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Arroyave Ramirez, Andres Mauricio, Daniel Motola, Mariana Guadalupe Morales Garcia, and Emilio Conde-Flores. "Impact of time-of-day administration of immunotherapy on overall survival among patients with metastatic renal cell carcinoma." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): e16537-e16537. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e16537.
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e16537 Background: Circadian rhythm influences adaptive immune response. In recent years, some studies have suggested a relationship between the time of day of immune checkpoint inhibitor (ICI) infusions and disease outcomes among cancer patients. Evening infusions (after 4:30 pm) are associated with shorter overall survival. This study aims to determine whether the time of day of immunotherapy infusion affects the efficacy of treatment in patients with metastatic renal cell cancer (mRCC) in a Mexican population. Methods: This is an observational, retrospective, single-center study that included patients with mCRC treated with Nivolumab plus Ipilimumab in first line diagnosed between 2018 and 2023. Patients who received <20% of infusions after 4:30 pm were assigned to early time of infusion (TOI) group, while patients who received ≥20% of infusions after that time were assigned to late TOI group. The primary end point was overall survival (OS), and the secondary end point was overall response rate (ORR). Both groups were compared using Kaplan-Meier analysis and Cox regression model. Results: 127 patients were included in the analysis. Most of the population were men (70.1%). Median age was 62 years. In addition, 100% had clear cell histology and 96% had intermediate/poor-risk disease. The early TOI group included 84 (66%) patients, while 43 patients were assigned to the late TOI group. In the overall population, median OS in the early TOI group was 64.8 months (95% CI, 53.4-68.8) versus 46.3 months (95% CI, 22.5-61.4) in the late TOI group, with a hazard ratio (HR) of 0.67 (95% CI, 0.51-0.83; p=0.03). Improvement in OS with early administration of therapy was seen across all subgroups that were evaluated. The impact of time of day of ICI administration was greater in patients with intermediate/poor-risk disease (median OS 56.4 months [95% CI 41.4-67.2] in the early TOI group versus 36.8 months [95% CI 18.9-51.3] in the late TOI group, HR 0.52 [95% CI 0.37-0.85]; p=0.002). In the overall population, the ORR was higher in the early TOI group (32.8% versus 22.4%; p= 0.04), with similar results in patients with intermediate and high-risk disease (34.5% versus 21.6%, and 30.5% versus 24.8% respectively). In the multivariate analysis, time-of-day administration of immunotherapy was an independent prognostic factor for death. Conclusions: Our results demonstrated improved OS and ORR in ICI-treated patients who received most infusions before 4:30 pm, particularly in patients with intermediate/poor-risk mRCC, in line with the findings of previous analyzes showing that chronomodulation influences the efficacy of immunotherapy. This is the first work in a Mexican population. Although larger prospective and controlled studies are necessary, early ICI infusion is a practical, safe and reasonable strategy that could be considered in the treatment of Mexican patients with metastatic renal cell cancer.
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Ortego, Ignacio, Javier Molina-Cerrillo, Alvaro Pinto, Matteo Santoni, Teresa Alonso-Gordoa, M. Pilar Lopez Criado, Alejandro Gonzalez-Morales, and Enrique Grande. "Time-of-day infusion of immunotherapy in metastatic urothelial cancer (mUC): Should it be considered to improve survival outcomes?" Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e16541-e16541. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e16541.
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e16541 Background: Immune-checkpoint inhibitors (ICIs) are key in the current management of mUC pts. Recent data in melanoma revealed a link in between the circadian rhythm of the immune-system and expected activity with ICIs (Quian et al, Lancet Oncol 2021). In preclinical models naïve CD4 and CD8 T cells in blood have shown to approach nadir levels around 4 P.M., and therefore, to lower adaptative immune responses after that time. We aimed to correlate the activity of single agent ICIs for the systemic treatment of mUC pts depending on the time of administration. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 1 in Italy of patients with mUC who initiated treatment with anti-PD1 or anti-PDL1 as 1st or subsequent line. ICIs were administered and managed according to product labelling. Time cut-off as adaptive immune-modulation for ICIs administration was considered after 4:30 PM. We divided pts into those who received at least 20% of their infusions after 4:30 PM and those who received fewer than 20% after that time. Other data such as patient characteristics and adverse-events related to the treatment were also collected. We carried out a survival analysis by a Cox regression model. Results: From 2016, 92 pts were treated with single agent ICIs for mUC. Most of the pts (n = 62; 67.4%) received less than 20% of the doses after 4:30 PM, while a lower proportion (n = 26; 28.3%) received at least 20% of the doses after that time. Median follow-up time of immunotherapy was 8.6 months. 35 (38.0%) and 57 (62.0%) pts received ICIs as 1st and subsequent lines of treatment respectively. There were no differences in the proportion of pts in 1st vs subsequent lines and time of administration, nor other well prognostic baseline factors like PD-L1 expression, or Bajorin or Bellmunt’s scoring. A significant benefit in both PFS (11.38 vs 3.58 months; HR 2.66: 95%CI 1.53-4.63; p = 0.001) and in OS (14.04 vs 6.80 months; HR 2.62: 95%CI 1.48-4.63: p = 0.001) benefited to pts who received less than 20% of the doses after 4:30 PM. Response rate also favored (59.3% vs 16.0%) the earlier administration of the treatments. Neither corticosteroids concomitant use nor immune-related toxicity appeared to impact on these outcomes. Conclusions: Time of the day administration of ICIs may influence the efficacy of ICIs in mUC pts. Although the small size of the sample and the short median follow-up is something to be considered, this data are promising and consistent with the previous studies. Prospective confirmation is needed.
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Dougherty, David W., Houry Leblebjian, Megan Duperrault, Mark M. Awad, Sylvia Bartel, Anne McDonnell, Craig A. Bunnell, et al. "Outcomes of immunotherapy administration for hospitalized cancer patients." Journal of Clinical Oncology 37, no. 27_suppl (September 20, 2019): 98. http://dx.doi.org/10.1200/jco.2019.37.27_suppl.98.
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98 Background: With approvals across multiple cancer types and favorable toxicity profiles, oncologists may consider using immunotherapy (IMT) while their patients are hospitalized. Inpatient IMT may be cost-prohibitive to administer for most institutions due to high cost and inpatient payment structure, but little data are available to evaluate outcomes for IMT in hospitalized patients. We investigated the survival benefit of administering IMT to hospitalized patients with cancer at an NCI-designated cancer center. Methods: We conducted a retrospective chart review of all patients receiving ipilimumab, nivolumab, or pembrolizumab during inpatient admission at Dana-Farber Cancer Institute/Brigham & Women’s Hospital in 2017. For each patient, we assessed: total dose, indication for dosing, cancer type, time between dose and discharge, time between discharge and death, and total cost (average wholesale price). Study follow up was January 1, 2017 to July 1, 2018. Results: Fifty doses of IMT were administered to 44 patients. Most patients (40) received 1 dose, 2 patients received 3 doses, 1 patient received 2 doses, and 1 patient received a combination of ipilimumab/nivolumab. The most common cancer types were lung (41%), gastrointestinal (18%), and head and neck (16%). Indications for IMT administration were: patient due for next dose (48%), disease progression (42%), and new diagnosis (11%). The majority of doses (70%) were received within 7 days prior to discharge, with 32% of doses within 1 day of discharge. The majority of patients (86%) died in the study period; 14% of patients died during admission. Average survival between discharge and death was 54 days (range: 0-444 days). Total cost of inpatient IMT administration was $413,370, an average of $9,395 per patient. Conclusions: To our knowledge, this is the largest analysis of outcomes for patients receiving IMT during a hospitalization. Inpatient use of IMT in cancer patients is associated with high cost and poor clinical outcomes. Dosing within one week prior to hospital discharge was common. Clinical factors such as PD-L1 status, disease status, and reason for admission, which may be important to understand which patients may benefit most from inpatient IMT, should be examined.
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Leblebjian, Houry, Megan Duperrault, Brett Glotzbecker, Mark M. Awad, Sylvia Bartel, Anne McDonnell, Craig A. Bunnell, Andrew J. Wagner, Lauren M. Hamel, and David W. Dougherty. "Outcomes of immunotherapy administration for hospitalized cancer patients." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e18225-e18225. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18225.
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e18225 Background: With approvals across multiple cancer types and favorable toxicity profiles, oncologists may consider using immunotherapy (IMT) while their patients are hospitalized. Inpatient IMT may be cost-prohibitive to administer for most institutions due to high cost and inpatient payment structure, but little data are available to evaluate outcomes for IMT in hospitalized patients. We investigated the survival benefit of administering IMT to hospitalized patients with cancer at an NCI-designated cancer center. Methods: We conducted a retrospective chart review of all patients receiving ipilimumab, nivolumab, or pembrolizumab during inpatient admission at Dana-Farber Cancer Institute/Brigham & Women’s Hospital in 2017. For each patient, we assessed: total dose, indication for dosing, cancer type, time between dose and discharge, time between discharge and death, and total cost (average wholesale price). Study follow up was January 1, 2017 to July 1, 2018. Results: Fifty doses of IMT were administered to 44 patients. Most patients (40) received 1 dose, 2 patients received 3 doses, 1 patient received 2 doses, and 1 patient received a combination of ipilimumab/nivolumab. The most common cancer types were lung (41%), gastrointestinal (18%), and head and neck (16%). Indications for IMT administration were: patient due for next dose (48%), disease progression (42%), and new diagnosis (11%). The majority of doses (70%) were received within 7 days prior to discharge, with 32% of doses within 1 day of discharge. The majority of patients (86%) died in the study period; 14% of patients died during admission. Average survival between discharge and death was 54 days (range: 0-444 days). Total cost of inpatient IMT administration was $413,370, an average of $9,395 per patient. Conclusions: To our knowledge, this is the largest analysis of outcomes for patients receiving IMT during a hospitalization. Inpatient use of IMT in cancer patients is associated with high cost and poor clinical outcomes. Dosing within one week prior to hospital discharge was common. Clinical factors such as PD-L1 status, disease status, and reason for admission, which may be important to understand which patients may benefit most from inpatient IMT, should be examined.
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Judd, Courtney A., Amy L. Parker, Eric A. Meier, and Michael S. Tankersley. "Successful administration of a 1-day imported fire ant rush immunotherapy protocol." Annals of Allergy, Asthma & Immunology 101, no. 3 (September 2008): 311–15. http://dx.doi.org/10.1016/s1081-1206(10)60497-8.
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Dvorak, Tomas, Thomas T. Maroney, Srujankumar Dhannapuneni, Ian Stephenson, and Amy Iarrobino Laughlin. "Assessment of outpatient chemotherapy and unplanned emergency department visits in a large community hospital system." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e18768-e18768. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e18768.
