Immunomodulatory Effects In Patients Research Articles

Insights on Nefecon®, a Targeted-Release Formulation of Budesonide and Its Selective Immunomodulatory Effects in Patients with IgA Nephropathy.

Immunoglobulin A nephropathy (IgAN) is a chronic, immune-mediated kidney disease characterized by the deposition of galactose-deficient immunoglobulin A1 (Gd-IgA1) in the kidneys. Excess Gd-IgA1 production in patients with IgAN is located within the mucosa-associated lymphoid tissue, particularly within the lamina propria in the distal ileum. Nefecon® is a targeted-release formulation of the corticosteroid budesonide, which became the first treatment approved by the US Food and Drug Administration (FDA; brand name, TARPEYO®) and European Medicines Agency (EMA; KINPEYGO®) for patients with primary IgAN at risk of rapid disease progression, after demonstrating clinically significant reduction of proteinuria in an interim analysis of the Phase III NefIgArd trial. After showing a significant reduction in estimated glomerular filtration rate decline in the full 2-year analysis of the trial, Nefecon was granted full approval by the FDA to reduce the loss of kidney function. Nefecon was specifically designed to deliver budesonide to the distal ileum, selectively targeting excess Gd-IgA1 production in the gut-associated lymphoid tissue. In this review, we describe the properties of Nefecon and the evidence to date that confirms its localized treatment effect. We also present unpublished evidence from Phase I trials investigating the pharmacokinetics and cortisol suppression effects of Nefecon in healthy participants. These studies demonstrated that Nefecon has a distinct pharmacokinetic profile from other budesonide products, allowing for targeted, localized action in the distal ileum. When considered alongside existing clinical trial data showing the effect of Nefecon on gut-associated biomarkers, available evidence indicates that Nefecon has a selective immunomodulatory mechanism of action and a direct disease-modifying effect in patients with IgAN, while having low systemic exposure and adverse effects.

Evidence of the Immunomodulatory Effects of Selective Serotonin Reuptake Inhibitors in Patients With Depression Through a Systematic Review.

Depression is a common illness, affecting >264 million people worldwide. According to the literature, depression patients have baseline subclinical inflammation. The immunomodulatory effects of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are largely unclear and poorly understood. Using evidence-based medicine, this study aimed to determine the immunomodulatory effects of SSRIs by assessing changes in immunomodulatory markers following SSRI treatment. Using the PubMed website, a literature search was conducted with various terminologies related to the treatment of depression and various markers of inflammation. Out of 387 retrieved articles, after critical appraisal and screening based on inclusion and exclusion criteria, 17 were selected. Qualitative synthesis and quantitative analysis were carried out. RevMan 5 software was used to synthesize and evaluate the data. Microsoft Word and Excel (Microsoft Corporation, Redmond, Washington, United States) were used for generating tables and figures. We extracted data from a total of 839 patients in 17 studies. A highly significant reduction in interleukins-6 (IL-6) (standardised mean difference (SMD) = 1.32 (95% confidence interval (CI): 0.58, 2.06), Z = 3.48, P = 0.0005), a significant reduction in tumor necrosis factor-alpha (TNF-α) (SMD = 1.29 (95% CI: 0.19, 2.39), Z = 2.30, P = 0.02) but no change in overall C-reactive protein (CRP) (SMD = 0.40 (95% CI: -0.26, 1.07), Z = 1.19, P = 0.23) levels were observed by using the random-effects model. There was substantial heterogeneity found between the studies. SSRIs have an immunomodulatory effect in patients with depression by significantly reducing the peripheral pro-inflammatory cytokine markers of IL-6 and TNF-α, which may contribute to ameliorating the response to antidepressant drug treatment. In contrast, no effects of SSRIs on acute-phase protein CRP were found.

