Modulation of Immune and Anti-Tumor Effects of Cancer Immunotherapy with Anti-Pd-1 Monoclonal Antibodies by the Pineal Hormone Melatonin: Preliminary Clinical Results

2020 ◽  
Author(s):  
Simonetta Tassoni
Keyword(s):  
Monoclonal Antibodies ◽  
Cancer Immunotherapy ◽  
Metastatic Cancer ◽  
Concomitant Administration ◽  
Clinical Results ◽  
Control Group ◽  
High Dose ◽  
Main Question ◽  
Anticancer Properties ◽  
Inflammatory Status

The recent cancer immunotherapy with inhibitors of the expression of PD-1 and its ligands represents one of the most promising strategies in cancer cure. Then, the main question is how to enhance its therapeutic efficacy, which could potentially achieved by its association with chemotherapy, Il-2 immunotherapy, and anti-angiogenic strategies. By taking into consideration that the immune system is physiologically under a neuroendocrine regulation, another possible strategy to enhance the efficacy of cancer immunotherapy could consist of a neuro immune approach, namely by the pineal hormone melatonin (MLT), which at present constitutes the most investigated endogenous neuroendocrine molecule provided by immune stimulatory anticancer properties. On these bases, a study was planned to evaluate the effects of a concomitant administration of high-dose MLT in metastatic cancer patients treated by the anti-PD-1 monoclonal antibody Nivolumab (NIVO). The study included 14 patients, and the results were compared to those observed in a control group of 50 patients. No small cell lung cancer and melanoma were the most frequent tumor histo types. MLT was given orally at 100 mg/day during the dark period of the day, and NIVO was injected i.e. at 3 mg/kg b.w. at 15-day intervals. The percentage of both objective tumor regressions and disease control (DC) were higher in patients concomitantly treated by MLT, even though the only difference in DC was statistically significant. This evidence was associated with a significantly higher increase in lymphocyte-to-monocyte ratio (LMR) in MLT group, by suggesting that MLT may be successfully associated with anti-PD-1 monoclonal antibodies to pilot the immune response in an antitumor way by stimulating lymphocyte proliferation and inhibiting macrophage-induced inflammatory status, which suppresses the antitumor immunity.

Blood Concentrations of Interleukin-15 in Cancer Patients and Their Variations during Interleukin-2 Immunotherapy: Preliminary Considerations

1998 ◽  
Vol 13 (3) ◽  
pp. 169-171 ◽  
Author(s):  
P. Lissoni ◽  
F. Rovelli ◽  
M. Mandalà ◽  
S. Barni
Keyword(s):  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Metastatic Cancer ◽  
Cell Cancer ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Control Group ◽  
Blood Concentrations ◽  
Significant Difference ◽  
Interleukin 15

In addition to the better known cytokines IL-2 and IL-12, IL-15, which is mainly produced by macrophages, is a new antitumor cytokine with a mechanism of action similar to that of IL-2. At present, however, there are no data about IL-15 secretion in cancer patients. This study was carried out to evaluate IL-15 blood concentrations in patients with early or advanced cancer and their possible variations in response to IL-2 cancer immunotherapy. The study included 40 patients with solid tumors, 24 of whom had metastatic disease. In addition, IL-15 secretion was evaluated during subcutaneous low-dose IL-2 therapy (6 million IU/day for 6 days/week for 4 weeks) in 14 metastatic renal cell cancer patients by collecting blood samples at weekly intervals. The control group consisted of 40 age-matched healthy subjects. Serum levels of IL-15 were measured by an enzyme immunoassay. No significant difference in mean serum levels of IL-15 was observed between cancer patients and controls. Moreover, the mean serum levels of IL-15 found in metastatic cancer patients were not significantly different from those found in patients with limited disease. Finally, no significant changes in mean levels of IL-15 occurred during IL-2 cancer immunotherapy. This preliminary study would suggest that IL-15 secretion is substantially within the normal range in cancer patients, both in early and advanced disease, and no variation seems to occur in response to IL-2 administration.

scholarly journals A Phase-2 Study on the Kinetics of the Improvement in Lymphocyte-toMonocyte Ratio by High-Dose Pineal Hormone Melatonin in Lymphocytopenic Untreatable Metastatic Cancer Patients

