Long-term Tolerability In Patients Research Articles

223 CD8+ T cells could be crucial for long-term tolerance in patients undergoing venom immunotherapy

223 CD8+ T cells could be crucial for long-term tolerance in patients undergoing venom immunotherapy

PO18 Successful Long-Term Tolerance in Patients with Hemophilia A and Inhibitors Receiving Emicizumab Prophylaxis: A Single Saudi Center Experience

PO18 Successful Long-Term Tolerance in Patients with Hemophilia A and Inhibitors Receiving Emicizumab Prophylaxis: A Single Saudi Center Experience

EP08.02-108 Osimertinib Long-Term Tolerability in Patients with EGFRm NSCLC Enrolled in the AURA Program or FLAURA Study

Osimertinib is a third-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits EGFR TKI-sensitizing (EGFRm) and EGFR T790M resistance mutations, including CNS metastases. Osimertinib is the preferred first-line treatment in metastatic EGFRm NSCLC, approved as ≥second-line treatment in EGFRm NSCLC with T790M mutations, and approved as adjuvant treatment in resectable EGFRm NSCLC. This post-hoc analysis of AURA program and FLAURA trials reports for the first time, long-term safety data in EGFRm metastatic NSCLC treated with osimertinib 80 mg once-daily (QD) for ≥36 months.

Иммунологический мониторинг эффективности экстракорпоральной фотохимиотерапии в профилактике отторжения трансплантата почки

The concept of the formation of immunological tolerance is a promising direction for correcting the renal transplant rejection. One of these methods is extracorporeal photochemotherapy (ECP), however, according to the literature, there is no single concept of its mechanisms of action in the formation of immunological tolerance in transplantology. To assess the effect of the preventive use of extracorporeal photochemotherapy on the factors of cellular immunity that contribute to the development of long-term tolerance in patients after kidney transplantation. A total of 24 patients after a cadaveric kidney transplantation with group matching were included in the study. During the first six months after transplantation, 15 patients of the main group (MG) underwent 10 sessions of ECP in combination with the standard immunosuppression protocol, and 9 patients of the control group (CG) received only standard immunosuppressive therapy. Immunological studies were carried out by the 3rd year after transplantation. The number of cells expressing the antigens CD3, CD4, CD8, CD19, CD16 and CD56, the expression of co-stimulating molecules CD25, CD28 on T-lymphocytes, the number of T-regulatory cells with the CD3+ CD4+ CD25+ (hi) CD127- phenotype was evaluated. Compared with early post-transplant period, the number of naive CD3+CD4+CD45RO-CD28+ T-cells and CD28+ antigen expression was not different between two groups by 3 years after transplantation and with a group of otherwise healthy individuals (p=0.47 and p=0.26, respectively). Three years after transplantation, the T-helper lymphocyte count (CD3+CD4+) in MG were significantly higher than in CG (48.5+/-7.3% vs. 43.0+/-4.6%, respectively; p=0,04), cytotoxic T-lymphocytes count (CD3+CD8+) was 29.5+/-8.9% in MG, compared to 36.1+/-8.6% in CG (p=0.09), the ratio of CD4+/CD8+ in MG was significantly higher (1.83+/-0.72) than in CG (1.29+/-0.49) (p=0.04). CD19+ lymphocytes count was significantly below normal values in both groups, but in the CG it was more pronounced than in the MG (5.06+/-2.1% and 7.73+/-3%, respectively, (p=0.02) In the long-term period, CD3+CD4+CD25+(hi)CD127- T-regulatory cells count in MG was significantly higher than in CG (20.6+/-10.76*106/L and 12.9+/-4.97*106/l, respectively) (p=0.04). ECP initiates immunological tolerance through the activation of a second co-activation pathway between B-7 and CTLA-4 molecules in the early period after kidney transplantation. As a result, a clone of tolerogenic CD3+CD4+ T-lymphocytes is formed, which differentiates into T-regulatory cells and maintains immunological tolerance in the long-term period. Using ECP as a part of combination therapy allows to normalize the indicators of cellular immunity in the long-term period. The concept of the formation of immunological tolerance is a promising direction for correcting the renal transplant rejection. One of these methods is extracorporeal photochemotherapy (ECP), however, according to the literature, there is no single concept of its mechanisms of action in the formation of immunological tolerance in transplantology. To assess the effect of the preventive use of extracorporeal photochemotherapy on the factors of cellular immunity that contribute to the development of long-term tolerance in patients after kidney transplantation. A total of 24 patients after a cadaveric kidney transplantation with group matching were included in the study. During the first six months after transplantation, 15 patients of the main group (MG) underwent 10 sessions of ECP in combination with the standard immunosuppression protocol, and 9 patients of the control group (CG) received only standard immunosuppressive therapy. Immunological studies were carried out by the 3rd year after transplantation. The number of cells expressing the antigens CD3, CD4, CD8, CD19, CD16 and CD56, the expression of co-stimulating molecules CD25, CD28 on T-lymphocytes, the number of T-regulatory cells with the CD3+ CD4+ CD25+ (hi) CD127- phenotype was evaluated. Compared with early post-transplant period, the number of naive CD3+CD4+CD45RO-CD28+ T-cells and CD28+ antigen expression was not different between two groups by 3 years after transplantation and with a group of otherwise healthy individuals (p=0.47 and p=0.26, respectively). Three years after transplantation, the T-helper lymphocyte count (CD3+CD4+) in MG were significantly higher than in CG (48.5+/-7.3% vs. 43.0+/-4.6%, respectively; p=0,04), cytotoxic T-lymphocytes count (CD3+CD8+) was 29.5+/-8.9% in MG, compared to 36.1+/-8.6% in CG (p=0.09), the ratio of CD4+/CD8+ in MG was significantly higher (1.83+/-0.72) than in CG (1.29+/-0.49) (p=0.04). CD19+ lymphocytes count was significantly below normal values in both groups, but in the CG it was more pronounced than in the MG (5.06+/-2.1% and 7.73+/-3%, respectively, (p=0.02) In the long-term period, CD3+CD4+CD25+(hi)CD127- T-regulatory cells count in MG was significantly higher than in CG (20.6+/-10.76*106/L and 12.9+/-4.97*106/l, respectively) (p=0.04). ECP initiates immunological tolerance through the activation of a second co-activation pathway between B-7 and CTLA-4 molecules in the early period after kidney transplantation. As a result, a clone of tolerogenic CD3+CD4+ T-lymphocytes is formed, which differentiates into T-regulatory cells and maintains immunological tolerance in the long-term period. Using ECP as a part of combination therapy allows to normalize the indicators of cellular immunity in the long-term period.