The radiopharmaceutical radium-223 has immunomodulatory effects in patients and facilitates anti-programmed death receptor-1 therapy in murine models of bone metastatic prostate cancer

Background & purposeRadium-223 (Ra223) improves survival in metastatic prostate cancer (mPC), but its impact on systemic immunity is unclear, and biomarkers of response are lacking. We examined markers of immunomodulatory activity during standard clinical Ra223 and studied the impact of Ra223 on response to immune checkpoint inhibition (ICI) in preclinical models. Materials & methodsWe conducted a single-arm biomarker study of Ra223 in 22 bone mPC patients. We measured circulating immune cell subsets and a panel of cytokines before and during Ra223 therapy and correlated them with overall survival (OS). Using two murine mPC models—orthotopic PtenSmad4-null and TRAMP-C1 grafts in syngeneic immunocompetent mice—we tested the efficacy of combining Ra223 with ICI. ResultsAbove-median level of IL-6 at baseline was associated with a median OS of 358 versus 947 days for below levels; p = 0.044, from the log-rank test. Baseline PlGF and PSA inversely correlated with OS (p = 0.018 and p = 0.037, respectively, from the Cox model). Ra223 treatment was associated with a mild decrease in some peripheral immune cell populations and a shift in the proportion of MDSCs from granulocytic to myeloid. In mice, Ra223 increased the proliferation of CD8+ and CD4+ helper T cells without leading to CD8+ T cell exhaustion in the mPC lesions. In one of the models, combining Ra223 and anti-PD-1 antibody significantly prolonged survival, which correlated with increased CD8+ T cell infiltration in tumor tissue. ConclusionThe inflammatory cytokine IL-6 and the angiogenic biomarker PlGF at baseline were promising outcome biomarkers after standard Ra223 treatment. In mouse models, Ra223 increased intratumoral CD8+ T cell infiltration and proliferation and could improve OS when combined with anti-PD-1 ICI.

The use of selenium-containing drugs in the prevention and treatment of complications in patients with COVID-19

Objective. To study literature data reflecting the use of selenium (Se) and selenium-containing drugs in the complex prophylaxis and treatment of complications in patients with COVID-19. Material and methods. Data analysis of 37 publications of scientists from Russian Federation, United States of America, People's Republic of China, Great Britain, India, France, Germany, Italy, Sweden, Canada, Brazil, United Arab Emirates, Saudi Arabia, Ireland, Holland, Greece, Australia, Poland, Pakistan, Sudan, Nepal was performed. The authors reflected on the epidemiology, diagnosis, pathogenesis, clinic, risk of acute respiratory distress syndrome, multiple organ failure, cardiovascular complications, mortality in patients with COVID-19, the importance of Se deficiency in the body and the preventive use of selenium-containing drugs in novel coronavirus infection. Results. Low dietary Se intake was associated with the development of acute respiratory distress syndrome in men and women with COVID-19. Deficiencies were associated with increased risk of morbidity and mortality. Organic forms of Se had the best bioavailability. Se had antioxidant, anti-inflammatory, antithrombotic, antiviral, immunomodulatory effects in patients with COVID-19. Conclusions. Thus, control and optimization of the selenium status in population of selenium-deficient areas with addition of Se-enriched food to the diet, as well as SELENBIO for women complex of Russian company "Parapharm" could be one of the directions of prevention and treatment of complications in patients with COVID-19.

Vitamin D: an essential adjuvant therapeutic agent in breast cancer.

Low serum levels of vitamin D have been reported as a risk factor for breast cancer. This narrative review provides an update on the impact of vitamin D on hormone receptors, notably estrogen receptor subunits, and gives insights on possible therapeutic interventions to overcome breast cancer. In addition, evidence that supports the beneficial use of vitamin D as adjuvant treatment of breast cancer is summarized. Vitamin D deficiency is significantly widespread in patients with triple-negative tumors. Several studies have observed a possible modulatory effect of vitamin D or its analogues on the expression of different hormone receptors in breast cancer and increased sensitivity to tamoxifen. Vitamin D possesses anti-inflammatory and immunomodulatory effects in patients with breast cancer, and the mechanism of action of vitamin D in patients with breast cancer is discussed. In conclusion, vitamin D appears to have a beneficial role in the prevention and management of breast cancer, however, large-scale, randomized controlled trials are needed to confirm the effects of vitamin D in breast cancer prevention or treatment.