2019 ◽  
Vol 2 (1) ◽  
pp. 14-19
Author(s):  
Lissoni Paolo ◽  
◽  
Porro Giorgio ◽  
Cenaj Vezika ◽  
Aymerich Tiziana ◽  
...  
Keyword(s):  
Cancer Patients ◽  
T Lymphocyte ◽  
Metastatic Cancer ◽  
Control Group ◽  
High Dose ◽  
Neoplastic Disease ◽  
Monocyte Count ◽  
Mean Values ◽  
T Lymphocyte Proliferation

It is known that lymphocytopenia is one of the most negative biomarkers in cancer patients, being an expression of cancer-related immunosuppression. Today it is known that, despite its complexity, the antitumor immunity is mainly mediated by dendritic cell-T lymphocyte system and suppressed by the macrophage-regulatory T lymphocyte system. Then, lymphocyte-to-monocyte ratio (LMR) has been proven to represent a more appropriate prognostic clinical index than the simple lyphocytopenia alone. Because of the fundamental role of lymphocytes in mediating tumor cell destruction, the correction of cancer-related lymphocytopenia could influence the clinical history of the neoplastic disease. At present, the only cytokine able to induce a clear in vivo lymphocytosisis IL-2. However, it has been demonstrated that the immune system is physiologically under a neuroendocrine control, and that the pineal hormone MLT may stimulate T lymphocyte proliferation and activation. On these bases, we have evaluated the effect of highdose MLT therapy in metastatic solid tumor patients with persistent lymphocytopenia and abnormally low values of LMR. The study included 14 patients, and the results were compared to those found in a control group of 20 lymphocytopenic untreatable metastatic cancer patients treated with the only best supportive care alone. Patients received MLT at a dose of 100 mg/day orally in the evening for 3 consecutive months. Lymphocyte mean count increases on MLT therapy, and the values observed after two months of therapy were significantly higher than the pretreatment ones, with a normalization of lymphocyte number in 4/14 (29%) patients, whereas no spontaneous lymphocyte rise occurred in the control group. On the other hand, monocyte count rapidly diminished on MLT therapy, and LMR mean values observed after only one month of treatment was significantly higher than that found prior to therapy, whereas it significantly decreases in controls. This preliminary study shows that high-dose MLT may improve the immune status of cancer patients, and be effective in the treatment of disseminated cancer-related lymphocytopenia.

scholarly journals Effect of Low and High Dose Sugammadex on the Coagulation and Fibrinolytic System in Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Nilay Taş ◽  
Özgür Yağan ◽  
Tevfik Noyan ◽  
Sema Nur Ayyıldız ◽  
Y. Burcu Üstün ◽  
...  
Keyword(s):  
Dose Group ◽  
Clinical Results ◽  
Fibrinolytic System ◽  
Control Group ◽  
High Dose ◽  
Reversal Agent ◽  
Group Vi ◽  
Group V ◽  
Coagulation Parameters ◽  
Group I

Background. Sugammadex is a new reversal agent that has entered use recently. It is known that with sugammadex some changes in coagulation parameters occur without documented clinical results. Aim of the Work. The objective of this study was to identify effects of sugammadex on liver functions, coagulation, and fibrinolytic systems. Methods. Thirty-six rats were randomized into six groups: Group I, control; Group II, rocuronium group; Group III, sugammadex administered in 16 mg kg−1 dose; Group IV, sugammadex administered in 96 mg kg−1 dose; Group V, rocuronium and sugammadex administered in 16 mg kg−1 dose; and Group VI, rocuronium and sugammadex administered in 96 mg kg−1 dose. After 120 minutes, blood samples were obtained for prothrombin time, activated partial thromboplastin time, D-dimer, fibrinogen, aspartate aminotransferase, alanine aminotransferase, albumin, platelet, and mean platelet volume analyses. Results. Compared to the control group, in all groups measured parameters did not show any effect from a statistical viewpoint either due to the administered drugs alone or due to interaction effects. Conclusion. The conclusion was reached that administration of sugammadex in rats did not have any significant effect on the fibrinolytic system, coagulation parameters, and liver function.

