[Show abstract][Hide abstract] ABSTRACT: Arthralgia is a common toxicity among women taking aromatase inhibitors (AIs) and can lead to premature discontinuation of therapy. We evaluated the association between arthralgia, co-morbid fatigue/insomnia and inflammatory biomarkers among women taking AIs.
Women taking AIs for early stage breast cancer completed a modified version of the Brief Pain Inventory, the Brief Fatigue Inventory, the Insomnia Severity Index, and provided blood samples for simultaneous assessment of 34 inflammatory biomarkers using a Luminex kit. Two-sided t-tests were used to compare inflammatory biomarker concentrations for patients with or without moderate to severe arthralgia. Multivariate linear regression analyses were performed to evaluate the relationship between comorbid arthralgia, fatigue and insomnia with identified biomarker concentrations.
Among 203 participants, severity of arthralgia, fatigue and insomnia significantly correlated with each other (p < 0.001 for all comparisons). After controlling for race, chemotherapy history, NSAID use, age and BMI, the co-existence of arthralgia, fatigue and insomnia was associated with elevated CRP (β 93.1, 95 % Confidence Interval (CI) [25.1, 161.1], p = 0.008), Eotaxin (β 79.9, 95 % CI [32.5, 127.2], p = 0.001), MCP-1 (β 151.2, 95 % CI [32.7, 269.8], p = 0.013), and VDBP (β 19422, 95 % CI [5500.5, 33344], p = 0.006).
Among women taking AIs, the co-existence of arthralgia, fatigue and insomnia was associated with increased levels of inflammatory biomarkers (elevated CRP, Eotaxin, MCP-1 and VDBP). These findings suggest a possible shared inflammatory mechanism underlying these common symptoms.
Breast cancer research: BCR 06/2015; 17(1):89. DOI:10.1186/s13058-015-0599-7 · 5.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: VGX – 1027, a novel oral immune modulator, is under development for the treatment of rheumatoid arthritis. The safety, tolerability and pharmacokinetics of single (1-800mg) and multiple (40-400mg) oral doses were evaluated in two clinical studies. The doses were well tolerated up to 800mg in single dose and 200mg BID in multiple doses. Adverse events were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant physical or laboratory findings. The pharmacokinetic data indicate that increases in Cmax and AUC(0−inf) were dose-proportional, and AUC(0−τ) was approximately dose-proportional. For the single-dose study, median Tmax ranged from 0.5 to 2 hours and mean t½ ranged from 4.9 to 8.7 hours. For the multiple-dose study, median Tmax ranged from 0.5 to 2.0 hours and mean t½ ranged from 7.05 to 10.05 hours. No accumulation of the drug was observed after day 1, indicating that steady state concentrations were attained with single and multiple dosing for 5 days. Approximately 90% of administered dose was excreted in urine as unchanged drug. This article is protected by copyright. All rights reserved
Clinical Pharmacology in Drug Development 04/2015; DOI:10.1002/cpdd.193
[Show abstract][Hide abstract] ABSTRACT: This study evaluated the safety and immunogenicity of PENNVAX(®)-B in twelve HIV infected individuals. PENNVAX(®)-B is a combination of three optimized synthetic plasmids encoding for multiclade HIV Gag and Pol and a consensus CladeB Env delivered by electroporation. HIV infected individuals whose virus was effectively suppressed using highly active antiretroviral therapy (HAART) received PENNVAX(®)-B DNA followed by electroporation with CELLECTRA®-5P at Study Weeks 0, 4, 8, and 16. Local administration site and systemic reactions to PENNVAX(®)-B were recorded after each treatment along with any adverse events. Pain of the treatment procedure was assessed using a Visual Analog Scale. Whole PBMCs were isolated for use in IFNγ ELISpot and Flow Cytometric assays. PENNVAX(®)-B was generally safe and well-tolerated. Overall, the four dose regimen was not associated with any serious adverse events or severe local or systemic reactions. A rise in antigen-specific SFU was detected in the INFγ ELISpot assay in all twelve participants. T cells from 8/12 participants loaded with both granzymeB and Perforin in response to HIV antigen, an immune finding characteristic of Long Term Non Progressors (LTNPs) and Elite Controllers (ECs). Thus administration of PENNVAX(®)-B may prove useful adjunctive therapy to ART for treatment and control of HIV infection.Molecular Therapy (2014); doi:10.1038/mt.2014.245.