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e18768 Background: Unplanned complications of outpatient chemotherapy can significantly affect patient oncologic outcomes, health, and increase cost of care. CMS rule OP-35 evaluates quality of care for Medicare patients by assessing the risk of emergency department (ED) visit within 30 days after outpatient chemotherapy administration. This study reviews this measure for all oncology patients treated in our community hospital setting. Methods: Patients treated between 02/2012 and 04/2021 were identified. Age at first chemotherapy administration, gender, cancer diagnosis, and chemotherapy regiment were evaluated. Chemotherapy was stratified into cytotoxic therapy, immunotherapy, targeted therapy, and endocrine therapy. ED visits were only those in our hospital system. 30-day risk of ED visit was calculated for individual chemotherapy administrations. Internal results were compared with our CMS OP-35 results for concordance. Results: There were 19,732 patients who received chemotherapy treatments between 02/2012 and 04/2021, with 262,379 chemotherapy administrations. Individual chemotherapy administration had 5.2% risk of a 30 day ED visit. Cumulative risk of a patient having a 30 day ED visit was 32.9%. From ED, patients had 61.2% rate of hospital admission, vs 24.8% rate for general ED population. By age at first chemotherapy administration, the risk of 30 day ED visit was 6.3% for age < 18, 5.4% for age 18-64, and 5.9% for age > = 65. Our rate was relatively stable between 2014 and 2020. Our corresponding CMS score was 5.5% in 2016, 5.5% in 2018, and 5.1% in 2019. By gender, the risk was 5.6% for male and 5.0% for female patients. By chemotherapy category, the risk was 5.9% for cytotoxic chemotherapy, 7.5% for immunotherapy, 4.2% for targeted therapy, and 5.2% for endocrine therapy. Carboplatin/paclitaxel was the most common drug combination administered, with 8.7% risk. Cytarabine/methotrexate combination had the highest risk at 57.0%. By ICD diagnosis, breast cancer accounted for most patients and most chemotherapy administrations, with 30 day ED visit risk of 3.6%. Multiple myeloma had the highest rate of chemotherapy administrations at 26.3 per patient and a risk of 4.0%, compared with 13.3 across the entire population. Stomach cancer had the highest risk of 30 day ED visit at 10.0%. Conclusions: The risk of 30 day unplanned ED visit was elevated in pediatric patients, and was similar in patients 18-64 and > = 65 years of age, and corresponded well to our CMS OP-35 metric, despite only tracking internal ED visits. Immunotherapy had significantly elevated risk compared with cytotoxic therapy, while targeted therapy had the lowest risk of ED visit. There were significant differences depending on disease site. We have established a baseline, and developed a live dashboard in our electronic medical record to monitor this metric globally, and to intervene in patients at high risk of 30 day ED visit.
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Lissoni, Paolo, Sofia Meregalli, Vittorio Fossati, Franco Paolorossi, Sandro Barni, Gabriele Tancini, and Franco Frigerio. "A Randomized Study of Immunotherapy with Low-Dose Subcutaneous Interleukin-2 plus Melatonin Vs Chemotherapy with Cisplatin and Etoposide as First-Line Therapy for Advanced Non-Small Cell Lung Cancer." Tumori Journal 80, no. 6 (December 1994): 464–67. http://dx.doi.org/10.1177/030089169408000611.
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Aims and Background The theraputic role of chemotherapy in advanced non-small cell lung cancer (NSCLC) is controversial because of its potentially detrimental action on host anticancer defenses. On the contrary, IL-2 would seem to prolong survival time by improving the immune status, even though it is generally less effective in determining tumor regression in NSCLC. Our previous studies have suggested the possibility of increasing tumor sensitivity to IL-2 by concomitant administration of immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). On this basis, a study was carried out to evaluate the efficacy of immunotherapy with low-dose IL-2 plus MLT versus chemotherapy in advanced NSCLC. Methods The study included 60 patients with locally advanced or metastatic NSCLC, who were randomized to receive immunotherapy or chemotherapy. The immunotherapy consisted of IL-2 (3 million IU/day subcutaneously for 6 days/week for 4 weeks) and MLT (40 mg/day orally every day, starting 7 days before IL-2); in nonprogressing patients, a second cycle was repeated after a 21-day rest period, then they underwent a maintenance period consisting of one week of therapy every month until progression. Chemotherapy consisted of cisplatin (20 mg/m2) and etoposide (100 mg/m2)/day intravenously for 3 days; cycles of chemotherapy were repeated every 21 days until progression. Results No complete response was obtained. A partial response was achieved in 7/29 patients treated with chemotherapy and in 6/31 patients receiving chemotherapy. The difference was not significant. In contrast, the mean progression-free period and the percentage survival at 1 year was significantly higher in patients treated with immunotherapy than in those treated with chemotherapy. Toxicity was substantially lower in patients receiving immunotherapy than in those given chemotherapy. Conclusions This randomized study showed that immunotherapy with low-dose IL-2 plus MLT is a better tolerated and more effective therapy in terms of survival time than chemotherapy containing cisplatin in patients affected by advanced NSCLC.
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Tsimafeyeu, I. V. "Nivolumab: 5 years from the day of international registration of immunotherapy of metastatic kidney cancer." Malignant tumours 10, no. 4 (July 7, 2021): 21–29. http://dx.doi.org/10.18027/2224-5057-2020-10-4-21-29.
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Five years ago, on November 23, 2015, the US Food and Drug Administration (FDA) approved nivolumab for the treatment of metastatic renal cell carcinoma, thus ushering in a new era of immunotherapy for this tumor. The purpose of this review is to systematize the accumulated results of studies of nivolumab in monotherapy and in combinations.
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Senti, Gabriela, Bettina M. Prinz Vavricka, Iris Erdmann, Mella I. Diaz, Richard Markus, Stephen J. McCormack, John J. Simard, et al. "Intralymphatic allergen administration renders specific immunotherapy faster and safer: A randomized controlled trial." Proceedings of the National Academy of Sciences 105, no. 46 (November 10, 2008): 17908–12. http://dx.doi.org/10.1073/pnas.0803725105.
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The only causative treatment for IgE-mediated allergies is allergen-specific immunotherapy. However, fewer than 5% of allergy patients receive immunotherapy because of its long duration and risk of allergic side effects. We aimed at enhancing s.c. immunotherapy by direct administration of allergen into s.c. lymph nodes. The objective was to evaluate safety and efficacy compared with conventional s.c. immunotherapy. In a monocentric open-label trial, 165 patients with grass pollen-induced rhinoconjunctivitis were randomized to receive either 54 s.c. injections with pollen extract over 3 years [cumulative allergen dose 4,031,540 standardized quality units (SQ-U)] or 3 intralymphatic injections over 2 months (cumulative allergen dose 3,000 SQ-U). Patients were evaluated after 4 months, 1 year, and 3 years by nasal provocation, skin prick testing, IgE measurements, and symptom scores. Three low-dose intralymphatic allergen administrations increased tolerance to nasal provocation with pollen already within 4 months (P < 0.001). Tolerance was long lasting and equivalent to that achievable after standard s.c. immunotherapy (P = 0.291 after 3 years). Intralymphatic immunotherapy ameliorated hay fever symptoms (P < 0.001), reduced skin prick test reactivity (P < 0.001), decreased specific serum IgE (P < 0.001), caused fewer adverse events than s.c. immunotherapy (P = 0.001), enhanced compliance (P < 0.001), and was less painful than venous puncture (P = 0.018). In conclusion, intralymphatic allergen administration enhanced safety and efficacy of immunotherapy and reduced treatment time from 3 years to 8 weeks.
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Lin, Lin, Ashraf S. Ibrahim, Beverlie Baquir, Andrew Palosaari, and Brad Spellberg. "Real-time tracking ATAK cells in vivo (52.1)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 52.1. http://dx.doi.org/10.4049/jimmunol.186.supp.52.1.
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Abstract Background: Activated Targeted Killer (ATAK) cells are a cellular immunotherapy which protects neutropenic mice from invasive candidiasis and aspergillosis. However,the lifespan and distribution of ATAK cells into organs has not been determined in vivo. Methods: ATAK cells were stably transfected with a luminescence reporter system. Neutropenic mice were imaged by IVIS after administration of coelentrazine substrate. RT-PCR was used to confirm the luminescence results. Results: On day 1 after ATAK cell administration, livers, kidneys, and spleens were infiltrated by the ATAK cells. By day 3, cells had infiltrated more significantly into the spleen, and also spread into the lungs. By day 5, cell signal began to wane. By day 8, the day after neutrophil recovery, there was no detectable signal. By RT-PCR, viable cells were detected at 6 hours and 3 days after treatment. By day 5, no mRNA was detected. Mouse immunity to ATAK cells was detectable by ELISA and flow cytometry post-neutrophil recovery. Discussion: ATAK cells are viable and circulate widely into visceral organs in neutropenic mice, commensurate with their ability to protect mice from tissue invasive fungal infections. Hence the cells can provide protection during the critical neutropenic period yet the risk of engraftment is minimized by host-versus-graft affect after marrow recovery.
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Denis, Michel, and Esfandiar Ghadirian. "Immunotherapy of Airborne Tuberculosis in Mice Via the Lung-Specific Delivery of Cytokines." Canadian Journal of Infectious Diseases 4, no. 1 (1993): 38–42. http://dx.doi.org/10.1155/1993/954372.
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The immunotherapeutic potential of interleukin-2 (IL-2), tumour necrosis factor alpha (TNFα) and interferon gamma (IFN-γ) administered by aerosol was examined on mice infected withMycobacterium tuberculosisby the aerogenic route. Infection ofbalb/c mice with 104colony forming units (cfu) ofM tuberculosisled to death of all mice at day 35 post infection after progressive microbial growth in the lungs. Aerosolization of IL-2 (100 μg per mouse) did not promote an increase in resistance to tuberculosis, as seen by growth ofM tuberculosisin the lungs. Administration of IFN-γ or TNFα (100 μg) by the aerosol route led to a significant reduction in microbial growth in the lungs and a 100% survival of infected mice at day 60. Similarly, aerosolization of TNFα and IFN-γ combined led to a very high degree of tuberculostatic activity in the lungs of infected animals, but not superior to that seen with either cytokine alone. Administration of similar amounts of cytokines by repeated intraperitoneal infusions led to a very marginal improvement in mouse resistance. These results suggest that localized cytokine administration may be beneficial in the treatment of lung diseases.
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He, Shuyang, Joseph Gleason, Nassir Habboubi, Robert Hariri, and Xiaokui Zhang. "EXTH-16. HUMAN PLACENTAL HEMATOPOIETIC STEM CELL DERIVED NATURAL KILLER CELLS FOR GLIOBLASTOMA IMMUNOTHERAPY." Neuro-Oncology 21, Supplement_6 (November 2019): vi85. http://dx.doi.org/10.1093/neuonc/noz175.350.
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Abstract Taniraleucel (CYNK-001) is an allogeneic, off-the-shelf cell therapy enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. CYNK-001 exhibits in vitro cytotoxicity against various cancer cell types, including glioblastoma multiforme (GBM), and secretes cytokines during co-culture with cancer cells. To evaluate in vivo anti-GBM activity, safety and persistence of CYNK-001, we conducted two studies in the non-obese diabetic (NOD)-scid IL2Rgammanull (NSG) immune deficient mouse models. First, CYNK-001 in vivo anti-GBM activity was assessed in a U-87MG orthotopic NSG mouse model. Luciferase-expressing U-87MG cells were stereotactically injected into the cranium of NSG mice at Day 0. Repeated dosing of 0.5x106 CYNK-001 cells at Day 14 and Day 25 by intracranial (IC) injection showed a statistically significant reduction of Bioluminescence Imaging (BLI) compared to the PBS control. Furthermore, intravenous (IV) and intracerebroventricular (ICV) routes of administration were evaluated compared to IC. CYNK-001 administered with IC resulted in a greater reduction of BLI than IV and ICV. Second, a single-dose toxicity study was conducted in naïve NSG mice to assess the safety and persistence of CYNK-001 following an IC injection. IC administration of 1×106 CYNK-001 was well tolerated, and no adverse clinical symptoms were observed. Quantitative polymerase chain reaction (qPCR) analysis for the human telomerase reverse transcriptase (hTERT) gene revealed that CYNK-001 persisted in the brain up to seven days. Our studies demonstrated that CYNK-001with IC administration appears safe and well tolerated in naïve as well as U-87MG tumor bearing NSG mice. Furthermore, CYNK-001 anti-tumor activity was exhibited in a GBM orthotopic NSG mouse model. Taken together, our data support a safety and efficacy evaluation of CYNK-001 in patients with GBM. A Phase 1 study in adult patients with recurrent/refractory GBM is planned to start this year evaluating the safety and efficacy of CYNK-001 with both IV and IC administrations.
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Khatibi, Azadeh Sharif, Nasim Hayati Roodbari, Keivan Majidzade-A, Parichehreh Yaghmaei, and Leila Farahmand. "In vivo tumor-suppressing and anti-angiogenic activities of a recombinant anti-CD3ε nanobody in breast cancer mice model." Immunotherapy 11, no. 18 (December 2019): 1555–67. http://dx.doi.org/10.2217/imt-2019-0068.