MUC1 antibody-based therapeutics: the promise of cancer immunotherapy

Immunotherapy ◽  
2020 ◽  
Vol 12 (17) ◽  
pp. 1269-1286
Author(s):  
Mona Pourjafar ◽  
Pouria Samadi ◽  
Massoud Saidijam
Keyword(s):  
Monoclonal Antibodies ◽  
Cancer Immunotherapy ◽  
Clinical Results ◽  
Bispecific Antibodies ◽  
High Efficacy ◽  
Cancer Markers ◽  
Crucial Step ◽  
Cancer Antigens ◽  
Tumor Associated Antigen ◽  
Specific Antigens

Antibody-based targeted therapies have been able to target cancers with enhanced specificity and high efficacy. In this regard, identifying cancer markers (antigens) that are only present (tumor-specific antigens) or have an increased expression (tumor-associated antigen) on the surface of cancer cells is a crucial step for targeted cancer treatment. Various cancer antigens have already been used for therapeutic and diagnostic purposes. MUC1 is one of the most important tumor markers with high levels of expression in various solid tumors which makes it as a potential target for antibody-based therapies. This review discusses preclinical and clinical results from various platforms based on monoclonal antibodies, nanobodies as well as bispecific antibodies against MUC1. We also highlight unmet challenges that must be overcome to generate more effective cancer immunotherapy strategies.

Acetaminophen: Neonatal hepatotoxicity due to late pregnancy exposure

1987 ◽  
Vol 45 ◽  
pp. 718-719
Author(s):  
G.A. Miranda ◽  
M.A. Arroyo ◽  
C.A. Lucio ◽  
M. Mongeotti ◽  
S.S. Poolsawat
Keyword(s):  
Low Dose ◽  
Fetal Liver ◽  
Late Pregnancy ◽  
Toxic Chemicals ◽  
Control Group ◽  
High Dose ◽  
Over The Counter ◽  
Liver And Kidney ◽  
Neonatal Liver ◽  
Childbearing Women

Exposure to drugs and toxic chemicals, during late pregnancy, is a common occurrence in childbearing women. Some studies have reported that more than 90% of pregnant women use at least 1 prescription; of this, 60% used more than one. Another study indicated that 80% of the consumed drugs were not prescribed, and of this figure, 95% were “over-the-counter” drugs. Acetaminophen, the safest of all over-the-counter drugs, has been reported to induce fetal liver necrosis in man and animals and to have abortifacient and embryocidal action in mice. This study examines the degree to which acetaminophen affects the neonatal liver and kidney, when a fatty diet is simultaneously fed to the mother during late pregnancy.Timed Swiss Webster female mice were gavaged during late pregnancy (days 16-19) with fat suspended acetaminophen at a high dose, HD = 84.50 mg/kg, and a low dose, LD = 42.25 mg/kg; a control group received fat alone.

Employing Gamma Ray Irradiated Giardia lamblia as Trialed Vaccine in Experimental Animal

2019 ◽  
Vol 9 (02) ◽  
Author(s):  
Amal Kamil Abdul Sada ◽  
Amany Mohamed Al-Kaysi
Keyword(s):  
Giardia Lamblia ◽  
Gamma Ray ◽  
Age Groups ◽  
Active Phase ◽  
Study Groups ◽  
Negative Control ◽  
Control Group ◽  
High Dose ◽  
Histopathological Changes ◽  
Gamma Irradiated