[Show abstract][Hide abstract] ABSTRACT: HIV-1-infected subjects, despite control of viral replication with ART, have an altered immune cytokine/chemokine milieu. Changes in systemic cytokines and chemokines can alter immune responses. IP-10, in particular, has been associated with pathogenesis in a number of conditions, and we found that IP-10 is increased in serum in subjects who are HIV-1 infected and on stable ART compared with HIV-1-uninfected individuals. In a series of in vitro studies, we found that PBMCs exposed to IP-10 showed a significant decrease in the number of cells capable of secreting IFN-γ, as well as other cytokines, when stimulated with recall antigens. Furthermore, treatment with IP-10 led to decreased antigen-specific calcium signaling and MAPK38 phosphorylation. Importantly, the cytokines, as well as proliferative responses, could be enhanced with an IP-10 Nab. Our findings suggest that IP-10-modulating drugs may potentially enhance T cell responses to vaccination and HIV-1 in HIV+ subjects on ART.
[Show abstract][Hide abstract] ABSTRACT: HIV-1-infected individuals, despite antiretroviral-therapy, often have impaired vaccine responses. We examined the role that immune activation and cellular phenotypes play in H1N1-vaccine responsiveness in HIV-infected-subjects on ART. Subjects received the H1N1-vaccine (15 µg-dose;Novartis), baseline and post-immunization antibody titers were evaluated, and classified as responders if at W3 sero-protection guidelines were met. Responders had higher percentages of baseline naïve T-cells and lower percentages of terminally-differentiated T-cells versus non-responders. Additionally, the naïve CD4+ T-cell percentage and age were negatively correlated. Preservation of naïve T-cell populations, by starting therapy early could impact vaccine responses against influenza and other pathogens, especially as this population ages.
The Journal of Infectious Diseases 03/2014; 210(4). DOI:10.1093/infdis/jiu132 · 5.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the effect of chemotherapy for ovarian cancer on immunologic function and to define the effect on the serologic response to the influenza vaccine.
Under IRB approved protocols, patients with ovarian cancer were administered seasonal trivalent killed influenza vaccines. Peripheral blood was collected for immunologic assessments. Serum was analyzed for hemagglutination inhibition (HAI) antibody titers. Peripheral blood mononuclear cells were isolated to characterize T and B cell populations and function.
Thirty-one patients were recruited: 13 in remission receiving a dendritic cell vaccine with or without a single dose of low-dose cyclophosphamide, 3 in remission not receiving treatment, and 15 undergoing standard therapy. Significant effects on T cell and B cell subset distributions were seen. Functional effects were also seen. Few patients were able to mount a 4-fold HAI antibody response. A 4-fold response was observed for H1N1 in 20%, for H3N2 in 26%, and for influenza B in 6%. Pre-existing exposure to influenza was predictive of responders.
Despite CDC recommendations that patients undergoing chemotherapy receive influenza vaccine, there is little evidence to support its serologic effectiveness in this population. Patients with ovarian cancer are almost uniformly unable to mount a meaningful antibody response. These findings have serious implications for future resource allocation for both seasonal and novel pandemic influenza outbreak and understanding the immunologic deficits as a result of chemotherapy may improve patient care.