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Aim: Achievements in cancer immunotherapy require augmentation of a host's anti-tumor immune response for anti-cancer modality. Materials & methods: Different concentrations of recombinant anti-CD3 nanobody were administered at predetermined time intervals during a 24-day treatment period and then expression of angiogenic biomarkers including VEGFR2, MMP9 and CD31, as well as tumor cell proliferation marker ki67, was determined in tumor sections by immunohistochemistry. Furthermore, expression of cytokines was examined in peripheral blood of mice. Results: Based on our results, administration of nanobody could reduce biomarker expression in tumor sections. Tumor growth was also delayed and survival rate was increased in response to nanobody treatment. Moreover, expression of pro-inflammatory cytokines was reduced. Conclusion: In conclusion, we demonstrated that administration of nanobody could effectively suppress angiogenesis as well as tumor growth.
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Marino, Patricia, Rajae Touzani, Myriam Palomares, Maria-Antonietta Cappiello, Anne Deborah Bouhnik, Najoua Guelmani, Magali Provansal, et al. "Phone call for chemotherapy validation in outpatient unit as a way to optimize health care without compromising patients' satisfaction and quality of life." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 6588. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6588.
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6588 Background: Patients’ satisfaction is known to be closely linked to the time spent with the physician. However, longer waiting times may be a source of dissatisfaction as well as organizational dysfunctions of the outpatient unit. Is a validation of chemotherapy by phone call instead of a medical consultation with a senior physician before chemotherapy (CT) is feasible without compromising patients’ satisfaction and quality of life? Methods: Pts with OMS < 1, able to respond to phone call, < 76 years, receiving day 8 and or d15 of CT were included. We enrolled 343 pts in a before/after study between 2013 and 2016. In the “before” step (control arm), 168 pts had a systematic physician consultation the same day before CT administration. In the intervention arm 175 pts received a phone call by a junior physician the day preceding CT administration. A specific questionnaire for CT -related toxicity of the previous cycle was recorded and CT was validated or not by physician. The day after, pts received prepared CT without appointment with the oncologist and delay in administration for already prepared CT. At the end of CT protocol, socio demographics, patients’ satisfaction (In-PatSat32) and health status (EQ-5D) questionnaires were completed by patients. Results: Questionnaires were completed by 83% and 74% in before and after step respectively, 241 questionnaires were analyzed. Satisfaction with care showed similar In-PatSat32 scores between arms, for satisfaction with: physician, nurse, organization and services. No differences of perceived health status and toxicity were observed between both groups, but patients’ time spent in hospital was lower in the intervention group versus the control group, (p = 0.007). Conclusions: An alternative care pathway implementing phone calls before CT administration if feasible without compromising pts’ satisfaction, quality of life and toxicity. We believe that saving time of pts, physicians and pharmacists is a way to optimize the model of care in outpatient unit, particularly in the immunotherapy area with more pts received intra venous treatment, probably for a long time.
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Ana Margarida, Mesquita, Coutinho Ricardo Moço, Plácido José Luís, and Coimbra Alice. "Impact of coronavirus pandemic on safety and time of administration of subcutaneous immunotherapy among pediatric patients." Journal of Child, Adult Vaccines and Immunology 6, no. 1 (September 2, 2022): 001–4. http://dx.doi.org/10.29328/journal.jcavi.1001008.
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Introduction: Allergen immunotherapy is the only targeted therapy that can modify the natural course of allergic diseases. In pediatric patients, SCIT with aeroallergens is an effective treatment and should be considered as a preventive strategy in the treatment of allergic diseases, even though one of the major concerns about it is its safety. The main purposes of this study were to assess the safety of SCIT ultra-rush schedules with polymerized extracts in a pediatric population and to determine the impact of the COVID-19 pandemic on the safety and time of administration of subcutaneous immunotherapy among pediatric patients. Methods: A retrospective medical records review of patients under 18 years of age undergoing SCIT was made and re-scheduling due to restrictions imposed by the COVID-19 pandemic was recorded. Results: A total of 192 pediatric patients were included. Fifty-nine (31%) had local reactions and systemic reactions were not reported. In March 2020, the first case of COVID-19 was diagnosed in Portugal and all non-urgent appointments and procedures were postponed. In our group of pediatric patients, 43 (22%) were referred to primary care, 38 (20%) stopped AIT definitively and 111 (58%) maintained administrations in the hospital. Only 2 (2%) of them had reactions upon reinitiation. Conclusion: In this study, the ultra-rush protocol using polymerized extracts was safe in pediatric patients. Although the effectiveness of AIT may be compromised due to prolonged suspension of the treatment, it is important to note that despite longer interruptions, administrations may continue without compromising safety, maintaining shorter visits and a lower number of injections.
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Parker, A. L., E. A. Meier, and L. L. Hagan. "Successful administration of a one-day imported fire ant (IFA) rush immunotherapy protocol in two children." Journal of Allergy and Clinical Immunology 115, no. 2 (February 2005): S99. http://dx.doi.org/10.1016/j.jaci.2004.12.411.
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Atallah, Aline, Arielle Grossman, Jean-Francois Pare, Robert Siemens, Tiziana Cotechini, and Charles H. Graham. "Abstract 3540: Effect of route of Bacillus Calmette Guerin administration on the immune microenvironment and growth of bladder tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3540. http://dx.doi.org/10.1158/1538-7445.am2022-3540.
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Abstract Background: Bladder cancer is the fifth most common cancer in North America. The standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG). However, it is possible that the efficacy of this modality of BCG administration is suboptimal, as most patients do not respond fully to this immunotherapy. Furthermore, our current understanding of the immunotherapeutic effect of BCG is incomplete. Using a mouse model of NMIBC, we compared the tumor immune microenvironment (TiME) following intravesical versus intravenous administration of BCG, as well as changes in tumor volume and mice survival. Methods: Female C57Bl/6 mice (6-8 weeks old) were catheterized and instilled with 2.5x105 MB49 bladder cancer cells after poly-L-lysine treatment. Beginning on day 7, mice were treated with intravenous (IV) or intravesical BCG (8 mg/ml) or saline once weekly for three weeks. Ultrasound was performed weekly to monitor tumor growth. Similarly, a cohort of non-tumor bearing mice was treated with poly-L-lysine on day one followed by three weekly intravesical instillations of BCG. In both cohorts, mice were sacrificed on day 23 and bladders were harvested, enzymatically dispersed to generate single-cell suspensions for analysis by flow cytometry, or snap frozen for transcriptomic analysis using NanoString nCounter Platform. Results: Mice receiving IV BCG had better survival and their bladder tumors were significantly smaller compared with mice receiving intravesical BCG. This reduction in tumor size was associated with a significantly increased proportion of CD8+ T cells and a significantly reduced proportion of inflammatory monocytes in bladder tumors from mice treated with IV BCG compared with intravesical BCG. Whole tumor transcriptome analysis revealed alterations in various signalling pathways associated with route of BCG administration. Our results demonstrate similar trends in the distribution of immune populations in the TiME following intravesical saline and IV BCG treatment, as well as following IV saline and intravesical BCG treatment. We also found that the TiME after intravesical BCG treatment has more immune cells which are predominantly immature myeloid cells. Moreover, our results indicate that intravesical BCG treatment leads to a significant population of immature myeloid cells in the bladders of non-tumor bearing mice. Conclusion/Significance: These results provide evidence that the route of BCG administration is an important determinant of the TiME composition and may influence anti-tumor responses. Understanding the link between the TiME and BCG therapy may facilitate the development of new approaches to improve outcomes and reduce recurrence rates in patients with NMIBC. Citation Format: Aline Atallah, Arielle Grossman, Jean-Francois Pare, Robert Siemens, Tiziana Cotechini, Charles H. Graham. Effect of route of Bacillus Calmette Guerin administration on the immune microenvironment and growth of bladder tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3540.
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Zhang, Jing, Xue Zhou, Yuming Jia, Shenglan Huang, Qiu Wang, Mao-Qiong Jiang, Ting Li, et al. "Prevention of pemetrexed-induced rash with low-dose dexamethasone in patients with NSCLC receiving immunotherapy: A prospective, single-arm clinical trial." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): e20596-e20596. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e20596.
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e20596 Background: Pemetrexed is highly active in non-small cell lung cancer (NSCLC). Rashes associated with pemetrexed are more commonly than other chemotherapies. It is recommended that patients receive pemetrexed are required dexamethasone as a pretreatment. However, the immunosuppressive effects of dexamethasone especially high doses of glucocorticoids may reduce the efficacy of immune checkpoint inhibitors (ICIs). This study aims to prospectively evaluate the efficacy of low-dose dexamethasone in pretreatment of pemetrexed-induced rash, particularly in NSCLC patients receiving immunotherapy. Methods: This is a prospective, single-arm clinical trial that enrolled NSCLC patients scheduled to receive chemotherapy including pemetrexed, with/without immunotherapy. Patients received low-dose dexamethasone: 8mg, 4mg, 2 mg of dexamethasone for 3 days recpectively from the day preceding pemetrexed (the recommended administration is 8 mg/day of dexamethasone for 3 days) . Rash severity is described according to CTCAE v5.0 (Common toxicity criteria for adverse events version 5.0). The primary endpoint was the 3-week incidence of rash after pemetrexed. Results: A total of forty-seven stage IIB-IVB patients were enrolled between February 2022 and December 2023, including eighteen patients were combined with immunotherapy. They all received the low-dose dexamethasone regimen prior to a total of 149 cycles of chemotherapy. The incidence of skin rash after 3 weeks was of 7 episodes in 149 cycles (4.70%), 7 patients (12.77%) presented rash. In the eighteen patients receiving immunotherapy, rash within 3 weeks after pemetrexed administration occurred in 4 episodes in 72 cycles (5.56%), 4 patients ( 22.22%) presented rash. And one patient presented two episodes of cutaneous toxicity. Most skin rash episodes were of grade 1 (approximately 85%), while the rest were grade 2 (approximately 15%). No grade 3 or 4 skin rash was reported in the entire study population. Most cutaneous toxicities occurred during the first or second cycle. The incidence of rash in this study was significantly lower than the rate of 67.5-93% reported in patients treated without corticosteroids and did not increase compared with the rate of 14-56% reported in patients treated with corticosteroids. Conclusions: Administration of low-dose dexamethasone (8mg, 4mg, 2 mg of dexamethasone for 3 days from the day preceding pemetrexed) significantly reduces the incidence of rash after pemetrexed. The regimen may provide a standard preventive strategy for pemetrexed-induced rash, especially in NSCLC patients combined with immunotherapy(This study is registered with the Chinese Clinical Trial Registry (ChiCTR2400079622). Clinical trial information: ChiCTR2400079622.
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Chataway, Jeremy, Keith Martin, Kevin Barrell, Basil Sharrack, Pelle Stolt, and David C. Wraith. "Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis." Neurology 90, no. 11 (February 21, 2018): e955-e962. http://dx.doi.org/10.1212/wnl.0000000000005118.
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ObjectiveTo assess safety, tolerability, and efficacy of the antigen-specific immunotherapy ATX-MS-1467 in participants with relapsing multiple sclerosis using different treatment protocols to induce tolerance.MethodsTwo open-label trials in adult participants with relapsing multiple sclerosis were conducted. Study 1 was a multicenter, phase 1b safety evaluation comparing intradermal (i.d.) (cohort 1) with subcutaneous (cohort 2) administration in 43 participants. Both cohorts received ATX-MS-1467 dosed at 25, 50, 100, 400, and 800 μg at 14-day intervals over 8 weeks, followed by 8 weeks with 4 additional 800-μg doses at 14-day intervals and 32 weeks off study medication. Study 2 was a phase 2a, multicenter, single-arm trial enrolling 37 participants. ATX-MS-1467 was titrated from 50 μg i.d. on day 1 to 200 μg on day 15 and 800 μg on day 29 followed by biweekly administration of 800 μg for 16 weeks and 16 weeks off study medication. Efficacy was evaluated on MRI parameters and clinical variables. Safety endpoints included treatment-emergent adverse events and injection-site reactions.ResultsIn study 1, there was a significant decrease in new/persisting T1 gadolinium-enhanced (GdE) lesions in cohort 1 from baseline to week 16, returning to baseline values at week 48. In study 2, the number of T1 GdE lesions were significantly reduced on treatment and remained reduced at study completion. Safety results were unremarkable in both studies.ConclusionRelatively slow ATX-MS-1467 titration and a longer full-dose i.d. treatment period is associated with reduction in GdE lesions and a sustained effect post treatment. Further trials of ATX-MS-1467 are warranted.Classification of evidenceThis work provides Class IV evidence that for patients with relapsing multiple sclerosis, slow ATX-MS-1467 titration and a longer full-dose i.d. treatment period is associated with reduction in GdE lesions.