This is an experimental trial to prepare a vaccine from gamma-irradiated Giardia lamblia which is evaluated in experimental animals. The study was conducted from December 2015 to April 2016. The field survey of the parasite was conducted from those patients attending the laboratories of the Alawi Children's Hospital in Rusafa and the Al-Yarmouk Teaching Hospital in Karkh, through which 1250 stool samples of different age groups were examined. Five groups of mice were used in the study; the first was injected with normal saline and considered as a negative control group, the second was injected with cystic form of non-irradiated Giardia lamblia and considered as a positive control group, whereas the other three groups were injected with gamma irradiated Giardia lamblia at three different doses 10, 15 and 25 rad respectively. Giardia lamblia was primarily cultivated in liver infusion agar for ten days to obtain the active phase. On the sixth day, the cystic phase was purified and standardized to be used in the infection of mice with or without the exposure of gamma rays. Mice showed high sensitivity to parasitic infestation, in the gamma non-irradiated and the irradiated with gamma 10 rad, and 15 rad irradiated groups which was 100%. The results expressed an excystation process of the depleted phases and the release of the feeder phases. The results of the three irradiated groups consisted of histopathological changes of the small, and the rectum by dissection after two weeks of infection, with intestine amputation lesions, as well as ulceration and inflammation of the inflammatory cells represented in small numbers of neutrophil, lymphocytes, and eosinophils. The presence of ulceration and fall of epithelial cells in the intestinal cavity has been shown, and different forms of the parasite have been observed. Mice which was injected with irradiated G lamblia at high dose (25 rad), not show and sensitivity to the challenge infection and no excystation of thy parasite had been done. After 2 wreaks, a comparison was achieved between all study groups in which no histopathological changes were noticed in the mice irradiated with dose of25 rad. After another two weeks, a challenge dose was given (un-attenuated G lamblia) and mice were dissected after another two weeks, no changes on the level of histopathology of intestinal tissue were noticed the results suggested that mice acquire an immunity against the parasite infection.

Recombinant adeno-associated virus 9-mediated expression of Kallistatin suppresses lung tumor growth in mice

2020 ◽  
Vol 20 ◽  
Author(s):  
Weihong Qu ◽  
Jianguo Zhao ◽  
Yaqing Wu ◽  
Ruian Xu ◽  
Shaowu Liu
Keyword(s):  
Lung Cancer ◽  
Gene Therapy ◽  
Tumor Growth ◽  
Lung Tumor ◽  
Control Group ◽  
High Dose ◽  
Blank Control Group ◽  
Adeno Associated Virus ◽  
Tumor Tissues ◽  
Subcutaneous Xenograft

Background:: Lung cancer remains the most common cause of cancer-related deaths in China and worldwide. Traditional surgery and chemotherapy do not offer an effective cure although gene therapy may be a promising future alter-native. Kallistatin (Kal) is an endogenous inhibitor of angiogenesis and tumorigenesis. Recombinant adeno-associated virus (rAAV) is considered the most promising vector for gene therapy of many diseases due to persistent and long-term transgen-ic expression. Objective:: The aim of this study was to investigate whether rAAV9-Kal inhibited NCI-H446 subcutaneous xenograft tumor growth in mice. Method:: The subcutaneous xenograft mode were induced by subcutaneous injection of 2×106 H446 cells into the dorsal skin of BALB/c nude mice. The mice were administered with ssrAAV9-Kal (single-stranded rAAV9) or dsrAAV9-Kal (double-stranded rAAV9）by intraperitoneal injection (I.P.). Tumor microvessel density (MVD) was examined by anti-CD34 stain-ing to evaluate tumor angiogenesis. Results:: Compared with the PBS (blank control) group, tumor growth in the high-dose ssrAAV9-Kal group was inhibited by 40% by day 49, and the MVD of tumor tissues was significantly decreased. Conclusion:: The results indicate that this therapeutic strategy is a promising approach for clinical cancer therapy and impli-cate rAAV9-Kal as a candidate for gene therapy of lung cancer.

scholarly journals Low-dose sublingual immunotherapy compared to subcutaneous immunotherapy and conventional therapy in childhood asthma

2016 ◽  
Vol 44 (6) ◽  
pp. 243
Author(s):  
Ariyanto Harsono
Keyword(s):  
Childhood Asthma ◽  
Low Dose ◽  
Sublingual Immunotherapy ◽  
Disease Onset ◽  
Ethics Committee ◽  
Subcutaneous Immunotherapy ◽  
Control Group ◽  
High Dose ◽  
Treat Ment ◽  
Group A