Treatment with ribociclib shows favourable immunomodulatory effects in patients with hormone receptor-positive breast cancer—findings from the RIBECCA trial

BackgroundInhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6i) have significantly improved clinical outcomes in patients with advanced hormone receptor-positive (HR+) breast cancer and have demonstrated favourable antitumour immune responses in preclinical studies. MethodsHere, we investigated peripheral immune responses to ribociclib in patients with metastatic HR+ breast cancer as a preplanned exploratory subanalysis of the RIBECCA trial (NCT03096847). Peripheral blood mononuclear cells were subjected to immune cell profiling, gene expression analysis of immune-related signatures, and deep T cell receptor profiling before treatment started and after 12 weeks of treatment with ribociclib. ResultsGene expression analysis revealed an upregulation of signatures associated with an activated adaptive immune system and a decrease in immunosuppressive cytokine signalling during treatment with ribociclib. Profiling of peripheral immune cell subpopulations showed a decrease in Treg cell frequencies, which was associated with treatment response. Furthermore, induction of CD4+ naive T cells could be seen, whereas effector and memory T cell populations remained largely unchanged. Correspondingly, T cell repertoire diversity remained mostly unchanged during treatment, although an increase in clonality could be observed in single patients. ConclusionsWe show that treatment with ribociclib has significant effects on the peripheral innate and adaptive immune response in patients with HR+ breast cancer. Our data suggest that these effects lead to an activation of an already existing immune response rather than a de novo induction and make a strong case for future combination strategies of CDK4/6i with immunotherapies to enhance the adaptive immune response in HR+ breast cancer.

Toll-like receptor 9–dependent interferon production prevents group 2 innate lymphoid cell–driven airway hyperreactivity

Group 2 innate lymphoid cells (ILC2s) are important mediators of allergic asthma. Bacterial components, such as unmethylated CpG DNA, a Toll-like receptor (TLR) 9 agonist, are known to possess beneficial immunomodulatory effects in patients with T cell-mediated chronic asthma. However, their roles in regulating ILC2s remain unclear. We sought to determine the role of TLR9 activation in regulating ILC2 function and to evaluate the therapeutic utility of an immunomodulatory microparticle containing natural TLR9 ligand (MIS416). We evaluated the immunomodulatory effects of CpG Ain IL-33-induced airway hyperreactivity (AHR) and airway inflammation. The roles of interferons were examined invivo and invitro by using signal transducer and activator of transcription 1 (Stat1)-/- mice and neutralizing antibodies against IFN-γ and IFN-α/β receptor subunit 1, and their cellular sources were identified. The therapeutic utility of MIS416 was investigated in the Alternaria alternata model of allergic asthma and in humanized NSG mice. We show that TLR9 activation by CpG Asuppresses IL-33-mediated AHR and airway inflammation through inhibition of ILC2s. Activation of TLR9 leads to production of IFN-α, which drives IFN-γ production by natural killer cells. Importantly, IFN-γ is essential for TLR9-driven suppression, and IFN-α cannot compensate for impaired IFN-γ signaling. We further show that IFN-γ directly inhibits ILC2 function through a STAT1-dependent mechanism. Finally, we demonstrate the therapeutic potential of MIS416 in A alternata-induced airway inflammation and validated these findings in human subjects. TLR9 activation alleviates ILC2-driven AHR and airway inflammation through direct suppression of cell function. Microparticle-based delivery of TLR9 ligands might serve as a therapeutic strategy for asthma treatment.

Immunomodulatory effects induced by intramuscular administration of autologous total immunoglobulin G in patients with atopic dermatitis

BackgroundPolyvalent human immunoglobulin G (IgG) preparations produced from the plasma pools of healthy blood donors have been used for the treatment of various autoimmune diseases and allergic diseases because of their anti-inflammatory and immunomodulatory effects. We hypothesized that intramuscular administration of autologous total IgG would induce immunomodulatory effects in patients with allergic diseases, based on the clinical efficacy of autologous blood therapy in patients with atopic dermatitis (AD). MethodsSixteen adult AD patients with IgE-mediated sensitization to the house dust mite (Dermatophagoides farinae) received intramuscular injections of 50 mg autologous total IgG twice a week for 4 weeks. The serum levels of IgE, IgG, and IgG4 antibodies to the recombinant group 2 major allergen of Dermatophagoides farinae (Der f 2) and serum levels of interleukin (IL)-10, IL-4, IL-12, and interferon gamma (IFN-γ) were measured by enzyme-linked immunosorbent assay at baseline and at weeks 4, 8, and 12. ResultsThe serum level of IgE antibodies to Der f 2 was significantly decreased at 12 weeks compared with baseline (p<0.005). The serum levels of IgG and IgG4 antibodies to Der f 2 were significantly increased at 4, 8, and 12 weeks compared with baseline (p<0.05). The serum levels of IL-10 and IFN-γ were significantly increased at 4, 8, and 12 weeks compared with baseline (p<0.05). There were no significant differences in the serum levels of IL-4 or IL-12 before and after intramuscular administrations of autologous total IgG (p>0.05). ConclusionIntramuscular administration of autologous total IgG induced anti-allergic immunomodulatory effects in AD patients. Further studies are required to evaluate the detailed immunological mechanism underlying these effects.