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Quiralte, Joaquín, María Angeles Lara, Gemma Vanesa Sánchez, Javier Monteserín, Luís Fernández, María Cruz Gómez-Fernández, Begoña Madariaga, et al. "Tolerability and surrogate efficacy parameters of a polymerized depot mixture pollen extracts without dilutional effect." Immunotherapy 11, no. 12 (August 2019): 1031–42. http://dx.doi.org/10.2217/imt-2019-0051.
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Aim: To evaluate tolerability of subcutaneous immunotherapy, in a polymerized mixture ( Olea europaea/ Phleum pratense) depot presentation. Patients & methods: A total of 47 poly-allergic patients received: an abbreviated schedule with three injections at weekly intervals or a cluster schedule with two administrations in 1 day. Both treatments continued with 3 monthly maintenance administrations. Results: Two systemic reactions, (4.3%). One grade 0 and one grade I. No local reactions. Immunoglobulin levels, increased significantly at final visit versus baseline in sIgG and sIgG4; in both schedules and allergens, no significant changes in specific immunoglobulin E levels were detected. Cutaneous reactivity at final visit decreased significantly. Conclusion: Both administration schedules with polymerized mixture of O. europaea/ P. pratense, presented an excellent tolerability profile and induced preliminary efficacy changes.
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Jablons, D., E. Bolton, S. Mertins, M. Rubin, P. Pizzo, S. A. Rosenberg, and M. T. Lotze. "IL-2-based immunotherapy alters circulating neutrophil Fc receptor expression and chemotaxis." Journal of Immunology 144, no. 9 (May 1, 1990): 3630–36. http://dx.doi.org/10.4049/jimmunol.144.9.3630.
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Abstract We performed functional assays on polymorphonuclear (PMN) leukocytes from 21 patients with advanced cancers, before, during, and after IL-2 administration. Of these, 19 were treated with high dose bolus IL-2 infusions (10(5) U/kg every 8 h) and 2 patients received low dose continuous infusions of IL-2 (250 U/kg/h). Five of six patients studied after IL-2 therapy had a decrease in their PMN chemotactic response to FMLP after bolus IL-2 (mean 8 doses) or, after the 4th day of continuous infusion IL-2 (pre-IL-2 values of 82% +/- 17% to 45% +/- 1% post-IL-2, p2 less than 0.004) compared with normal control values. In 8 of 10 patients studied, PMN capacity to oxidize intracellular dichlorofluorescein dye, an indirect measurement of O2- production in response to PMA stimulation, decreased after IL-2 administration (pre-IL-2 mean dichlorofluorescein oxidation (by channel number) 243 +/- 128 vs 3-day post-IL-2 87 +/- 86, p2 less than 0.02). Furthermore, a marked decrease in Fc gamma R III (Leu-11, CD16) expression was observed in 12/13 patients' PMN studied after IL-2 therapy (mean percent of PMN population with positive FcR expression was 81.1 +/- 15.4% pre-IL-2 which decreased to 56.0 +/- 30.5% post-IL-2, p2 less than 0.001). Other PMN surface markers (My4, My7, ICAM-1, LFA1, LFA3, Mac1) did not change significantly. PMN-mediated antibody-dependent cellular cytotoxicity did not change after IL-2 therapy (only 4/15 patients demonstrated more than 50% reduction in antibody-dependent cellular cytotoxicity). PMN phagocytosis of Staphylococcus aureus was also not significantly altered by IL-2 administration in six patients studied (pre-IL-2, 99 +/- 17% vs 111 +/- 28% post-IL-2, p2 greater than 0.2). We conclude that the systemic administration of IL-2 by intermittent or continuous administration is associated with marked changes in PMN function and cell surface receptor expression. These alterations may contribute to the apparent increased susceptibility to bacterial infection observed in these patients.
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Barba, David, Stephen C. Saris, Carol Holder, Steven A. Rosenberg, and Edward H. Oldfield. "Intratumoral LAK cell and interleukin-2 therapy of human gliomas." Journal of Neurosurgery 70, no. 2 (February 1989): 175–82. http://dx.doi.org/10.3171/jns.1989.70.2.0175.
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✓ Adoptive immunotherapy using lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) offers the possibility of a new treatment for patients with malignant glial tumors. In a clinical trial, the effectiveness of a 5-day treatment cycle of direct intratumoral administration of both LAK cells and IL-2 via a reservoir/catheter system in patients with recurrent malignant gliomas was studied. Ten patients were entered into the study, nine of whom were treated with 15 cycles of LAK cells (0.9 to 21.0 × 109 cells) and IL-2 (49 to 450 × 103 U/kg). The 10th patient in the study was not treated because of the onset of severe neurological deficits prior to beginning immunotherapy. Of the nine patients treated, one had a partial tumor response to immunotherapy as documented by computerized tomography. Neurological side effects occurred in all patients undergoing treatment and were related to increases in cerebral edema that appeared to be mediated by the immunotherapy. This report demonstrates the present limitations of regional adoptive immunotherapy with LAK cells and IL-2 in the treatment of human glial tumors.
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Barlow, Brett, Haris Hatic, Charles Douglas Bodine, Amitkumar Mehta, Gaurav Goyal, and Mayur Narkhede. "Safety of same day HD-MTX with induction therapy for DLBCL with concurrent CNS disease or as prophylaxis for high risk of CNS relapse." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e19545-e19545. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e19545.
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e19545 Background: High-dose methotrexate (HD-MTX) at a dose between 2.5 to 5 gm/m2 is commonly administered in conjunction with standard induction chemotherapy to patients with Diffuse Large B Cell Lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse, as defined by the Lymphoma International Prognostic Index (CNS-IPI). Optimal timing of HD-MTX in relation to induction chemotherapy is unknown. A recent study suggested that HD-MTX intercalated with R-CHOP cycles was associated with increased toxicity and treatment delays without improvement in survival or CNS relapse compared with end of treatment MTX (Wilson et al 2020). This retrospective study evaluates the toxicities and treatment delays associated with HD-MTX administered on day 1 of cycles of chemo-immunotherapy. Methods: This single center retrospective cohort study included 45 patients (pts) with DLBCL with concurrent CNS disease or at high risk of CNS relapse who received HD MTX on day 1 of chemo-immunotherapy at our center. Data was abstracted from chart review and included variables describing clinical and treatment characteristics, time to MTX clearance, toxicities experienced and treatment delays. Results: 31 pts received HD-MTX on the day of R-CHOP chemotherapy, 6 pts received HD-MTX on the day of R-EPOCH (Rituximab, Etoposide, Doxorubicin, Vincristine, Cyclophosphamide, and Prednisone), and 8 pts received HD-MTX with R-MiniCHOP (dose reduced R-CHOP). Same day HD MTX with chemo-immunotherapy was associated with acute kidney injury (AKI; 17-25%), treatment delays >7 days (13-17%), and grade 2 mucositis (11-50%). The burden of toxicities was numerically higher in patients treated with R-EPOCH vs. R-CHOP (Table). Clinical outcomes are summarized in table below. Conclusions: In our heterogeneous population of pts, we describe that the incidence of toxicities and treatment delays experienced with same day HD-MTX are higher with R-EPOCH than with R-CHOP. Comparative studies with intercalated or end of treatment MTX will determine if the incidence of treatment delays, toxicities and de-escalations are higher with same day HD-MTX administration. [Table: see text]
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Shevela, E. Ya, V. G. Degtyareva, A. V. Sosnovskaya, E. V. Voronova, M. Yu Kafanova, I. M. Rashchupkin, A. A. Ostanin, and E. R. Chernykh. "Therapeutic effect of soluble factors of M2 phenotype macrophages in children with language impairments." Medical Immunology (Russia) 23, no. 5 (November 17, 2021): 1137–50. http://dx.doi.org/10.15789/1563-0625-teo-2224.
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The aim of the present study was to assess safety and clinical efficacy of inhalation immunotherapy based on intranasal administration of bioactive factors produced by the M2 phenotype macrophages in children with language impairments, as well as to study the effect of inhalation immunotherapy on the cytokine profile in the patients' blood serum. The study was carried out according to the NCT04689282 protocol (www.ClinicalTrials.gov) and included 14 children (9 boys / 5 girls), aged 3 to 8 years, with language impairments associated with perinatal or postnatal CNS lesions of various origin. The children recruited into the study were assessed by a neurologist and speech therapist before the therapy, at the end of the course (1 month), and 6 months later. Serum samples for cytokine analysis were obtained before and 1 month after therapy. The course of intranasal inhalations by the conditioned M2 media (2 ml one time per day for 28-30 days) was safe and well tolerated. None of the 14 treated children had significant adverse reactions and severe undesirable events. Intranasal immunotherapy led to a decrease in the severity of language problems, which manifested by improved speech understanding by 45%; the sensorimotor level of speech, by 51%; word formation skills, by 72%, as well as a twofold increase in general and fine motor skills. In children with signs of autism spectrum disorders, along with a language improvement, a decrease in the severity of autistic symptoms was registered, as evidenced by statistically significant decrease in the CARS score from 42.5 to 38.5 after 1 month, and to 33 points after 6 months (p < 0.05). The clinical effect was revealed rather soon, i.e., within a month after the first procedure, being maintained or intensified during a follow-up for 6 months. At the same time, two-thirds of the children showed a clear clinical improvement, with insignificant effect in the rest of patients. Comparative analysis of the serum cytokine levels in these subgroups showed that children with a pronounced positive response to inhaled immunotherapy differed in the following parameters: (1) initially higher level of VEGF and IGF-1, and (2) decrease the level of TNFα in response to intranasal immunotherapy. In summary, we first tested a fundamentally new approach based on the use of soluble factors from M2-type macrophages and intranasal route of their administration in order to treat the children with severe language impairments, demonstrating safety and obtained preliminary data on effectiveness of such approach.
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Ballas, Z. K. "Lymphokine-activated killer (LAK) cells. I. Differential recovery of LAK, natural killer cells, and cytotoxic T lymphocytes after a sublethal dose of cyclophosphamide." Journal of Immunology 137, no. 7 (October 1, 1986): 2380–84. http://dx.doi.org/10.4049/jimmunol.137.7.2380.
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Abstract The effect of a sublethal dose of cyclophosphamide (CTX) administered in vivo on murine natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and cytotoxic T lymphocytes (CTL) was examined. It was found that such a dose of CTX abolished all of the killer cell responses examined. The recovery of each response was then examined as a function of time. Allogeneic CTL responses were the first to recover and could be generated from spleen cells obtained 6 days after CTX administration. Fresh NK cell activity recovered by days 9 to 12. However, when spleen cells obtained 12 days after CTX administration were cultured with interleukin 2 (IL 2) for 5 days, they lost the ability to lyse YAC-1 cells, suggesting a distinction between "augmented" and "fresh" NK cell activity. H-2-restricted, trinitrophenyl-specific CTL activity could be generated by day 14 after CTX, provided the cultures were supplemented with exogenous IL 2. LAK could not be induced until day 21 post-CTX treatment. These data suggest that LAK precursors, CTL precursors, and NK cells are distinct cell populations. Additionally, this report introduces a model that may be useful in examining the differential contribution of NK and LAK to successful adoptive tumor immunotherapy.
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Santoni, Matteo, Javier Molina-Cerrillo, Giorgio Santoni, Elaine T. Lam, Francesco Massari, Veronica Mollica, Giulia Mazzaschi, Bernardo L. Rapoport, Enrique Grande, and Sebastiano Buti. "Role of Clock Genes and Circadian Rhythm in Renal Cell Carcinoma: Recent Evidence and Therapeutic Consequences." Cancers 15, no. 2 (January 7, 2023): 408. http://dx.doi.org/10.3390/cancers15020408.
