI68295.
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Article has an altmetric score of 85

Exenatide and the treatment of patients with Parkinson’s disease

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Abstract

Background. There is increasing interest in methods to more rapidly and cost-efficiently investigate drugs that are approved for clinical use in the treatment of another condition. Exenatide is a type 2 diabetes treatment that has been shown to have neuroprotective/neurorestorative properties in preclinical models of neurodegeneration.

Methods. As a proof of concept, using a single-blind trial design, we evaluated the progress of 45 patients with moderate Parkinson’s disease (PD), randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. Their PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months and after a further 2-month washout period (14 months).

Results. Exenatide was well tolerated, although weight loss was common and l-dopa dose failures occurred in a single patient. Single-blinded rating of the exenatide group suggested clinically relevant improvements in PD across motor and cognitive measures compared with the control group. Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037).

Conclusion. These results demonstrate a potential cost-efficient approach through which preliminary clinical data of possible biological effects are obtainable, prior to undertaking the major investment required for double-blind trials of a potential disease-modifying drug in PD.

Trial registration. Clinicaltrials.gov NCT01174810.

Funding. Cure Parkinson’s Trust.

Authors

Iciar Aviles-Olmos, John Dickson, Zinovia Kefalopoulou, Atbin Djamshidian, Peter Ell, Therese Soderlund, Peter Whitton, Richard Wyse, Tom Isaacs, Andrew Lees, Patricia Limousin, Thomas Foltynie

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