Abstract CT159: IFN-γ analysis in blood and tissue as a potential prognostic and/or predictive biomarker

Abstract Background SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer (NSCLC), demonstrated similar overall survival (OS) in both treatment arms. Immune correlate analyses including pre-treatment IFN-γ levels in blood and tumor tissue were used to potentially identify prognostic and/or predictive correlation with clinical outcome. Methods Serum was isolated from all randomized NSCLC patients at screening, periodically during treatment and at disease progression for evaluation of IFN-γ levels using the SimoaTM assay (Myriad RBM, Austin, TX, USA). Available archival tissue was also tested for 91- immune gene activation markers, including IFN-γ by the Fluidigm-based gene-expression platform (Sirona Dx, Lake Oswego, OR, USA). Kaplan-Meier statistical methods and Cox proportion hazards models were utilized to evaluate and contrast the correlation of peripheral and intratumoral IFN-γ levels with OS. Patients were classified paradoxically as IFN-γ "low" with a favorable disease prognosis versus "high" associated with more aggressive disease based on the median. Results Pretreatment serum results were available for 582 out of the 597 randomized patients. Each patient was classified to be pre-treatment IFN-γ high or low (&amp;lt; cut-off) using cut-off 0.093 pg/ml, which is the median IFN-γ value in the D+B group. Median overall survival (mOS) in all patients with IFN-γ low is 11.3 months (95% confidence interval [CI], 10.1-13.5) versus 10.4 months (95% CI, 8.4-11.3) in all IFN-γ high; p=0.047. mOS of D+B arm is 11.6 months (95% CI, 10.2-13.9) and 11.1 months (95% CI, 9.1-14.7) in the D group; p=0.982 for IFN-γ low. mOS of D+B arm is 9.0 months (95% CI, 6.7-11.2) and 10.6 months (95% CI, 8.9-13.0) in the D group; p=0.252 for IFN-γ high. With the limited intratumoral IFN-γ gene expression data (n=33), no statistically significant correlation with OS was observed. Conclusions Correlative approaches identified low peripheral low IFN-γ at pretreatment as a biomarker of interest correlating with more favorable clinical outcomes and is consistent with the hypothesis that bavituximab may demonstrate more immunomodulatory effects in patients with “immune cold” tumors. Citation Format: Nikoletta Kallinteris, Leora Horn, Min Tang, Tobias Guennel, Shen Yin, Jennifer Lai, Joseph Shan, Rachel E. Sanborn. IFN-γ analysis in blood and tissue as a potential prognostic and/or predictive biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT159. doi:10.1158/1538-7445.AM2017-CT159

Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota

Helminth parasites have been reported to have beneficial immunomodulatory effects in patients with allergic and autoimmune conditions and detrimental consequences in patients with tuberculosis and some viral infections. Their role in coinfection with respiratory viruses is not clear. Here we investigated the effects of strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus (RSV) infection in a mouse model. A murine helminth/RSV coinfection model was developed. Mice were infected by means of oral gavage with 200 stage 3 H polygyrus larvae. Ten days later, mice were infected intranasally with either RSV or UV-inactivated RSV. H polygyrus-infected mice showed significantly less disease and pulmonary inflammation after RSV infection associated with reduced viral load. Adaptive immune responses, including TH2 responses, were not essential because protection against RSV was maintained in Rag1-/- and Il4rα-/- mice. Importantly, H polygyrus infection upregulated expression of type I interferons and interferon-stimulated genes in both the duodenum and lung, and its protective effects were lost in both Ifnar1-/- and germ-free mice, revealing essential roles for type I interferon signaling and microbiota in H polygyrus-induced protection against RSV. These data demonstrate that a strictly enteric helminth infection can have remote protective antiviral effects in the lung through induction of a microbiota-dependent type I interferon response.

Repository corticotropin injection in patients with refractory psoriatic arthritis: a case series.