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Circadian rhythm regulates cellular differentiation and physiology and shapes the immune response. Altered expression of clock genes might lead to the onset of common malignant cancers, including Renal Cell Carcinoma (RCC). Data from Cancer Genome Atlas (TCGA) indicate that clock genes PER1-3, CRY2, CLOCK, NR1D2 and RORα are overexpressed in RCC tissues and correlate with patients’ prognosis. The expression of clock genes could finely tune transcription factor activity in RCC and is associated with the extent of immune cell infiltration. The clock system interacts with hypoxia-induced factor-1α (HIF-1α) and regulates the circadian oscillation of mammalian target of rapamycin (mTOR) activity thereby conditioning the antitumor effect of mTOR inhibitors. The stimulation of natural killer (NK) cell activity exerted by the administration of interferon-α, a cornerstone of the first era of immunotherapy for RCC, relevantly varies according to circadian dosing time. Recent evidence demonstrated that time-of-day infusion directly affects the efficacy of immune checkpoint inhibitors in cancer patients. Compounds targeting the circadian clock have been identified and their role in the era of immunotherapy deserves to be further investigated. In this review, we aimed at addressing the impact of clock genes on the natural history of kidney cancer and their potential therapeutic implications.
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Gonçalves, Lisa, Duarte Goncalves, Teresa Esteban Casanelles, Laura Pratas Guerra, Maria B. Menezes, Vanessa Duarte Branco, Joana Alves Luís, et al. "Retro TIMing: A multicentric retrospective analysis of immunotherapy timing in metastatic melanoma." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 9542. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.9542.
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9542 Background: Immune checkpoint inhibitors (ICI) targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now the standard of care in the treatment of metastatic melanoma (mM). The interplay between cancer cells and tumor microenvironment cells (e.g. immune cells) impacts cancer cell survival, local invasion, and metastatic dissemination. Chrono-immunotherapy is an emerging field as circadian oscillations are observed in the immune landscape (e.g immune cell numbers) as well as in the expression of immunotherapy targets (e.g. PD-1). Recently, a growing body of evidence suggests the outcome can be influenced by the time of the day when immunotherapy is administered (morning versus in the afternoon). This work aims to evaluate the impact of immunotherapy with ICIs administration timing on the overall survival (OS) and progression-free survival (PFS) of patients with mM. Methods: Multicentric, retrospective cohort study of mM patients under immunotherapy (ipilimumab/nivolumab, nivolumab, or pembrolizumab) with PS 0-1, between July 2016 and June 2023. Clinical, demographic characteristics, and time of treatment administration were obtained from medical records. Patients were distributed in two groups: those who received less than 75% of infusions after 2pm (morning group), and those who received at least 75% of infusions after 2pm (afternoon group). OS and PFS were calculated with Kaplan-Meier method and tested using a Cox regression model, with a 95% confidence interval. Results: We identified 168 patients from the 7 Oncology Centers included. The majority were men (n=100, 59.5%), with a median age of 69 years old, and 22% of the patients (n=37) were included in the afternoon group. No significant demographic or tumor burden differences were found between the morning and afternoon groups. The median follow-up time was 29 months, the estimated median PFS was 11.8 months (CI 95%, 8.0 - 14.6) and median OS was 31.4 months (CI 95%, 20.6 - NR). Patients in the afternoon group presented with shorter OS compared with those in the morning group (14.4 vs 37.6 months; HR 1.94 [CI 95% 1.16 to 3.23]; p 0,014). No statistically significant differences were observed in PFS. Subgroup analysis showed an increased detriment of performing ICIs infusions in the afternoon in women (OS 8.7 (4.2, 21.2) versus 30.9 months (18.9, NR), p=0.002; afternoon versus morning) and those older than 65 years old (OS 14.2 months (4.7, 31.4) versus 24.2 months (18.3, NR), p=0.002); afternoon versus morning). Conclusions: This work provides valuable insights into the potential role of the circadian timing of immunotherapy treatments for mM, suggesting patients may benefit from having ICIs infusion in the morning. Prospective randomized studies with a translational approach are needed to validate and fully understand the underlying mechanisms at play in circadian timing efficacy.
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Rykov, M. Yu, and I. S. Dolgopolov. "Experience in the use of dendritic vaccines in the treatment of patients with recurrent gliomas." Research and Practical Medicine Journal 9, no. 4 (December 1, 2022): 18–29. http://dx.doi.org/10.17709/2410-1893-2022-9-4-2.
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Purpose of the study. To substantiate the expediency of cellular immunotherapy in the treatment of patients with relapses of high-grade gliomas and evaluate the safety of injecting allogeneic cells directly into the cerebrospinal fluid.Materials and methods. Our study included 5 patients, median age 7,6 years (2–16). Three patients had anaplastic astrocytoma (AA) (1st recurrence – 1 patient, 2nd recurrence – 2 patients), 1 patient had glioblastoma multiforme (GBM) (3rd recurrence) and 1 had diffuse brainstem glioma (BSG). The median time to the first relapse was 12 months (4 to 16), to the second one was 5 months (1 to 8). The protocol of immunotherapy included combined administration of autologous dendritic cell-based vaccine (DV) and repeated intrathecal/intraventricular injections of donor allogenic immunocompetent cells (alloIC) for at least 2 years.Results. Two of 3 patients with AA experienced a progression-free interval of 67 and 71 months One patient with 3rd GBM relapse is alive without any therapy 13.3 years after immunotherapy start. The median time of follow-up was 67 months with the 2‑years overall survival was 58 %. Two patients died from disease progression within 6 and 7 months from the start of immunotherapy. Over the period of treatment the patients received a median of 20 (8 to 60) alloIC injections and 18 (8 to 44) DV administrations. No serious side-effect was observed.Conclusion. Immunotherapy could be an attractive option for treating patients with high-grade malignant gliomas irresponsible to conventional therapy and is worthy of further investigation.
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Fletcher, James, Sebastian Kang, Amy Brown, Sabe S. Sabesan, Megan Lyle, Ritwik Pandey, Andrew Lui, et al. "Administration of immune checkpoint inhibitors using teleoncology model of care in Far North Queensland: A multicenter review of safety outcomes." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 2084. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.2084.
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2084 Background: The Teleoncology model of care, as developed and implemented across health services in Far North Queensland (Australia), improves access to specialist oncology services, including telehealth supervised administration of Oncology drugs for patients in rural/remote towns. There is limited published data regarding the safety of checkpoint inhibitor immunotherapy when it is administered via Teleoncology. Aim: Evaluate safety of immunotherapy administration via Teleoncology, including immune-related adverse events (irAE), treatment delays, hospital admissions and interhospital transfers, in comparison to a retrospective control population. Methods: Retrospective review of all patients treated with immunotherapy via Teleoncology as part of Cairns and Hinterland Hospital and Health Service (CHHHS) and the Townsville Teleoncology Network (TTN) between January 2015 and April 2019. A retrospective cohort treated at Townsville Cancer Centre over the same time period was used as a control group. Results: Fifty-one patients received a total of 624 cycles of immunotherapy (all single agent anti-PD-1/L-1) via Teleoncology. The control population included 142 patients who received 1697 cycles of immunotherapy. Baseline characteristics were well matched between groups. Compared to the control population, patients treated via telehealth did not have statistically significant differences in the rate of Grade 3+ irAE (13.7% v 8%), hospital admissions (13.7% v 7.4%) or protocol suspensions due to immune toxicity (16% v 10%). One patient with Grade 3+ irAE required interhospital transfer for investigation and management, which occurred within 24 hours of presentation to hospital. There were no treatment-related mortalities in either group. Conclusions: Checkpoint inhibitor immunotherapy can safely be delivered using the Teleoncology model of care in rural and remote centres. The incidence of toxicity for single agent immunotherapy was predictably low and not significantly different between groups, however the numbers in this retrospective study were small. The time to recognition and management of immune mediated toxicity in rural and remote centres is an important factor that was not assessed in this study and will be considered in future work.
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Ho, Jeremy, Antonia Susnjar, Jessica Rhudy, Antons Sizovs, Graziano Lolli, Ramiro Pino, Corrine Ying Xuan Chua, E. Brian Butler, Sandra Demaria, and Alessandro Grattoni. "Localizing radioimmunotherapy via nanochannel device for sustained intratumoral drug delivery for solid tumor treatment." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 37. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.37.
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37 Background: Immune related adverse events still occur in up to 91% of patients receiving immunotherapy. Intratumoral administration is a potential solution to limit these events by reducing systemic exposure while increasing local concentration. However, intratumoral injection is hindered by rapid clearance of drug from the tumor. Our group has developed an intratumoral nanochannel implant for sustained delivery of immunotherapy (NDES) as a solution. Recent clinical and preclinical studies have found success in the combination of radiotherapy and immunotherapy in improving both local and distant tumor response. We propose a combination of radiotherapy followed by sustained intratumoral delivery of immunotherapy as a treatment regimen to improve tumor response and reduce side effects. Methods: Mice were implanted with the 4T1 murine mammary carcinoma and separated into treatment and control groups. CD40 agonist antibody was delivered intratumorally via NDES. Radiotherapy was administered at 8 Gy for three consecutive days and implantation of the NDES occurred the day after the final fraction of radiation. The tumor growth curve was plotted and tumor, spleen, lymph nodes, lungs, and blood were collected at the study endpoint for further flow cytometry and histological analysis. Results: The combination of radiotherapy and sustained intratumoral CD40 antibody showed significantly decreased tumor growth rates over radiotherapy or sustained intratumoral immunotherapy alone. Both intratumoral and systemic T-cell activation was observed. Mice treated with sustained intratumoral CD40 antibody showed decreased toxicity when compared to those receiving comparable systemic dosage. Conclusions: Radiotherapy combined with local sustained intratumoral immunotherapy is a potential strategy for improving treatment of solid tumors which currently show suboptimal response to current immunotherapy regimens and for inducing a systemic response to distant metastases while minimizing adverse side effects. The sustained delivery profile of the NDES presents an opportunity for practical intratumoral administration and avoidance of repeated invasive procedures in patients.
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Yatsenko, Elena M., Denis S. Baranovsky, Marianna D. Pronkevich, Elena V. Isaeva, Anna N. Smirnova, Vasiliy N. Petrov, Sergey A. Ivanov, and Andrey D. Kaprin. "EFFECTS OF THE IMMUNOMODULATOR ‘GALAVIT’ ON THE DEVELOPMENT OF B16 MELANOMA IN MICE." Siberian Journal of Life Sciences and Agriculture 15, no. 2 (April 30, 2023): 454–69. http://dx.doi.org/10.12731/2658-6649-2023-15-2-454-469.
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In recent years, major attention has been devoted to immunotherapy in oncology. Immunotherapy is a promising treatment approach targeted to inhibit tumor growth via stimulating the body’s antitumor immune response.
Purpose. The study was aimed to investigate the relationship between melanoma growth and metastasis in mice with the various schemes of Galavit treatment.
Materials and methods. We used B16-F10 melanoma in F1-mouse as an experimental model. We divided animals in 3 groups: control (no therapy after tumor transplantation); immediate Galavit therapy at a dose of 5 mg/mouse after tumor transplantation; postponed Galavit therapy a week after tumor transplantation at doses of 5mg/mouse. We evaluated the rate of tumor node growth, 50-day survival rate and metastatic development after the 50th day follow-up period.
Results. We revealed 80% survival rate for 50-day observation period in the control group. Interestingly, the 50-day survival rate was 60% for the animals treated with Galavit immediately after tumor inoculation. In other group with postponed Galavit therapy, survival rate was 100 %. A similar pattern was observed for tumor growth rates.
Conclusion. We found that therapy with Galavit a week after tumor inoculation significantly increased the 50-day survival rate, suppressed tumor growth and the development of metastases in comparison with the control group and the group with immediate Galavit administration.
