Notes

Possibility involving deuterium magnet resonance spectroscopy of 3-O-Methylglucose in 6 Tesla.
specially second-line immunotherapy consideration.Objective To review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases. Methods We systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and "breastmilk," "breast milk," "breastfeeding," or "lactation." From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria. One additional study was added after the literature search based on expert knowledge of an additional article. These 30 studies were reviewed. These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women. Results Drug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion. Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 120 for infliximab. Relative infant dose, a metric comparing the infant with maternal drug dose ( less then 10% is generally considered safe), was evaluated for certolizumab ( less then 1%), rituximab ( less then 1%), and natalizumab (maximum of 5.3%; cumulative effects of monthly dosing are anticipated). Importantly, a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections. Conclusions The current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development.Background Tumor ablation techniques, like cryoablation, are successfully used in the clinic to treat tumors. The tumor debris remaining in situ after ablation is a major antigen depot, including neoantigens, which are presented by dendritic cells (DCs) in the draining lymph nodes to induce tumor-specific CD8+ T cells. We have previously shown that co-administration of adjuvants is essential to evoke strong in vivo antitumor immunity and the induction of long-term memory. However, which adjuvants most effectively combine with in situ tumor ablation remains unclear. Methods and results Here, we show that simultaneous administration of cytidyl guanosyl (CpG) with saponin-based adjuvants following cryoablation affects multifunctional T-cell numbers and interleukin (IL)-1 induced polymorphonuclear neutrophil recruitment in the tumor draining lymph nodes, relative to either adjuvant alone. The combination of CpG and saponin-based adjuvants induces potent DC maturation (mainly CpG-mediated), antigen cross-presentation (mainly saponin-based adjuvant mediated), while excretion of IL-1β by DCs in vitro depends on the presence of both adjuvants. Most strikingly, CpG/saponin-based adjuvant exposed DCs potentiate antigen-specific T-cell proliferation resulting in multipotent T cells with increased capacity to produce interferon (IFN)γ, IL-2 and tumor necrosis factor-α in vitro. Also in vivo the CpG/saponin-based adjuvant combination plus cryoablation increased the numbers of tumor-specific CD8+ T cells showing enhanced IFNγ production as compared with single adjuvant treatments. Conclusions Collectively, these data indicate that co-injection of CpG with saponin-based adjuvants after cryoablation induces an increased amount of tumor-specific multifunctional T cells. The combination of saponin-based adjuvants with toll-like receptor 9 adjuvant CpG in a cryoablative setting therefore represents a promising in situ vaccination strategy.Background Interleukin-15 (IL-15) promotes growth and activation of cytotoxic CD8+ T and natural killer (NK) cells. Bioactive IL-15 is produced in the body as a heterodimeric cytokine, comprising the IL-15 and IL-15 receptor alpha chains (hetIL-15). Several preclinical models support the antitumor activity of hetIL-15 promoting its application in clinical trials. Methods The antitumor activity of hetIL-15 produced from mammalian cells was tested in mouse tumor models (MC38 colon carcinoma and TC-1 epithelial carcinoma). The functional diversity of the immune infiltrate and the cytokine/chemokine network within the tumor was evaluated by flow cytometry, multicolor immunohistochemistry (IHC), gene expression profiling by Nanostring Technologies, and protein analysis by electrochemiluminescence and ELISA assays. Results hetIL-15 treatment resulted in delayed primary tumor growth. Increased NK and CD8+ T cell tumoral infiltration with an increased CD8+/Treg ratio were found by flow cytometry and IHC in hetIL-15 t incorporation of hetIL-15 in tumor immunotherapy approaches to promote the development of antitumor responses by favoring effector over regulatory cells and by promoting lymphocyte and DC localization into tumors through the modification of the tumor chemokine and cytokine milieu.Background A minority of patients with advanced non-small-cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Ineffective effector function of activated T and NK cells may lead to reduced tumor cell death, even when these activated effector cells are released from their immune checkpoint brake. Hence, in this study we aimed to assess the association of baseline serum granzyme B, as well as germline variation of the GZMB gene, with clinical outcome to programmed cell death protein 1 (PD-1) blockade. Methods A total of 347 patients with stage IV NSCLC who started nivolumab treatment between June 2013 and June 2017 were prospectively included. selleck compound Baseline serum and whole blood was