PurposeAlthough numerous treatment options are available for patients with psoriatic arthritis (PsA), a need for effective and tolerable treatments remains for patients with refractory disease who have failed previous therapies and continue to experience tender and/or swollen joints, pain, and disease activity. Repository corticotropin injection (RCI) is believed to produce steroidogenic, steroid-independent, anti-inflammatory, and immunomodulatory effects in patients with rheumatic disorders, such as PsA. Limited literature exists on the use of RCI in patients with refractory PsA. The objective of this case series is to provide information on the clinical features of patients with refractory PsA and their response to RCI.PatientsNine patients treated with RCI for refractory PsA were retrospectively identified and included in the case series.ResultsAll the nine patients experienced at least transient improvements in their active skin and joint disease. In some patients, it was necessary to titrate the RCI to an appropriate dose. RCI was used in some patients to bridge with another PsA therapy, such as apremilast or certolizumab. RCI was well tolerated, but discontinued in three patients due to preexisting conditions (hypertension and hyperglycemia).ConclusionRCI may be a safe and effective option for patients with refractory PsA who failed therapy with multiple previous treatments.

The association of renin-angiotensin system blockades and pneumonia requiring admission in patients with COPD.

BackgroundThe hallmark of COPD is chronic airway inflammation, which may be mediated by renin–angiotensin system. The renin–angiotensin system blockers such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) have exhibited anti-inflammatory and immunomodulatory effects in patients with various diseases. We explored the effects of ACEi and ARBs on the risk of pneumonia in patients with COPD.MethodsA nested case–control study was performed on COPD patients recruited from January 2010 to August 2013 in two referral hospitals in Korea. A total of 130 COPD patients admitted with pneumonia were included, and 245 COPD patients without pneumonia were selected as controls from a total of 1,646 such patients. Controls were matched with test patients by age, sex, and severity of airflow limitation. The effects of ACEi/ARBs use on the odds ratio (OR) for the development of pneumonia were tested through conditional logistic regression.ResultsElderly patients (over 70 years of age) constituted ~30% of each group; most of the patients were male (85%). Of the COPD patients with pneumonia, 21.5% had taken ACEi/ARBs for a mean of 9.8 months (standard deviation ±3.5 months). The proportions of ACEi/ARBs users and the mean duration of such use did not differ when compared to those of the control patients (26.9%, P=0.25; 9.6±3.6 months, P=0.83). Univariate analyses indicated that the use of ACEi/ARBs was not associated with a decreased risk of pneumonia (OR =0.70, 95% confidence interval 0.41–1.23, P=0.21), whereas both a history of pulmonary tuberculosis (OR =1.85, 95% confidence interval 1.12–3.06, P=0.02) and exposure to systemic steroids (OR =2.33, 95% confidence interval 1.28–4.23, P=0.005) did show an association. After adjustment for a history of tuberculosis, comorbid chronic renal disease, and exposure to corticosteroids, ACEi/ARBs reduced the risk of pneumonia in COPD patients (OR =0.51, 95% confidence interval 0.27–0.98, P=0.04).ConclusionThis study revealed that the use of ACEi/ARBs was associated with reducing the risk of pneumonia in patients with COPD. Further prospective studies are necessary to confirm the protective effect of ACEi/ARBs and elucidate the underlying mechanisms in COPD patients.

The effect of high dose of Vitamin D3 on the prognosis of patients with Multiple Sclerosis

Introduction. Multiple Sclerosis is a chronic inflammatory neurodegenerative disease of large magnitude in the world. Method and Goal. To analyze primary studies associating high dose of vitamin D with the prognosis of patients with multiple sclerosis. Results. 9 studies were selected, including 1022 participants. 630 of them were randomized to vitamin D3 supplementation in high dose, 171 in low-dose and 221 receiving placebo. Conclusion. There is evidence that high dose of Vitamin D3 provide immunomodulatory effects in patients with Multiple Sclerosis, showing improvement in the patients' prognosis.