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Tritarelli, E., E. Rocca, U. Testa, G. Boccoli, A. Camagna, F. Calabresi, and C. Peschle. "Adoptive immunotherapy with high-dose interleukin-2: kinetics of circulating progenitors correlate with interleukin-6, granulocyte colony-stimulating factor level." Blood 77, no. 4 (February 15, 1991): 741–49. http://dx.doi.org/10.1182/blood.v77.4.741.741.
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Abstract Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells results in significant tumor regression in patients with advanced cancer. We have investigated the kinetics of circulating erythroid (BFU-E) and granulocytic-macrophage (CFU-GM) progenitors after IL-2 therapy in 11 cancer patients, mainly affected by metastatic melanoma and renal cell carcinoma. Administration of IL-2 from day 1 through day 5 constantly induced a dramatic decrease of the number of circulating BFU-E and CFU-GM, which then showed a striking rebound (up to values fourfold and sevenfold higher, respectively, than the pretherapy levels) on discontinuation of IL-2, ie, from day 5 through day 10. A similar kinetic pattern was observed during and after the second cycle of IL-2 administration. 3[H]-thymidine killing experiments showed that the cycling activity of the progenitors was virtually unmodified in the rebound phases. To explore the mechanism(s) underlying this kinetic pattern, we have analyzed the plasma concentration of several hematopoietic growth factors, including IL-1 beta, IL-3, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and erythropoietin (Ep). No modifications in the levels of IL-3, GM-CSF, or IL-1 beta were observed, whereas a pronounced increase of IL-6 and G-CSF concentration was monitored, starting at day 3 and peaking at day 5 of treatment (a parallel, but modest, increase of Ep level was also observed). The elevation of IL-6 and G-CSF concentration is directly correlated with and may, at least in part, underlie the subsequent rebound of circulating hematopoietic progenitors. Furthermore, the increase in IL-4 level observed at day 10 of therapy may mediate the eosinophilia gradually starting at this stage of treatment.
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Tritarelli, E., E. Rocca, U. Testa, G. Boccoli, A. Camagna, F. Calabresi, and C. Peschle. "Adoptive immunotherapy with high-dose interleukin-2: kinetics of circulating progenitors correlate with interleukin-6, granulocyte colony-stimulating factor level." Blood 77, no. 4 (February 15, 1991): 741–49. http://dx.doi.org/10.1182/blood.v77.4.741.bloodjournal774741.
Full textAbstract:
Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells results in significant tumor regression in patients with advanced cancer. We have investigated the kinetics of circulating erythroid (BFU-E) and granulocytic-macrophage (CFU-GM) progenitors after IL-2 therapy in 11 cancer patients, mainly affected by metastatic melanoma and renal cell carcinoma. Administration of IL-2 from day 1 through day 5 constantly induced a dramatic decrease of the number of circulating BFU-E and CFU-GM, which then showed a striking rebound (up to values fourfold and sevenfold higher, respectively, than the pretherapy levels) on discontinuation of IL-2, ie, from day 5 through day 10. A similar kinetic pattern was observed during and after the second cycle of IL-2 administration. 3[H]-thymidine killing experiments showed that the cycling activity of the progenitors was virtually unmodified in the rebound phases. To explore the mechanism(s) underlying this kinetic pattern, we have analyzed the plasma concentration of several hematopoietic growth factors, including IL-1 beta, IL-3, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and erythropoietin (Ep). No modifications in the levels of IL-3, GM-CSF, or IL-1 beta were observed, whereas a pronounced increase of IL-6 and G-CSF concentration was monitored, starting at day 3 and peaking at day 5 of treatment (a parallel, but modest, increase of Ep level was also observed). The elevation of IL-6 and G-CSF concentration is directly correlated with and may, at least in part, underlie the subsequent rebound of circulating hematopoietic progenitors. Furthermore, the increase in IL-4 level observed at day 10 of therapy may mediate the eosinophilia gradually starting at this stage of treatment.
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Zhukova, N. V., R. V. Orlova, Ye A. Kaledina, A. M. Malkova, P. A. Naymushina, N. P. Belyak, and A. S. Demchenkova. "Immunotherapy of Metastatic Melanoma Yesterday, Today, Tomorrow." Effective Pharmacotherapy 17, no. 11 (May 29, 2021): 22–28. http://dx.doi.org/10.33978/2307-3586-2021-17-11-22-28.
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For a long time, the main drug for the treatment of patients with metastatic melanoma remained dacarbazine, approved by the US Food and Drug Administration in 1975. This method of treatment could hardly guarantee the significant increase in overall survival. Taking in account the high immunogenicity of melanoma, back in the XIX and XX centuries, scientists began to develop immuno-oncological drugs aimed at activating antitumor immunity. Many studies were conducted before the goal was achieved. So in the arsenal of an oncologist there appeared check-point inhibitors – which are in fact the most effective method of treating melanoma, which radically changed the prognosis of the disease.
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Ackerstein, A., E. Kedar, and S. Slavin. "Use of recombinant human interleukin-2 in conjunction with syngeneic bone marrow transplantation in mice as a model for control of minimal residual disease in malignant hematologic disorders." Blood 78, no. 5 (September 1, 1991): 1212–15. http://dx.doi.org/10.1182/blood.v78.5.1212.1212.
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Abstract Unlike allogeneic bone marrow transplantation (BMT), autologous BMT is not accompanied by immune-mediated graft-versus-leukemia (GVL) effects; hence, the relapse rate observed after autologous BMT in malignant hematologic disorders is higher than that observed after allogeneic BMT. Autologous BMT represents a much safer medical procedure available for many patients in need in situations where allogeneic BMT is not feasible or risky. The present experiments were designed to investigate whether it might be possible to combine the therapeutic benefits of autologous BMT with additional immunotherapy after BMT. The tumor model used for investigating GVL effects was the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. BALB/c mice inoculated with 10(3) BCL1 leukemia cells were treated on day-1 with cyclophosphamide 100 mg/kg and transplanted with normal syngeneic BM cells on day 0. High-dose recombinant interleukin-2 (rIL-2) (100,000 Cetus units x 3/day intraperitoneally x 5 consecutive days) was initiated on day +1, +7, or +21 after BMT. Kinetics of lymphocyte reconstitution after syngeneic BMT indicated a steep increase in the absolute number of peripheral blood lymphocytes on days 17 through 24. All experimental groups were observed for relapse. Mice receiving no rIL-2 therapy relapsed and died within 50 days after BMT, whereas mice receiving rIL-2 showed long-term disease-free survival. Optimal time for administration of rIL-2 was noted at 3 weeks post-BMT, with 90% of the mice surviving with no evidence of disease for more than 1 year. Similarly, when 10(4) BCL1 cells were given 1 day after syngeneic BMT to simulate minimal residual disease after syngeneic BMT, rIL-2 therapy administered at 14 days post-BMT seemed effective in prolonging disease-free survival in contrast to the same regimen given at 1 day after BMT. Our data suggest that immunotherapy with rIL-2 should be further investigated as a new immunotherapeutic tool for decreasing the relapse rate after BMT for hematologic malignancies.
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Ackerstein, A., E. Kedar, and S. Slavin. "Use of recombinant human interleukin-2 in conjunction with syngeneic bone marrow transplantation in mice as a model for control of minimal residual disease in malignant hematologic disorders." Blood 78, no. 5 (September 1, 1991): 1212–15. http://dx.doi.org/10.1182/blood.v78.5.1212.bloodjournal7851212.
Full textAbstract:
Unlike allogeneic bone marrow transplantation (BMT), autologous BMT is not accompanied by immune-mediated graft-versus-leukemia (GVL) effects; hence, the relapse rate observed after autologous BMT in malignant hematologic disorders is higher than that observed after allogeneic BMT. Autologous BMT represents a much safer medical procedure available for many patients in need in situations where allogeneic BMT is not feasible or risky. The present experiments were designed to investigate whether it might be possible to combine the therapeutic benefits of autologous BMT with additional immunotherapy after BMT. The tumor model used for investigating GVL effects was the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. BALB/c mice inoculated with 10(3) BCL1 leukemia cells were treated on day-1 with cyclophosphamide 100 mg/kg and transplanted with normal syngeneic BM cells on day 0. High-dose recombinant interleukin-2 (rIL-2) (100,000 Cetus units x 3/day intraperitoneally x 5 consecutive days) was initiated on day +1, +7, or +21 after BMT. Kinetics of lymphocyte reconstitution after syngeneic BMT indicated a steep increase in the absolute number of peripheral blood lymphocytes on days 17 through 24. All experimental groups were observed for relapse. Mice receiving no rIL-2 therapy relapsed and died within 50 days after BMT, whereas mice receiving rIL-2 showed long-term disease-free survival. Optimal time for administration of rIL-2 was noted at 3 weeks post-BMT, with 90% of the mice surviving with no evidence of disease for more than 1 year. Similarly, when 10(4) BCL1 cells were given 1 day after syngeneic BMT to simulate minimal residual disease after syngeneic BMT, rIL-2 therapy administered at 14 days post-BMT seemed effective in prolonging disease-free survival in contrast to the same regimen given at 1 day after BMT. Our data suggest that immunotherapy with rIL-2 should be further investigated as a new immunotherapeutic tool for decreasing the relapse rate after BMT for hematologic malignancies.
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Mirsoian, Annie, Myriam N. Bouchlaka, Gail Sckisel, Mingyi Chen, Chien-Chun Steven Pai, Emanuel Maverakis, Richard Spencer, et al. "Adiposity As a Principal Component of Lethal Cytokine Storm Following Cancer Immunotherapy in Aged Mice." Blood 124, no. 21 (December 6, 2014): 460. http://dx.doi.org/10.1182/blood.v124.21.460.460.
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Abstract The use of immunotherapy (IT) in cancer has recently resulted in impressive responses. Yet, their usages, especially those involving cytokine therapies, have also resulted in the induction of severe systemic toxicities often not previously characterized in their preclinical animal studies. Our laboratory has demonstrated that treatment of EL4 lymphoma with a combination immunotherapy consisting of monoclonal agonistic antibody CD40 and IL-2 resulted in significant anti-tumor responses leading to overall increases in survival using young inbred mice (2-6 months of age). Yet, the majority of hematological cancers occur in aged individuals, with most diagnoses occurring past the age of 60. We now demonstrate that systemic immunotherapy administration in aged (>16 months of age), but not young, mice resulted in the induction of a rapid cytokine release syndrome, also known as “cytokine storm”, culminating in multi-organ damage (liver, lung, and gut) leading to rapid lethality by day 2 of treatment. Aging is accompanied by an overall redistribution of body mass, with a decrease in lean muscle mass and increase in adiposity. Similarly, we found that normal aging in inbred mice housed under specific pathogen free conditions was accompanied by increases in visceral fat that was similar to young obese (ob/ob or diet-induced obese [DIO]) mice. We therefore assessed the impact of aging and obesity on inflammatory responses to cancer immunotherapeutics. We determined the effects of increased body fat on systemic immunotherapy tolerance in aged mice compared to young obese mice. Both young ob/ob and DIO generated pro-inflammatory cytokine (ie TNFa and IL6) levels and organ pathologies comparable to aged WT mice following immunotherapy, culminating in rapid lethality after several days of therapy. We observed that young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNFa+ macrophages in comparison to young lean mice with immunotherapy. Administration of aCD40/IL-2 with macrophage depletion or TNF-blockade prevented the development of cytokine storms within young obese mice, providing protection from lethality, suggesting that the toxicity was macrophage mediated through increases in TNFa. Calorie-restricted aged mice contain less visceral fat and upon aCD40/IL-2 administration displayed reduced cytokine levels, protection from organ pathology, and protection from lethality. Our data demonstrates adiposity as a critical factor in the age-associated inflammatory pathologic responses to systemic anti-cancer immunotherapy and may have a significant impact when immunotherapy is used clinically within cancer therapy regimens. These data also underscore the critical importance of taking aging and body fat into consideration with preclinical assessments. Disclosures No relevant conflicts of interest to declare.