[Show abstract][Hide abstract] ABSTRACT: Background. DNA vaccines have been very poorly immunogenic in humans but have been an effective priming modality in prime-boost regimens. Methods to increase the immunogenicity of DNA vaccines are needed.Methods. HIV Vaccine Trials Network (HVTN) studies 070 and 080 were multicenter, randomized, clinical trials. The human immunodeficiency virus type 1 (HIV-1) PENNVAX®-B DNA vaccine (PV) is a mixture of 3 expression plasmids encoding HIV-1 Clade B Env, Gag, and Pol. The interleukin 12 (IL-12) DNA plasmid expresses human IL-12 proteins p35 and p40. Study subjects were healthy HIV-1-uninfected adults 18-50 years old. Four intramuscular vaccinations were given in HVTN 070, and 3 intramuscular vaccinations were followed by electroporation in HVTN 080. Cellular immune responses were measured by intracellular cytokine staining after stimulation with HIV-1 peptide pools.Results. Vaccination was safe and well tolerated. Administration of PV plus IL-12 with electroporation had a significant dose-sparing effect and provided immunogenicity superior to that observed in the trial without electroporation, despite fewer vaccinations. A total of 71.4% of individuals vaccinated with PV plus IL-12 plasmid with electroporation developed either a CD4(+) or CD8(+) T-cell response after the second vaccination, and 88.9% developed a CD4(+) or CD8(+) T-cell response after the third vaccination.Conclusions. Use of electroporation after PV administration provided superior immunogenicity than delivery without electroporation. This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans.
The Journal of Infectious Diseases 07/2013; 208(5). DOI:10.1093/infdis/jit236 · 5.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Donor leukocyte infusions (DLI) can induce potent graft-versus-leukemia (GvL) activity for patients with relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT). Unfortunately, except for chronic phase chronic myelogenous leukemia, responses to DLI have been disappointing. GvL induction is likely to be most effective in the setting of minimal residual disease. Therefore, prevention of relapse by using DLI prophylactically for high-risk patients may improve outcomes of allogeneic HSCT. We have previously reported that ex-vivo co-stimulated T cells infusions (activated DLI, or aDLI) as treatment for relapse are safe and have potent GvL effects. We hypothesized that prophylactic aDLI can be given safely and prevent relapse in high-risk patients after allogeneic HSCT. METHODS: Eighteen patients with AML (14), ALL (3), or MDS (1) received allogeneic SCT after a reduced intensity-conditioning (RIC) regimen with alemtuzumab, fludarabine, and busulfan. Graft-versus-host-disease (GvHD) prophylaxis consisted of tacrolimus and methotrexate with a planned early and rapid taper of tacrolimus. Patients without GvHD, off immune suppression and in remission received aDLI at a dose of 1 x10(7) CD3+ cells/kg (aDLI #1) at D+120, and a second infusion of 1 x 10(8) CD3 cells/kg (aDLI #2) at D+180. RESULTS: At median follow-up of 58 months, 5/18 (28%) patients are alive and 4 remain in remission. Eleven (65%) relapsed at median time of 191 days. Twelve of 18 patients received at least one aDLI. Six of the 12 aDLI#1 patients also received aDLI#2. Six patients did not receive any aDLI due to early relapse (2), protocol ineligibility (1), and GvHD (3). Of the 12 patients who received aDLI#1, only 2/12 developed GVHD. Two out of 12 patients remain in remission. Disease recurrence was the cause of death in 10/13 (77%) patients who died. CONCLUSION: Prophylactic ex-vivo co-stimulated CD3/CD28 DLI is safe, feasible, and not associated with significant GvHD. Relapse remains the major cause of treatment failure after RIC HSCT even with rapid withdrawal of immune suppression and the use of prophylactic aDLI. Better strategies to prevent relapse are needed.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2013; 19(7). DOI:10.1016/j.bbmt.2013.04.021 · 3.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: DNA vaccines have moved into clinical trials in several fields and their success will be important for licensure of this vaccine modality. An effective vaccine for HIV-1 remains elusive and the development of one is troubled by safety and efficacy issues. Additionally, the ability for an HIV-1 vaccine to induce both the cellular and humoral arms of the immune system is needed. DNA vaccines not only offer a safe approach for the development of an HIV-1 vaccine but they have also been shown to elicit both arms of the immune system. Areas covered: This review explores how DNA vaccine design including the regimen, genetic adjuvants used, targeting, and mode of delivery continues to undergo improvements, thereby providing a potential option for an immunogenic vaccine for HIV-1. Expert opinion: Continued improvements in delivery technology, in particular electroporation, and the use of prime-boost vaccine strategies will aid in boosting the immunogenicity of DNA vaccines. Basic immunology research will also help discover new potential adjuvant targets that can be combined with DNA vaccination, such as inhibitors of inhibitory receptors.