Association of Circulating Vitamin D Concentrations with Intestinal but Not Systemic Inflammation in Inflammatory Bowel Disease

Vitamin D may mediate immunomodulatory effects in patients with inflammatory bowel disease (IBD). The relationships between disease activity and circulating levels of total, free, and bioavailable 25(OH) vitamin D (25(OH)D) are poorly defined. The aim of this study was to measure circulating components of the vitamin D axis in patients with IBD and healthy controls and to correlate these with markers of disease activity, adjusting for potential confounders. Clinical data were obtained and serum was analyzed for 25(OH)D and vitamin D-binding protein in patients with IBD and controls. Markers of systemic and intestinal (fecal calprotectin) inflammation were measured. Serum 25(OH)D concentration was similar across 23 controls, 40 patients with Crohn's disease, and 31 with ulcerative colitis. An inverse correlation between 25(OH)D and calprotectin was noted in Crohn's disease (Pearson's r = -0.35, P = 0.040), ulcerative colitis (r = -0.39, P = 0.039), and all IBD together (r = -0.37, P = 0.003), but not with systemic markers. A similar trend was noted for free and bioavailable 25(OH)D. This inverse correlation remained after partial correlation analysis correcting for sunlight exposure, total oral vitamin D intake, and obesity and was also noted among the subgroup without small intestinal involvement. Despite total, free, and bioavailable 25(OH)D concentrations being similar to those in a healthy control population, they inversely correlated strongly with intestinal inflammation. This was independent of potential malabsorption, sunlight exposure, and total vitamin D intake and obesity. Vitamin D may play an immunomodulatory role in IBD.

Systemic Isotretinoin Therapy Normalizes Exaggerated TLR-2-Mediated Innate Immune Responses in Acne Patients

Retinoids are used in the treatment of inflammatory skin diseases and malignancies, but studies characterizing the in vivo actions of these drugs in humans are lacking. Isotretinoin is a pro-drug for all-trans retinoic acid that can induce long-term remissions of acne; however, its complete mechanism of action is unknown. We hypothesized that isotretinoin induces remission of acne by normalizing the innate immune response to the commensal bacterium P. acnes. Compared to normal subjects, peripheral blood monocytes from acne patients expressed significantly higher levels of TLR-2 and exhibited significantly greater induction of TLR-2 expression following P. acnes stimulation. Treatment of patients with isotretinoin significantly decreased monocyte TLR-2 expression and subsequent inflammatory cytokine response to P. acnes by one week of therapy. This effect was sustained six months following cessation of therapy, indicating that TLR-2 modulation may be involved in the durable therapeutic response to isotretinoin. This study demonstrates that isotretinoin exerts immunomodulatory effects in patients and sheds light on a potential mechanism for its long-term effects in acne. The modulation of TLR-2 expression on monocytes has important implications in other inflammatory disorders characterized by TLR-2 dysregulation.

Phase II Multicenter Trial of Lenalidomide: Clinical and Immunomodulatory Effects in Patients with CTCL

Abstract 1638 Background:Lenalidomide is currently being used in various hematological malignancies and solid tumors. The mechanism of action is unknown, but appears to be immune-mediated with stimulation of T- and NK cell function, induction of Th1 cytokine production and cytotoxic activity. The biologic effects of lenalidomide in relapsed CTCL have not been defined. We performed a phase II multicenter trial in relapsed CTCL patients, and investigated the immunomodulatory effects of lenalidomide in a subset of the patients. Methods: Thirty-five heavily pretreated patients (median prior tx 7; range, 1–14) have been enrolled with 28 and 32 patients evaluable for response and toxicity, respectively. The first 18 enrolled patients received 25 mg daily for 21 days with 7 days rest of a 28-day cycle. Because of unacceptable cutaneous flare reactions, the study was amended and subsequent patients received a starting dose of 10 mg and then titrated up to 25 mg as tolerated. A subset of patients underwent immunomodulatory assessment. Blood samples of 6 patients before and 3 weeks into therapy have been analyzed by flow cytometry for various T- and NK cell subsets. Results: Clinical stages were: 7 (24%) stage IB, 2 (7%) stage IIA, 4 (14%) stage IIB; 6 (21%) stage III; 8 (28%) stage IVA, 1 (4%) stage IVB. The overall response rate was 32% (9 pts-all PR with 25 mg daily dose) with median response duration of 5 months (range, 1–12+). The stable-disease rate was 61% (17 pts), and 7% (2 pts) had PD. The median time to first response was 3 months (range, 1–5). Grade 3 adverse events were fatigue (22%), infection (9%), leukopenia (3%), and neutropenia (3%). No grade 4 toxicity occurred. Eight patients (25%) experienced grade 1 or 2 tumor flare after starting treatment with lenalidomide. There was less flare in patients dose escalated. When compared with baseline levels, 4 of 6 patients screened for immunomodulatory changes revealed a decrease in CD4+ T-cells (range, 24% – 68%) with concomitant decrease in CD4+CD25+ T regulatory cells (range, 18% to 87%). When compared to clinical response 2 of these patients achieved PR and 2 patients remained stable during therapy. The remaining 2 patients (2× SD) experienced an increase of CD4+ T-cells (2%, 43%) with increase of CD4+CD25+ T regulatory cells (50%, 73%). Conclusions: In our study oral lenalidomide demonstrates activity in patients with relapsed/advanced CTCL consistent with activity of other currently available agents, with a manageable toxicity profile. Our data suggest that the immunomodulatory cutaneous effects of lenalidomide could be associated with decreased Treg and correlates with blood CD4+ T-cell number. Skin biopsies from 6 patients are being investigated for cytokine expression before and during therapy. Use as maintenance therapy or in combination with other biologic agents is worth investigating. Disclosures:Off Label Use: Lenalidomide. Rosen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:kyowa: Consultancy, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Consultancy. Kuzel:Celgene: Research Funding, Speakers Bureau.