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Zhang, Zhipeng, Ningning Liu, and Mingyu Sun. "Research Progress of Immunotherapy for Gastric Cancer." Technology in Cancer Research & Treatment 22 (January 2023): 153303382211505. http://dx.doi.org/10.1177/15330338221150555.
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Gastric cancer (GC) is one of the most common gastrointestinal tract cancers worldwide, which has high incidence and mortality rates and poor prognosis. Although multidisciplinary comprehensive therapies consisting of surgery, chemotherapy, radiotherapy, and targeted therapy have made great progress in GC treatment, a satisfactory curative effect still cannot be achieved in many circumstances, and the 5-year survival of patients with GC remains to be very low. In China, about 75% of patients with GC are diagnosed in the advanced stage and thus miss the opportunity of surgical resection. Although the conventional treatment of GC has improved the survival time of advanced patients to a certain extent, the clinical efficacy has encountered a bottleneck and cannot bring higher survival benefits to patients. With the development of immunologic and molecular biologic technologies, immunotherapy has gradually become a new essential treatment for GC, which has attracted extensive attention in the field of oncology. The US Food and Drug Administration (USFDA) and China Food and Drug Administration (CFDA) have approved a variety of immune-related drugs for the treatment of GC, and all of which have achieved good efficacy. In this review, we summarize the recent development in nonspecific enhancer therapy, adoptive immunocell therapy, tumor vaccine therapy, oncolytic virus therapy, and immune checkpoint inhibitor therapy, and their roles in the treatment of GC.
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Ilonidis, G., G. Anogianakis, Chr Trakatelli, A. Anogeianaki, J. Giavazis, M. Trakatellis, and I. Michalis. "The Effects of Long-Term Treatment by Immunotherapy and Fluticazone on Broncial Hyperreactivity." European Journal of Inflammation 1, no. 1 (January 2003): 13–16. http://dx.doi.org/10.1177/1721727x0300100104.
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Thirty subjects (20 female and 10 male), all allergic to the mites D. Pteronyssinus and D. Farinae, participated in the present study which covered a period of four years. The subjects were randomly divided in two groups. Group I included 10 female and 5 male subjects, with an average age of 25.8 (+/− 3.5) years who received immunotherapy only. Group II had an average age of 31.5 (+/− 4) years and they received immunotherapy along with fluticazone propionate (1000mcg/day). The protocol for immunotherapy was the same for both groups. The basis FEV1 was determined for each subject of both Groups I and II and afterwards they were subjected to provocation tests of nebulized methacholine solution administered in consecutively larger concentrations until a drop in FEV1 >20 % (PC20), was observed. Three years later, when their therapy was completed, all subjects were subjected to the same provocation test and a significant reduction in bronchial hyperactivity was documented for both groups. In particular, for Group I, the percentage of change in FEV1 values was 27.25 +/- 5.23 % and PC20 5.11 +/− 2.64 mg/ml before immunotherapy, while after immunotherapy the same indicators were 22.22 +/- 7.08 % (P<0.05) and 6.85 +/− 4.03 mg/ml, (P<0.05) respectively. For Group II, the percentage of change in FEV1 values was 26.28 +/− 2.5 % and PC20 5.42 +/− 2.5 mg/ml before immunotherapy, while after immunotherapy the same indicators were 12.27 +/- 2.49 % (P<0.01)and 11.64 +/− 5.14 mg/ml, P<0.01 respectively. It is concluded that although significant reduction in hyperreactivity can be achieved through immunotherapy, the combination of immunotherapy with daily fluticazone propionate administration shows the most promising results.
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Griffiths, Robert, Mark Danese, Michelle Gleeson, and Kevin Knopf. "Patterns of Chemotherapy/Immunotherapy and Survival in Mantle Cell Lymphoma: Evidence from SEER-Medicare." Blood 112, no. 11 (November 16, 2008): 5293. http://dx.doi.org/10.1182/blood.v112.11.5293.5293.
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Abstract Introduction: Mantle cell lymphoma (MCL) is a relatively rare form of non-Hodgkin’s lymphoma (NHL) comprising approximately 6% of all new NHL cases. Methods: Using the National Cancer Institute’s SEER registry linked to Medicare claims, we identified 503 patients with MCL (histology code 9673) as their first malignancy between January 1, 1999 and December 31, 2002. Patients were followed until the development of a second primary cancer, transition to an HMO, the end of their claims history (December 31, 2005), or death. Medicare claims were used to identify and classify chemotherapy and/or immunotherapy (C/I) regimens as well as to identify radiation therapy. The initial C/I treatment approach (no treatment, chemotherapy only, and immunotherapy with or without chemotherapy) was based on the first 90 days after diagnosis. The specific regimen was identified using the 30 day period after the initial C/I administration. Multivariate Cox proportional hazards analyses were performed to identify patient socio-demographic and clinical factors associated both with time to treatment initiation and with survival. Potential risk factors in the models included age, gender, race, stage, comorbidity burden*, year of diagnosis, education, rural/urban status, poverty indicators, nodal involvement, anemia*, neutropenia*, and thrombocytopenia* (*=based on diagnosis codes). Results: Median age was 76 years, 65% were male, 11% were non-white, and 57% were diagnosed with Stage IV disease. Overall, 81% (n=405) received C/I of whom 30% (n=123) received radiation at any time during follow up. The median time to first C/I was 51 (95% CI 46–56) days. Among patients receiving C/I, 138 received rituximab with or without CHOP or CVP, 101 received either CHOP or CVP alone, 96 could not be clearly classified into these groups, and 70 did not have identifiable C/I agents in the data (only administration codes were present). In multivariate analysis of time to initiating C/I, patients age ≥ 80 years were 46% less likely to initiate C/I (compared to age 66–70), those with advanced disease (Stage III or IV) were 41% (Stage III) or 59% (Stage IV) more likely to initiate C/I (compared to Stage I), and those with anemia were 49% more likely to initiate C/I (p<0.05 for all). Unadjusted median survival for the cohort was 29 (95% CI 26–31) months. Unadjusted median survival was 20 (95% CI 12–30) months in patients untreated with either chemo- or immunotherapy, 28 (95% CI 24–31) months in patients treated with chemotherapy only, and 33 (95% CI 28–39) months in patients treated with immunotherapy (with or without chemotherapy). In multivariate survival analysis, compared to no C/I treatment, immunotherapy with or without chemotherapy was associated with 44% lower risk of death (95% CI 23% to 60%), while chemotherapy alone was not significantly different. Other factors significantly associated with mortality included increasing age, increasing stage, and diagnosis of anemia. Conclusion: Findings indicate the majority of patients in this elderly population received C/I within the first 2 months following diagnosis. Immunotherapy, but not chemotherapy alone, was associated with improved survival. However, because these are observational data, even with extensive adjustment, the possibility of residual confounding should be kept in mind.
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Zeter, Daniel, and Ina J. Patel. "Immunotherapy-related toxicities: A retrospective analysis of barriers to prompt detection and initiation of treatment in renal cell carcinoma." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e16547-e16547. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e16547.
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e16547 Background: In 2021, there was an estimated 76,000 patients diagnosed with kidney cancer in the United States, and 90% of these patients were diagnosed with renal cell carcinoma (RCC). The current treatment for RCC is the use of immune checkpoint inhibitors (ICIs), which allow the body to naturally fight against cancer cells without impedance. A common side effect of this therapy, however, is immunotherapy-related adverse events (irAE), which are toxicities where the bodies overactive immune system attacks noncancerous organs. When irAEs arise, the patient’s immunotherapy is stopped, and a steroid regiment is begun to dampen the immune system before re-starting immunotherapy. Time is crucial when treating irAEs, and this study is aimed to identify barriers in the onset of steroid treatment and identify interventions that can help providers and patients identify toxicities and begin steroid treatment as soon as possible. Methods: We conducted a retrospective study analyzing adult patients (ages 18-75) being treated for RCC at UT Southwestern Medical Center and Moncrief Cancer Institute (MCI). We specifically looked at patients being treated with ipilimumab, nivolumab, and pembrolizumab. The first portion included a chart review to identify patients and identify barriers to prompt treatment, i.e. fear of worsening hyperglycemia in diabetics, access to healthcare, delay of re-initiating immunotherapy. The second portion of this study will be to identify and test a possible intervention for these patients to ensure timely recognition of toxicities and prompt initiation of steroids. Results: Upon review of 201 patients with RCC stage III/IV, the most common toxicity found was colitis (28.4%), followed by transaminitis (9.0%) and pneumonitis (9.0%). The most common method for identification of toxicities was routine lab work performed before immunotherapy administration (30.4%), check-ins at regularly scheduled appointments (21.7%), and after-hour physician telephone lines (19.6%). Additionally, the average time from irAE identification to steroid administration was 1.45 days. Excluding toxicities found either at office appointments or on routine lab work, the average time to steroids from identification was 3.55 days. Our data collection also demonstrated that routine labs were the most likely factor to identify immunotherapy toxicity in a timely manner. Conclusions: Continuation of current practices can lead to further decreases in time to steroid treatment. This study can be used as a blueprint and expanded to further investigate irAEs in other solid tumors as well as contribute to management of the ever-evolving immunotherapy landscape.
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Matysiak, Joanna, Eliza Matuszewska, Marek L. Kowalski, Sławomir W. Kosiński, Ewa Smorawska-Sabanty, and Jan Matysiak. "Association between Venom Immunotherapy and Changes in Serum Protein—Peptide Patterns." Vaccines 9, no. 3 (March 12, 2021): 249. http://dx.doi.org/10.3390/vaccines9030249.
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Venom immunotherapy (VIT) is administered to allergic patients to reduce the risk of dangerous systemic reactions following an insect sting. To better understand the mechanism of this treatment and its impact on the human organism, we analysed serum proteomic patterns obtained at five time-points from Hymenoptera-venom-allergic patients undergoing VIT. For statistical analyses, patients were additionally divided into two groups (high responders and low responders) according to serum sIgG4 levels. VIT was found to be associated with changes in seven proteins: the fibrinogen alpha chain, complement C4-A, complement C3, filamin-B, kininogen-1, myosin-9 and inter-alpha-trypsin inhibitor heavy chain H1. The number of discriminative m/z (mass-to-charge ratio) features increased up to the 90th day of VIT, which may be associated with the development of immunity after the administration of increased venom doses. It may also suggest that during VIT, there may occur processes involved not only in protein synthesis but also in protein degradation (caused by proteolytic venom components). The results are consistent with measured serum sIgG4 levels, which increased from 2.04 mgA/I at baseline to 7.25 mgA/I at 90 days. Moreover, the major proteomic changes were detected separately in the high responder group. This may suggest that changes in protein–peptide profiles reflect the actual response to VIT.
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Mayrink, W., P. A. Magalhaes, and M. S. M. Michalick. "IMMUNOTHERAPY AS A TREATMENT OF AMERICAN CUTANEOUS LEISHMANIASIS: PRELIMINARY STUDIES IN BRAZIL." Pediatrics 95, no. 6 (June 1, 1995): 891. http://dx.doi.org/10.1542/peds.95.6.891.
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Treatment of American cutaneous leishmaniasis has been successful with antimony compounds for 80 years. There are certain conditions where the chemotherapy cannot be used—pregnant women and patients with heart or renal disease. A group in Brazil carried out a sequential trial (not a random controlled trial) of vaccine composed of killed parasites from five stocks of the leishmania, while another group received the traditional therapy of antimony. The immunotherapy program was intensive requiring 10 daily injections followed by a 10-day free period. Of 62 patients (aged 3 to 70 years) so treated, 47 (76%) were considered clinically cured; 41 required 2-10 of the 10-day treatment courses; and the other 6 required 11-19 courses. There were no adverse effects. Results were better in patients with single cutaneous and multiple cutaneous lesions, and less effective in those patients with mucocutaneous lesions. The authors make the point that because leishmaniasis occurs especially in rural areas, it would be possible to give patients a supply of syringes and vials and have self-administration at home, whereas, with the antimony treatment, close supervision of patients is necessary.