[Show abstract][Hide abstract] ABSTRACT: Abstract Stress is implicated in the pathogenesis and progression of HIV. The Transcendental Meditation (TM) is a behavioral stress reduction program that incorporates mind-body approach, and has demonstrated effectiveness in improving outcomes via stress reduction. We evaluated the feasibility of implementing TM and its effects on outcomes in persons with HIV. In this community-based single blinded Phase-I, randomized controlled trial, outcomes (psychological and physiological stress, immune activation, generic and HIV-specific health-related quality of life, depression and quality of well-being) were assessed at baseline and at six months, and were compared using parametric and nonparametric tests. Twenty-two persons with HIV were equally randomized to TM intervention or healthy eating (HE) education control group. Retention was 100% in TM group and 91% in HE control group. The TM group exhibited significant improvement in vitality. Significant between group differences were observed for generic and HIV-specific health-related quality of life. Small sample size may possibly limit the ability to observe significant differences in some outcomes. TM stress reduction intervention in community dwelling adults with HIV is viable and can enhance health-related quality of life. Further research with large sample and longer follow-up is needed to validate our results.
AIDS Care 02/2013; 25(10). DOI:10.1080/09540121.2013.764396 · 1.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chinese translation BACKGROUND: HIV-infected persons have less robust antibody responses to influenza vaccines. OBJECTIVE: To compare the immunogenicity of high-dose influenza vaccine with that of standard dosing in HIV-positive participants. DESIGN: Randomized, double-blind, controlled trial. (ClinicalTrials.gov: NCT01262846) SETTING: The MacGregor Clinic of the Hospital of the University of Pennsylvania, Philadelphia, from 27 October 2010 to 27 March 2011. PARTICIPANTS: HIV-infected persons older than 18 years. INTERVENTION: Participants were randomly assigned to receive either a standard dose (15 mcg of antigen per strain) or a high dose (60 mcg/strain) of the influenza trivalent vaccine. MEASUREMENTS: The primary end point was the rate of seroprotection, defined as antibody titers of 1:40 or greater on the hemagglutination inhibition assay 21 to 28 days after vaccination. The primary safety end point was frequency and intensity of adverse events. Secondary end points were seroconversion rate (defined as a greater than 4-fold increase in antibody titers) and the geometric mean antibody titer. RESULTS: 195 participants enrolled, and 190 completed the study (93 in the standard-dose group and 97 in the high-dose group). The seroprotection rates after vaccination were higher in the high-dose group for the H1N1 (96% vs. 87%; treatment difference, 9 percentage points [95% CI, 1 to 17 percentage points]; P = 0.029), H3N2 (96% vs. 92%; treatment difference, 3 percentage points [CI, -3 to 10 percentage points]; P = 0.32), and influenza B (91% vs. 80%; treatment difference, 11 percentage points [CI, 1 to 21 percentage points]; P = 0.030) strains. Both vaccines were well-tolerated, with myalgia (19%), malaise (14%), and local pain (10%) the most frequent adverse events. LIMITATIONS: The effectiveness of the vaccine in preventing clinical influenza was not evaluated. The number of participants with CD4 counts less than 0.200 × 109 cells/L was limited. CONCLUSION: HIV-infected persons reach higher levels of influenza seroprotection if vaccinated with the high-dose trivalent vaccine than with the standard-dose. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases and Center for AIDS Research of the University of Pennsylvania.