Phase II study of alternate sunitinib schedule in patients with metastatic renal cell carinoma.

4513 Background: Sunitinib is an antiangiogenic agent indicated for the treatment of metastatic renal cell carcinoma (mRCC). Sunitinib is given in a 4 week on, 2 week off (4/2) schedule. Significant toxicities are observed in patients in the 3rd and 4th weeks of therapy. We hypothesized that a 2 week on, 1 week off (2/1) schedule would provide improved toxicity without compromising efficacy. Methods: A multicenter, single arm study was performed, with patients initiating sunitinib 50mg on a 2/1 schedule. Schedule and dose alterations were performed if grade > 3 toxicities were observed. The primary objective was to determine the percentage of patients who experienced grade > 3 fatigue, diarrhea, or HFS. The sample size of 60 patients was selected to ensure the upper bound of a 95% confidence would fall below standard schedule rate of 25%-30% if sample rate was 10%-15%, respectively. Secondary outcomes included response rate (RR), progression free survival (PFS) and dose reductions. Results: Between August 2014 and April 2016, 60 patients were enrolled, and 59 treated. Patients had a median age of 65.5 years (ranging from 45-92). 24% of patients (14/59) had grade 3 or higher fatigue, diarrhea, or HFS (95% CI: 13.6%, 36.6%). This is similar to the average of the 4 week on, 2 week off schedule of 25%-30%, and the lower bound of the confidence interval is in the center of our target rate of 10%-15%. Among events at least possibly related to study drug, patients were most likely to experience the expected events of diarrhea (75% with 5 grade 3 events), fatigue (71% with 6 grade 3 events), and HFS (54% with 3 grade 3 events). 22 (37%) patients responded (25.0%, 50.9%). Among patients with secondary endpoint data available, median PFS was 19.3 months (95% CI: 8.2, NR) and 33/56 (59%) of patients underwent dose reduction. Conclusions: Sunitinib administered in a 2/1 schedule in this study did not result in a lower rate of grade 3 or higher fatigue, diarrhea or HFS when compared to historical data from trials employing a 4/2 schedule. However, efficacy data showed robust response rate and a prolonged PFS, suggestive of long-term tolerability in patients receiving sunitinib on a 2/1 schedule. Evaluation of toxicity kinetics and patient quality of life is ongoing. Clinical trial information: NCT02060370.

New developments in immunotherapies for food allergy.

Food allergy affects around 10% of the population. As the prevalence of food allergy continues to increase, disproportionately in children, new therapies for food allergy are being investigated. While there are no approved treatments for food allergy, immunotherapy facilitates significant desensitization and protection from accidental exposure. Nevertheless, current immunotherapies do not entirely nor permanently eliminate sensitivity to the food allergen. Since the rates of sustained unresponsiveness are significantly lower than desensitization, future therapies that enhance the rates of long-term tolerance in patients will catalyze progress in this field over the next 5-10 years.