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Blethen, Kathryn, Samuel Sprowls, Tasneem Arsiwala, Cullen Wolford, Dhruvi Panchal, Ross Fladeland, Morgan Glass, et al. "BSBM-11 COMBINING IMMUNOTHERAPY AND WHOLE-BRAIN RADIATION THERAPY IN A NOVEL SYNGENEIC LUNG CANCER BRAIN METASTASIS PRECLINICAL MODEL: DOES TIMING OF ADMINISTRATION MATTER?" Neuro-Oncology Advances 5, Supplement_3 (August 1, 2023): iii2—iii3. http://dx.doi.org/10.1093/noajnl/vdad070.007.
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Abstract Approximately 50% of all brain metastasis cases originate from primary lung tumors. Whole-brain radiation therapy (WBRT) is a common treatment for patients with multiple brain metastases, but patients rarely survive longer than one year after diagnosis. Recent studies demonstrate improved outcomes with combinatorial radiotherapy and immunotherapy, but the optimal timing of immunotherapy administration is unclear. Eliciting a robust immune response post-immunotherapy is vital for therapeutic efficacy. Our work shows that the BBB is disrupted and proinflammatory cytokines are increased in the brain 12 hours post-WBRT in immunocompetent but not immunocompromised mice. Additionally, efflux transporter activity is decreased at this time point. This study utilizes a novel Lewis Lung Carcinoma cell line, LLC-Br, which was developed in our laboratory to preferentially metastasize to the brain. Mice were treated with immune checkpoint inhibitors (ICIs) before or after WBRT then we evaluated tumor progression, survival, and blood-tumor barrier (BTB) permeability. We hypothesized administration of ICI following WBRT would increase survival, decrease tumor burden, and increase BTB permeability in our preclinical syngeneic lung cancer brain metastasis model.
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Marté, Jennifer L., Nicole J. Toney, Lisa Cordes, Jeffrey Schlom, Renee N. Donahue, and James L. Gulley. "Early changes in immune cell subsets with corticosteroids in patients with solid tumors: implications for COVID-19 management." Journal for ImmunoTherapy of Cancer 8, no. 2 (November 2020): e001019. http://dx.doi.org/10.1136/jitc-2020-001019.
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BackgroundThe risk–benefit calculation for corticosteroid administration in the management of COVID-19 is complex and urgently requires data to inform the decision. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation associated with poor prognosis in both COVID-19 and cancer. Investigating NLR as an inflammatory marker and lymphocyte levels as a critical component of antiviral immunity may inform the dilemma of reducing toxic hyperinflammation while still maintaining effective antiviral responses.MethodsWe performed a retrospective analysis of NLR, absolute neutrophil counts (ANCs) and absolute lymphocyte counts (ALCs) in patients with cancer enrolled in immunotherapy trials who received moderate-dose to high-dose corticosteroids. We compared paired presteroid and available poststeroid initiation values daily during week 1 and again on day 14 using the Wilcoxon signed-rank test. Associated immune subsets by flow cytometry were included where available.ResultsPatients (n=48) with a variety of solid tumors received prednisone, methylprednisolone, or dexamethasone alone or in combination in doses ranging from 20 to 190 mg/24 hours (prednisone equivalent). The median NLR prior to steroid administration was elevated at 5.0 (range: 0.9–61.2). The corresponding median ANC was 5.1 K/µL (range: 2.03–22.31 K/µL) and ALC was 1.03 K/µL (0.15–2.57 K/µL). One day after steroid administration, there was a significant transient drop in median ALC to 0.54 K/µL (p=0.0243), driving an increase in NLR (median 10.8, p=0.0306). Relative lymphopenia persisted through day 14 but was no longer statistically significant. ANC increased steadily over time, becoming significant at day 4 (median: 7.31 K/µL, p=0.0171) and remaining significantly elevated through day 14. NLR was consistently elevated after steroid initiation, significantly at days 1, 7 (median: 8.2, p=0.0272), and 14 (median: 15.0, p=0.0018). Flow cytometry data from 11 patients showed significant decreases in activated CD4 cells and effector memory CD8 cells.ConclusionsThe early drop in ALC with persistent lymphopenia as well as the prolonged ANC elevation seen in response to corticosteroid administration are similar to trends associated with increased mortality in several coronavirus studies to include the current SARS-CoV-2 pandemic. The affected subsets are essential for effective antiviral immunity. This may have implications for glucocorticoid therapy for COVID-19.
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Ciprandi, Giorgio, Matteo Naso, and Maria Angela Tosca. "Tablet allergen immunotherapy." Allergologia et Immunopathologia 52, no. 3 (May 1, 2024): 73–77. http://dx.doi.org/10.15586/aei.v52i3.990.
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For the first time 15 years ago, tablet allergen immunotherapy (T-AIT) formulations were approved by regulatory agencies for treating allergic rhinitis caused by grass pollen in adults and children aged >5 years. Extensive evidences existed about effectiveness and safety of AIT. However, the safety profile is particularly compelling in children. Generally, T-AIT causes local reactions, mostly in the oral cavity, that are usually mild-to-moderate and often self-resolving. However, systemic allergic reactions are also observed with T-AIT, anaphylaxis representing the most fearsome adverse event, considering that it occurs in subjects treated for allergic rhinitis. Therefore, we conducted a literature search of patients reporting anaphylaxis because of T-AIT. Nine cases of anaphylactic reactions were reported in literature. Notably, no death was reported using T-AIT. This outcome was very important as it underscored the substantial safety of T-AIT. However, T-AIT deserves careful attention, mainly in the pediatric population. In this regard, after the first report of anaphylactic reaction at the first administration of T-AIT, manufacturers recommended that the first dose should be administered in a medical facility in the presence of staff with experience in managing anaphylaxis and the patient should be observed for at least 30 min. Interestingly, reported anaphylactic reactions were due to grass pollen extracts, with no report concerning other allergen extracts. However, it is relevant to note that anaphylactic reactions because of T-AIT are not reported in recent years.
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Leyva-Grado, Victor H., Gene S. Tan, Paul E. Leon, Mark Yondola, and Peter Palese. "Direct Administration in the Respiratory Tract Improves Efficacy of Broadly Neutralizing Anti-Influenza Virus Monoclonal Antibodies." Antimicrobial Agents and Chemotherapy 59, no. 7 (May 4, 2015): 4162–72. http://dx.doi.org/10.1128/aac.00290-15.
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ABSTRACTThe emergence of influenza virus strains resistant to approved neuraminidase inhibitors and the time constrains after infection when these drugs can be effective constitute major drawbacks for this class of drugs. This highlights a critical need to discover new therapeutic agents that can be used for the treatment of influenza virus-infected patients. The use of broadly neutralizing anti-influenza monoclonal antibodies (MAbs) has been sought as an alternative immunotherapy against influenza infection. Here, we tested in mice previously characterized broadly neutralizing anti-hemagglutinin (HA) stalk MAbs prophylactically and therapeutically using different routes of administration. The efficacy of treatment against an influenza H1N1 pandemic virus challenge was compared between two systemic routes of administration, intraperitoneal (i.p.) and intravenous (i.v.), and two local routes, intranasal (i.n.) and aerosol (a.e.). The dose of MAb required for prophylactic protection was reduced by 10-fold in animals treated locally (i.n. or a.e.) compared with those treated systemically (i.p. or i.v.). Improved therapeutic protection was observed in animals treated i.n. on day 5 postinfection (60% survival) compared with those treated via the i.p. route (20% survival). An increase in therapeutic efficacy against other influenza virus subtypes (H5N1) was also observed when a local route of administration was used. Our findings demonstrate that local administration significantly decreases the amount of broadly neutralizing monoclonal antibody required for protection against influenza, which highlights the potential use of MAbs as a therapeutic agent for influenza-associated disease.
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Dolgopolov, I. S., and M. Yu Rykov. "Immunotherapy for children with malignant brain tumors." Russian Journal of Immunology 27, no. 1 (August 6, 2024): 85–94. http://dx.doi.org/10.46235/1028-7221-16566-ifc.
Full textAbstract:
The incidence of high-grade malignant gliomas (MG) ranges from 35 to 46% of all central nervous system tumors. Despite combined therapy including surgery, radiation treatment and chemotherapy, overall five-year survival does not exceed 10%. The advent of novel immunotherapeutic strategies has promoted a renewed hopes for the treatment of MG. The aim of the present study was to improve the survival rates of glioma patients. Our study included 5 pediatric patients at the median age of 7.6 years (2-16). Three pts had anaplastic astrocytoma (AA) (1st relapse, 1 pt; 2nd relapse, in 2 pts), One patient was diagnosed with glioblastoma multiforme (GBM) (3rd recurrence), and 1 child had diffuse brainstem glioma (BSG). The median time to the first relapse was 12 months (4 to 16), the second relapse occurred at a median of 5 months (1 to 8). The protocol of immunotherapy included combined administration of autologous dendritic cell-based vaccine (DV) and repeated intrathecal/intraventricular injections of donor allogeneic immunocompetent cells (alloIC) for at least 2 years. Two of 3 pts with AA experienced a progression-free interval of 67 and 71 months. One patient with 3rd GBM relapse is alive without any treatment for 13.3 years after starting the immunotherapy. The median time of follow-up was 67 months, with the 2-year overall survival rate of 58%. Two pts died from the disease progression within 6 and 7 months from the beginning of immunotherapy. Over the period of treatment, the patients received a median of 20 alloIC injections (8 to 60), and 18 DV administrations (8 to 44). No serious side-effects were observed. Immunotherapy could be an promising option for treating patients with high-grade malignant gliomas refractory to conventional therapy and, therefore, deserves further investigations.
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Fell, William R., Richard L. Mabry, and Cynthia S. Mabry. "Quality of Life Analysis of Patients Undergoing Immunotherapy for Allergic Rhinitis." Ear, Nose & Throat Journal 76, no. 8 (August 1997): 528–36. http://dx.doi.org/10.1177/014556139707600809.
Full textAbstract:
Allergic rhinitis has been conservatively estimated to affect 35 million Americans, with an annual US expenditure of more than $2 billion for treatment. Immunotherapy is generally administered to patients with allergic rhinitis when avoidance is impossible or impractical, when pharmacotherapy provides insufficient relief, and/or symptoms span more than one season. Immunotherapy based on quantified testing (e.g., dilutional intradermal testing [SET] or in vitro methods [RAST, ELISA]) allows administration of antigens in a manner that achieves therapeutic antigen doses more rapidly, yet more safely than immunotherapy administered through a schedule that mixes all antigens at the same concentration and advances on an empirical basis. Sixty patients who received at least one year of quantified testing-based immunotherapy were evaluated using a quality of life questionnaire and individual interviews. Changes in physical, social and emotional well-being were determined. Also investigated were changes in productivity and medication usage. The majority of patients noted significant improvement in all areas within four to six months of initiating immunotherapy, and an overwhelming majority felt that such treatment represented a worthwhile investment of their time and money.
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Poirier, Marie-Denise, Houda Haban, and Abdeljabar El Andaloussi. "A Combination of Systemic and Intracranial Anti-CD25 Immunotherapy Elicits a Long-Time Survival in Murine Model of Glioma." Journal of Oncology 2009 (2009): 1–8. http://dx.doi.org/10.1155/2009/963037.
Full textAbstract:
Abrogating the suppression of glioma-infiltrating Tregs in the periphery and the central nervous system is essential to successful glioma rejection. We sought to improve the immune response in glioma-bearing mice, by investigating new strategies using the anti-CD25 immunotherapy. We found a complete long-term survival of glioma-bearing mice treated with a combination of systemic and intracranial anti-CD25 mAb immunotherapy as compared to systemic administration of anti-CD25 mAb. In addition, the group of mice that had been cured by the combined anti-CD25 mAb showed long-term survival without late tumor relapse when challenged with the GL261 glioma. The antitumor immune response was investigated by analysis of antitumor immune response (CTL). Results showed that the use of the combined injections of anti-CD25 mAb induced efficient targeting of Tregs expansion inside and outside of the brain and altered Tregs trafficking in the bone marrow and brain areas where antitumor immunity was primed.