Treatment with Lenalidomide Has a Positive Immunomodulatory Effect in Patients with Chronic Lymphocytic Leukemia.

Lenalidomide (Revlimid) is known to downregulate TNF-a, IL-6, IL-8, and VEGF, impair bone marrow microenviroment-neoplastic cell interaction, activate NK cells, and stimulate T-cell activity. Based on these properties, we sought to further evaluate the immumodulatory activity of treatment with lenalidomide in patients with previously untreated chronic lymphocytic leukemia age 65 and older. Nineteen patients enrolled in a phase II clinical trial were treated with lenalidomide, given orally at the dose of 5mg daily for 28 days followed by individual titration up of 5mg increments every 28 days to reach a maximum dose of 25mg daily. Patients were evaluated for response after 3 months and if an objective response or disease stability was obtained, the treatment was continued until obvious disease progression. Peripheral blood (15ml) was collected at baseline, after three months and every six months thereafter while on treatment in patients that agreed to optional correlative studies. Data at baseline and after three months of treatment are presented. Plasma cytokine levels were determined by Luminex Multiplex assay system. Percentages of CD3, CD4, and CD8 T cells and natural regulatory T cells (TR, CD4+CD25hiFoxP3+) cells, and the ability of anti-CD3 activated T cells to synthesize of IL-2, IFN-g, TNF-a, and IL-10 were measured by multi-color flow cytometry. Eleven patients had a partial response (responder, R) and 8 patients failed to respond (non-responder, NR) after 3 months of therapy. All patients had significantly higher percentages of CD3+ and CD4+ T-cells (P = 0.012) after three months of treatment respect to baseline, but only R patients had a significantly higher percentage of TR cells (P = 0.041). Both R (P = 0.016) and NR (P = 0.025) patients had higher percentages of IFN-g-producing CD8+ T cells after three months of therapy. Moreover in NR patients, the percentage of TR cells negatively correlated with the percentages of CD4+ T cells that produced IL-2 and TNF-a, and of CD8+ T cells that produced IFN-g and TNF-a. Following 3 months of therapy, plasma levels of IL-10 were significantly increased in both R (P =0.012) and NR (P = 0.05); IL-1b plasma level was elevated in NR (P = 0.012) but not in R; IL-17 plasma level was decreased in R (P = 0.006); neither R nor NR had changes in plasma levels of IL-1RA, IL-2, IL-6, TNF-a, TNF-R1, VEGF, and VEGF-R (R1, R2, R3). In conclusion treatment with lenalidomide increased the percentages of T-helper cells in both R and NR patients and of TR cells in R patients. Treatment with lenalidomide also increased the function of CD8+ T cells as exhibited by the synthesis of IFN-g in both R and NR patients. These preliminary data suggest that lenalidomide has a favorable immunomodulatory effect on patients with B-CLL. Sample collection is ongoing for further analyses.