Annals of internal medicine 01/2013; 158(1):19-26. DOI:10.7326/0003-4819-158-1-201301010-00005 · 16.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report the safety and tolerability of 87 infusions of lentiviral vector modified autologous CD4 T cells (VRX496-T; Lexgenleucel-T) in 17 HIV patients with well controlled viremia. Antiviral effects were studied during analytic treatment interruption in a subset of 13 patients. VRX496-T was associated with a decrease in viral load set points in 6/8 subjects (p=0.08) In addition, A-to-G transitions were enriched in HIV sequences post infusion, consistent with a model where transduced CD4 T cells exert anti-sense mediated genetic pressure on HIV during infection. Engraftment of vector modified CD4 T cells was measured in gut associated lymphoid tissue (GALT), and correlated with engraftment in blood. The engraftment half-life in the blood was approximately 5 weeks, with stable persistence in some patients for up to five years. Conditional replication of VRX496 was detected periodically through one year post infusion. No evidence of clonal selection of lentiviral vector transduced T cells or integration enrichment near oncogenes was detected. This is the first demonstration that gene modified cells can exert genetic pressure on HIV. Thus gene modified T cells have the potential to decrease the fitness of HIV-1, and conditionally replicative lentiviral vectors have a promising safety profile in T cells. (Study registered at clinical trials.gov #NCT00295477).
[Show abstract][Hide abstract] ABSTRACT: Please cite this paper as: Kersun et al. (2012) A prospective study of chemotherapy immunologic effects and predictors of humoral influenza vaccine responses in a pediatric oncology cohort. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12058. Background: Pediatric oncology patients represent a cohort of individuals uniquely at risk of complications from influenza, yet less likely to respond to the vaccine. It is not yet clear how to best protect this vulnerable population. Methods: We performed a prospective analysis of 177 pediatric oncology patients to define the predictors of influenza vaccine responses. Each variable was examined over three time points and a repeated measure analysis was performed. Results: Patients with ALL vaccinated during induction phase had superior influenza vaccine responses than those subjects vaccinated during post-induction or maintenance phases (P = 0·0237). Higher aggregate HAI titer responses were associated with a higher baseline B-cell count (P = 0·0240), and higher CD4 and CD8 influenza-specific T-cell responses, suggesting prior antigen exposure is a significant contributor. The solid tumor cohort had equivalent responses during all time frames of chemotherapy. Discussion: The optimal protection from influenza of pediatric patients on chemotherapy should include vaccination, but it is clear that not all patients produce high titers of antibodies after vaccination. This study identified biomarkers that could be used to individualize vaccine approaches. Immunologic predictors might have a role in targeting resources, as B-cell counts predicted of vaccine responses among the patients with ALL.
Influenza and Other Respiratory Viruses 11/2012; 7(6). DOI:10.1111/irv.12058 · 1.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Children with high-risk neuroblastoma have a poor prognosis with chemotherapy alone and hematopoietic stem cell transplantation offers improved survival. As a dose escalation strategy, tandem transplants have been utilized, but are associated with persistent immune compromise. This study evaluated the provision of an autologous co-stimulated, activated T cell product to support immunologic function. EXPERIMENTAL DESIGN: Nineteen subjects with high risk neuroblastoma were enrolled in a pilot phase and twenty three subjects were entered in to the randomized study. Immunologic reconstitution was defined by flow cytometry and functional assays. Next generation sequencing was performed to identify changes to the T cell repertoire. Twenty-two patients were vaccinated to define effects on antibody responses. RESULTS: Subjects who received their autologous co-stimulated T cell product on Day 2 had significantly superior T cell counts and T cell proliferation compared to those who received T cells on Day 90. Early administration of autologous T cells suppressed oligoclonality and enhanced repertoire diversity. The subjects who received the Day 2 T cell product also had better responses to the pneumococcal vaccine. CONCLUSIONS: The infusion of activated T cells can improve immunologic function especially when given early after transplant. This study demonstrated the benefit of providing cell therapies during periods of maximum lymphopenia.