available, allowing for protein quantification and targeted DNA sequencing. Clinical outcome was based on best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors, V.1.1, progression-free survival (PFS), and overall survival (OS). Results Patients with low serum levels of granzyme B had worse PFS (HR 1.96; 95% CI 1.12 to 3.43; p=0.018) and worse OS (HR 2.08; 95% CI 1.12 to 3.87; p=0.021) than patients with high baseline serum levels. To validate the findings, germline variation of GZMB rs8192917 was assessed. Patients with homozygous and heterozygous variants of GZMB rs8192917 had worse BOR (OR 1.60; 95% CI 1.01 to 2.52; p=0.044) and worse PFS (HR 1.38; 95% CI1.02 to 1.87; p=0.036) than wild types. Conclusions A low baseline serum level of granzyme B and germline variation of GZMB was associated with worse clinical outcome in NSCLC, emphasizing the relevance and additional value of monitoring germline genetic variations which mirror cytotoxic functions of T cells in ICI therapy. Trail registration number Dutch Trial Registry (NL6828).Background Patients with biliary tract cancer (BTC) have poor prognosis with few treatment options. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-βRII receptor (a TGF-β 'trap') fused to a human IgG1 antibody blocking programmed death ligand 1 (PD-L1), has shown clinical efficacy in multiple solid tumors. Methods In this phase I, open-label trial expansion cohort, Asian patients with BTC whose disease progressed after first-line chemotherapy received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint is safety/tolerability, while the secondary endpoints include best overall response per Response Evaluation Criteria in Solid Tumors version 1.1. Results As of August 24, 2018, 30 patients have received bintrafusp alfa for a median of 8.9 (IQR 5.7-32.1) weeks; 3 patients remained on treatment for >59.7 weeks. Nineteen (63%) patients experienced treatmgation in patients with BTC (NCT03833661 and NCT04066491). Trial registration number NCT02699515.Background There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors. Methods A total of 80 cases of HGSC were analyzed in this study. Whole exome and RNA sequencing was performed for these tumors. Methylation arrays were also carried out to examine BRCA1 and RAD51C promoter methylation status. Mutations, neoantigen load, antigen presentation machinery, and local immune profile were investigated, and the relationships of these factors with clinical outcome were also analyzed. Results As expected, the numbers of predicted neoAgs were lower in HR-proficient (n=46) than HR-deficient tumors (n=34). However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs and better survival than patients with lower numbers of neoAgs. Incorporation of human leukocyte antigen (HLA)-class I expression status into the survival analysis revealed that patients with both high neoAg numbers and high HLA-class I expression (neoAghiHLAhi) had the best progression-free survival (PFS) in HR-proficient HGSC (p=0.0087). Gene set enrichment analysis demonstrated that the genes for effector memory CD8 T cells, TH1 T cells, the interferon-γ response, and other immune-related genes, were enriched in these patients. Interestingly, this subset of patients also had better PFS (p=0.0015) and a more T-cell-inflamed tumor phenotype than patients with the same phenotype (neoAghiHLAhi) in HR-deficient HGSC. Conclusions Our results suggest that immune checkpoint inhibitors might be an alternative to explore in HR-proficient cases which currently do not benefit from PARP inhibition.Background Radioimmunotherapy has a promising antitumor effect in hepatocellular carcinoma (HCC), depending on the regulatory effect of radiotherapy on tumor immune microenvironment. Ionizing radiation (IR)-induced DNA damage repair (DDR) pathway activation leads to the inhibition of immune microenvironment, thus impairing the antitumor effect of radioimmunotherapy. However, it is unclear whether inhibition of the DDR pathway can enhance the effect of radioimmunotherapy. In this study, we aim to explore the role of DDR inhibitor AZD6738 on the combination of radiotherapy and immune checkpoint inhibitors (ICIs) in HCC. Methods C57BL/6 mouse subcutaneous tumor model was used to evaluate the ability of different treatment regimens in tumor growth control and tumor recurrence inhibition. Effects of each treatment regimen on the alterations of immunophenotypes including the quantification, activation, proliferating ability, exhaustion marker expression, and memory status were assessed by flow cytometry. Results AZivation of cyclic GMP-AMP synthase /stimulator of interferon genes (cGAS/STING) signaling pathway. Furthermore, triple therapy led to stronger immunologic memory and lasting antitumor immunity than radioimmunotherapy, thus preventing tumor recurrence in mouse models. Conclusions Our findings indicate that AZD6738 might be a potential synergistic treatment for radioimmunotherapy to control the proliferation of HCC cells, prolong survival, and prevent tumor recurrence in patients with HCC by improving the immune microenvironment.
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