Immunomodulatory Effects of Yunzhi-Danshen on Nasopharyngeal Carcinoma Patients

RATIONALE: Nasopharyngeal carcinoma (NPC) is a prevalent tumor disease in Hong Kong. The immune system of such patients could be adversely affected during the course of conventional chemotherapy or radiotherapy. We investigated the immunomodulatory effects of Yunzhi-Danshen capsules in NPC patients. METHODS: Twenty-seven patients with histologically proven NPC were recruited to take Yunzhi (50 mg/kg body weight) and Danshen (20 mg/kg body weight) capsules (TCM group) or placebo daily for 4 months respectively. Flow cytometry was used to assess the percentages and absolute counts of human lymphocyte subsets in whole blood. Gene expressions of cytokines and cytokine receptors in peripheral blood mononuclear cells (PBMC) were analyzed by cDNA expression array. RESULTS: The decrease of the percentage and the absolute count of T lymphocytes in TCM group was less than that in placebo group after taking the capsules for 16 weeks (p < 0.05). Besides, the decrease of the absolute count of T suppressor and T helper cells in TCM group was significantly lower than that in the placebo group after taking the capsules for 16 weeks (all p < 0.05). These results suggest that Yunzhi-Danshen can alleviate the lymphopenia and other side effects of radiotherapy. cDNA expression array showed that the gene expression of tumor necrosis factor receptor 2 (TNFR2) was significantly down-regulated in patients after taking the TCM capsules 7 days without radiotherapy (p < 0.05). CONCLUSIONS: This study shows that selected traditional Chinese medicine such as Yunzhi and Danshen have immunomodulatory effects in patients with NPC.

Immunomodulatory Effects of Lingzhi and San-Miao-San Supplementation on Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune joint disease. We evaluated a standard preparation of Lingzhi (Ganoderma lucidum) and San-Miao-San (Rhizoma atractylodis, Cortex phellodendri, Radix achyranthes bidentatae) capsules (TCM group) for its supplementary treatment efficacy for RA. There was no significant difference in the absolute count, percentage, and ratios of CD4+/CD8+/natural killer/B lymphocytes between the TCM and placebo groups after taking the capsules (all p > 0.05). There was no significant change in concentrations of plasma cytokines of interferon-γ-induced protein-10 (IP-10), monocyte chemoattractant protein-1, monokine induced by IFN-γ, regulated upon activation normal T-cell expressed and secreted, interleukin (IL)-8, and IL-18 after taking the capsules for 8 and 24 weeks (all p > 0.05). The percentage change in ex vivo-induced level of inflammatory cytokine IL-18 was significantly lower in the TCM group than in the placebo group after taking the capsules for 24 weeks (p < 0.05). Therefore, Lingzhi and San-Miao-San capsules might exert a beneficial immunomodulatory effect in patients with rheumatoid arthritis.

Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock

Stress doses of hydrocortisone are known to have immunomodulatory effects in patients with hyperdynamic septic shock. The prognosis correlates with the presence and severity of septic encephalopathy. However, neurological evaluation is influenced by the use of analgesia sedation during artificial ventilation. The objective of this study was to demonstrate the effect of stress doses of hydrocortisone during the initial phase of human septic shock on the serum values of the neurospecific protein S-100B in comparison to the inflammation markers interleukin (IL)-8 in serum and polymorphonuclear (PMN) elastase in plasma. A total of 24 consecutive patients, who met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock, were enrolled in this prospective, randomized, double-blind, single-center trial. The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. Multi-organ dysfunction syndrome was described by the Sepsis-related Organ Failure Assessment (SOFA) score. All patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days. Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/mL at study entry to 0.07 ng/mL 6 days later without significant differences compared to the placebo group. Initial IL-8 serum levels were significantly higher in the hydrocortisone group up to 12 h after study entry, and significantly decreased from 715 to 17 pg/mL at the end of the observation period. Median PMN elastase plasma levels were not affected by hydrocortisone infusion. Patients with initial S-100B serum levels > 0.50 ng/mL revealed significantly higher SOFA scores up to 30 h, IL-8 serum levels up to 12 h, and PMN elastase plasma levels up to 36 h after study entry than those patients with < or = 0.50 ng/mL. These effects were independent of the amount of fluid correction for hemodilution. Starting S-100B, IL-8 and PMN elastase values of the hydrocortisone group were within the ranges already known in patients with out-of-hospital cardiac arrest or severe traumatic brain injury. Stress doses of hydrocortisone resulted in a significant reduction in IL-8 serum, but not in S-100B serum and PMN elastase plasma concentrations in patients with hyperdynamic septic shock. For the first time, a similar extent of S-100B increase in serum of septic patients at the time of diagnosis was shown as reported for cardiac arrest or severe traumatic brain injury.