Clinical Cancer Research 10/2012; 18(24). DOI:10.1158/1078-0432.CCR-12-1432 · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The efficacy of influenza vaccination in patients treated with rituximab is a clinically important question. Rheumatology clinics are populated with patients receiving rituximab for a broad array of disorders. Although several studies have explored the efficacy of other vaccines in rituximab-treated populations, results have been conflicting. We wished to define influenza vaccine efficacy in a rituximab-treated cohort. We examined 17 evaluable subjects treated with rituximab for rheumatologic conditions. T cell subsets, B cells subsets, T cell function, and B cell function were evaluated at specific time points along with hemagglutinination inhibition titers after receiving the standard inactivated influenza vaccine. T cell subset counts were significantly different than controls but did not change with rituximab. B cells depleted in all patients but were in various stages of recovery at the time of vaccination. Influenza vaccine responsiveness was poor overall, with only 16 % of subjects having a four-fold increase in titer. Pre-existing titers were retained throughout the study, however. The ability to respond to the influenza vaccine appeared to be related to the degree of B cell recovery at the time of vaccination. This study emphasizes that antibody responses to vaccine are impaired in subjects treated with rituximab and supports the concept that B cell recovery influences influenza vaccine responsiveness.
[Show abstract][Hide abstract] ABSTRACT: There are few data characterizing the immunologic consequences of chemotherapy for acute myeloid leukemia (AML) and almost nothing is known about the effects of chemotherapy in a pediatric AML cohort. We identified T-cell subsets, B-cell subsets, and used Enzyme-linked immunosorbent spot analyses to define the function of T cells and B cells in 7 pediatric patients with AML on chemotherapy. The data show that the effects of chemotherapy disproportionately target the B cell and depletion of B cells is associated with impaired responses to the inactivated influenza vaccine. Diminished T-cell numbers were also observed although the magnitude of the effect was less than what was seen for B cells. Furthermore, measures of T-cell function were largely intact. We conclude that humoral immunity is significantly affected by chemotherapy for AML.
Journal of Pediatric Hematology/Oncology 09/2012; DOI:10.1097/MPH.0b013e318266c0c8 · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current study assessed the immunogenicity and protective efficacy of various prime-boost vaccine regimens in rhesus macaques using combinations of recombinant DNA (rDNA), recombinant MVA (rMVA), and subunit gp140 protein. The rDNA and rMVA vectors were constructed to express Env from HIV-1 subtype CRF01_AE and Gag-Pol from CRF01_AE or SIVmac 239. One of the rMVAs, MVA/CMDR, has been recently tested in humans. Immunizations were administered at months 0 and 1 (prime) and months 3 and 6 (boost). After priming, HIV env-specific serum IgG was detected in monkeys receiving gp140 alone or rMVA but not in those receiving rDNA. Titers were enhanced in these groups after boosting either with gp140 alone or with rMVA plus gp140. The groups that received the rDNA prime developed env-specific IgG after boosting with rMVA with or without gp140. HIV Env-specific serum IgG binding antibodies were elicited more frequently and of higher titer, and breadth of neutralizing antibodies was increased with the inclusion of the subunit Env boost. T cell responses were measured by tetramer binding to Gag p11c in Mamu-A*01 macaques, and by IFN-γ ELISPOT assay to SIV-Gag. T cell responses were induced after vaccination with the highest responses seen in macaques immunized with rDNA and rMVA. Macaques were challenged intravenously with a novel SHIV-E virus (SIVmac239 Gag-Pol with an HIV-1 subtype E-Env CAR402). Post challenge with SHIV-E, antibody titers were boosted in all groups and peaked at 4 weeks. Robust T cell responses were seen in all groups post challenge and in macaques immunized with rDNA and rMVA a clear boosting of responses was seen. A greater than two-log drop in RNA copies/ml at peak viremia and earlier set point was achieved in macaques primed with rDNA, and boosted with rMVA/SHIV-AE plus gp140. Post challenge viremia in macaques immunized with other regimens was not significantly different to that of controls. These results demonstrate that a gp140 subunit and inclusion of SIV Gag-Pol may be critical for control of SHIV post challenge.