Background Evidence begin to accumulate that high-dose sub-lingual immunotherapy (SLIT) is as effective as subcutaneousimmunotherapy (SIT) in the treatment of childhood asthma.Since the capacity of sublingual area is similar whether the doseis high or low, the efficacy of low dose may be important to bestudied.Objective To investigate the efficacy of low-dose sublingual im-munotherapy in the treatment of childhood asthma.Methods Parents signed informed consent prior to enrollment,after having received information about the study. Patients weremoderate asthma aged 6-14 years with disease onset of lessthan 2 years before the commencement of the study and peakexpiratory flow rate (PEFR) variability of more than 15%. Pa-tients were randomly allocated into group A, B, and C whoreceived subcutaneous immunotherapy, low-dose sublingualimmunotherapy, and conventional asthma therapy, respectively.Randomization was stratified into two strata according to agei.e., 6-11 years or 11-14 years. Patients of each stratum wererandomized in block of three for each group. At the end of threemonths, lung function tests were repeated. The primary outcomewas PEFR variability at the end of the study. The study wasapproved by the Ethics Committee of Soetomo HospitalSurabaya.Results Distribution of variants as represented by sex, age,eosinophil count, and total IgE concentration were normal inthe three groups. PEFR variability decreased significantly from16.97+0.81 to 8.50+5.08 and 17.0+0.87 to 8.40+4.72 in groupreceiving SIT and SLIT, respectively (p<0.05), but decreasednot significantly from 17.00+0.83 to 10.82+0.5.41 in control group(p>0.05).Conclusion Low-dose SLIT is as efficacious as SIT in the treat-ment of moderate asthma in children

274 High-dose medroxyprogesterone acetate (MPA) in metastatic cancer patients

1983 ◽  
Vol 19 ◽  
pp. 91
Author(s):  
P. Schmidt-Rhode ◽  
G. Sturm ◽  
K.-D. Schulz ◽  
H.J. Künzig ◽  
M. Wunsch
Keyword(s):  
Cancer Patients ◽  
Medroxyprogesterone Acetate ◽  
Metastatic Cancer ◽  
High Dose

scholarly journals Study on the Mechanism of Shugan Xiaozhi Fang on Cells with Non-alcoholic Fatty Liver Disease

2019 ◽  
Vol 17 (1) ◽  
pp. 1328-1338
Author(s):  
Yufeng Xing ◽  
Chuantao Zhang ◽  
Fenfen Zhai ◽  
Tianran Zhou ◽  
Xiang Cui ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver Disease ◽  
Dose Group ◽  
Control Group ◽  
High Dose ◽  
Model Group ◽  
Alcoholic Fatty Liver ◽  
Oil Red O Staining ◽  
Alcoholic Fatty Liver Disease ◽  
Oil Red O

AbstractCells with non-alcoholic fatty liver disease (NAFLD) were studied to determine the mechanism of liver deficiency via the AdipoR2-PPARa pathway. NAFLD cells were randomly divided into a normal control group, blank control group, model group, low dose group, medium dose group, and high dose group. The NAFLD models were established by incubating the cells with linoleic acid (LA) and palmitic acid (PA) (2:1) for 24 h. The test groups were incubated with different doses of Shugan Xiaozhi Fang extract. The pathological changes in cells that accumulated lipids were detected by Oil Red O staining. Malondialdehyde (MDA) and triglyceride (TG) levels were measured. The apoptosis of cells was evaluated by flow cytometry. The levels of AdipoR2, PPARa, CD36, acyl-CoA mRNA, and protein were confirmed by RT- PCR and Western blot. The results of the Oil Red O staining demonstrated that the NAFLD cell model was successfully established. Compared with the model group, the levels of TG and MDA in the groups that received low, medium, and high doses of Shugan Xiaozhi were significantly lower (P<0.01), and a dose effect was evident. In addition, the expression of AdipoR2, PPARa, CD36, acyl-CoA protein, and mRNA in the Shugan Xiaozhi-treated groups was upregulated. Furthermore, the levels of AdipoR2, PPAR, CD36, acyl-CoA protein, and mRNA in all drug treatment groups that were extracted from L-O2 normal human hepatocytes were significantly upregulated (P<0.01). Moreover, the factor pattern of HepG2 human liver carcinoma cells was similar to that of L-O2. The levels of AdipoR, CD36, acyl-CoA, and AdipoR mRNA in the HepG2 low group were increased (P<0.05). AdipoR, PPAR, CD36, and acyl-CoA protein levels and AdipoR mRNA expression were significantly increased in the intermediate dose group and high dose group (P<0.01). Shugan Xiaozhi Fang attenuates hepatic lipid deposition in NAFLD induced by incubating with LA and PA for 24 h, which is associated with the activation of the AdipoR2-PPARα pathway.

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