Vagus Nerve Stimulation for the management of depression: Rationale, anatomical and physiological basis of efficacy and future prospects

Treatment-resistant depression (TRD) is a major public health concern due to its high costs to society. One of the novel approaches for the treatment of depression is the Vagus Nerve Stimulations (VNS). Therapeutic brain stimulation through delivery of pulsed electrical impulses to the left cervical vagus nerve now has established safety and efficacy as an adjunct treatment for medication-resistant epilepsy (1). Vagus nerve stimulation therapy is US FDA approved for the adjunctive treatment of epilepsy and has also been applied for the medication resistant depression (2-6). Owing to its novel route into the brain, it has no drug-drug interactions or systemic side effects. This treatment also appears to have high long term tolerability in patients, with low rates of patients relapsing on Vagus nerve stimulation or becoming tolerant. However, alongside the excitement and enthusiasm for this new treatment, a lack of Class I evidence of efficacy in treatment depression is currently slowing down adoption by psychiatrists. Much more research is needed regarding exactly how to refine and deliver the electrical pulses and how this differentially affects brain function in health and disease. In this clinical study, 10 patients (7 women, 3 men) who have diagnosis of major depression, the ages of patients are between 31 and 44. After two years follow up, the patients’ Hamilton depression scores have been improved significantly. In the present literature, heavy cases are advised to be excluded (7). Very interestingly, in this study a 44 year old lady, who was repeatedly talking about suicide, soon after the activation of the vagal nerve implant rescued. As to our first prelaminar report about Vagus nerve stimulators and management of depression indicate that, VNS treatment may be an alternative to treatment for major depression patients

Basophil response and the induction of a tolerance in venom immunotherapy: a long‐term sting challenge study

There is no in vitro test to predict the induction of long-term tolerance in patients treated with venom immunotherapy (VIT). The aim of this study was to investigate whether immunotherapy-induced changes in basophil responsiveness reflect a state of protection and the induction of a tolerance. Twenty-three patients with allergic reaction after Hymenoptera sting (11 wasp and 12 honeybee) were treated with VIT. In all patients, a CD63 basophil activation test was performed before the beginning of immunotherapy, after 1 year and after completing 4-6.5 years of immunotherapy (approximately 1 year after stopping). The tolerance was then evaluated by a sting challenge test. The basophil activation test was repeated 3-6 months after the challenge. Twenty-two subjects showed a negative sting challenge, and one subject, a positive sting challenge. Allergen-specific basophil response remained unchanged after 1 year of immunotherapy. However, after immunotherapy, a significant and approximately fourfold decrease was demonstrated in all tolerant subjects mainly in response to submaximal 0.1 μg/ml allergen concentration. This depression was sustained and did not change with the sting challenge test. In a nontolerant patient with a positive sting challenge, basophil response did not change. Our results suggest that the depression of allergen-specific basophil response seems to be associated with the induction of a tolerance after completing a course of VIT.

Long-Term Tolerability of Etoricoxib in Patients with Previous Reactions to Non-Steroidal Anti-Inflammatory Drugs

Non-steroidal anti-inflammatory drugs frequently cause adverse reactions. This retrospective study was based on analysis of the data obtained from interviews conducted with 173 patients, who underwent and tolerated a challenge test with etoricoxib (a selective cyclooxigenase 2 enzyme inhibitor). Only one of 82 patients who were treated with etoricoxib reported reactions. We can conclude that etoricoxib shows a high long-term tolerability in patients with non-steroidal anti-inflammatory drug hypersensitivity.

Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders

Vagus nerve stimulation is an interesting new approach to treating neuropsychiatric diseases within the class of brain-stimulation devices sometimes labeled ‘neuromodulators’. With vagus nerve stimulation, a battery-powered generator implanted in the chest wall connects to a wire wrapped around the vagus nerve in the neck, and sends intermittent pulses of electricity along the nerve directly into the brain. This mechanism takes advantage of the natural role of the vagus nerve in conveying information into the brain concerning homeostatic information (e.g., hunger, chest pain and respirations). Vagus nerve stimulation therapy is US FDA approved for the adjunctive treatment of epilepsy and has recently been FDA approved for the treatment of medication-resistant depression. Owing to its novel route into the brain, it has no drug–drug interactions or systemic side effects. This treatment also appears to have high long-term tolerability in patients, with low rates of patients relapsing on vagus nerve stimulation or becoming tolerant. However, alongside the excitement and enthusiasm for this new treatment, a lack of Class I evidence of efficacy in treating depression is currently slowing down adoption by psychiatrists. Much more research is needed regarding exactly how to refine and deliver the electrical pulses and how this differentially affects brain function in health and disease.