interacts_with DB06186?
VIPhyb , an antagonist of vasoactive intestinal peptide receptor , enhances cellular antiviral immunity in murine cytomegalovirus infected mice . Vasoactive intestinal peptide ( P01282 ) is a neuropeptide hormone that suppresses Th1-mediated cellular immunity . We previously reported that P01282 -knockout ( P01282 -KO ) mice have enhanced cellular immune responses and increased survival following murine cytomegalovirus ( mCMV ) infection in C57BL/6 mice . In this study , we tested whether treatment with a P01282 receptor antagonistic peptide protects C57BL/6 and BALB/c mice from mCMV-infection . One week of daily subcutaneous injections of VIPhyb was non-toxic and did not alter frequencies of immune cell subsets in non-infected mice . VIPhyb administration to mCMV-infected C57BL/6 and BALB/c mice markedly enhanced survival , viral clearance , and reduced liver and lung pathology compared with saline-treated controls . The numbers of effector/memory CD8+ T-cells and mature NK cells were increased in VIPhyb-treated mice compared with PBS-treated groups . Pharmacological blockade of P01282 -receptor binding or genetic blockade of P01282 -signaling prevented the up-regulation of Q9NZQ7 and P18621 expression on DC and activated CD8+ T-cells , respectively , in mCMV-infected mice , and enhanced P33681 , P42081 , and MHC-II expression on conventional and plasmacytoid DC . VIPhyb-treatment increased type-I IFN synthesis , numbers of IFN-γ- and P01375 -α-expressing NK cells and T-cells , and the numbers of mCMV-M45 epitope-peptide-MHC-I tetramer CD8+ T-cells following mCMV infection . P01282 -treatment lowered the percentage of Treg cells in spleens compared with PBS-treated WT mice following mCMV infection , while significantly decreasing levels of serum P15692 induced by mCMV-infection . The mice in all treated groups exhibited similar levels of anti-mCMV antibody titers . Short-term administration of a P01282 -receptor antagonist represents a novel approach to enhance innate and adaptive cellular immunity in a murine model of CMV infection . DB06186 in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer : results from a randomized , double-blind , multicenter phase 2 trial . BACKGROUND : DB06186 , an anti- P16410 monoclonal antibody , demonstrated survival benefit in melanoma with immune-related ( ir ) adverse events ( irAEs ) managed by the protocol-defined guidelines . This phase 2 study evaluated ipilimumab+paclitaxel ( DB01229 ) /carboplatin in extensive-disease-small-cell lung cancer ( ED-SCLC ) . DESIGN : Patients ( n=130 ) with chemotherapy-naïve ED-SCLC were randomized 1 : 1 : 1 to receive paclitaxel ( 175 mg/m2 ) /carboplatin ( area under the curve=6 ) with either placebo ( control ) or ipilimumab 10 mg/kg in two alternative regimens , concurrent ipilimumab ( ipilimumab+paclitaxel/carboplatin followed by placebo+paclitaxel/carboplatin ) or phased ipilimumab ( placebo+paclitaxel/carboplatin followed by ipilimumab+paclitaxel/carboplatin ) . Treatment was administered every 3 weeks for a maximum of 18 weeks ( induction ) , followed by maintenance ipilimumab or placebo every 12 weeks . End points included progression-free survival ( PFS ) , irPFS , best overall response rate ( BORR ) ; irBORR , overall survival ( OS ) , and safety . RESULTS : Phased ipilimumab , but not concurrent ipilimumab , improved irPFS versus control [ HR ( hazard ratio ) =0.64 ; P=0.03 ] . No improvement in PFS ( HR=0.93 ; P=0.37 ) or OS ( HR=0.75 ; P=0.13 ) occurred . Phased ipilimumab , concurrent ipilimumab and control , respectively , were associated with median irPFS of 6.4 , 5.7 and 5.3 months ; median PFS of 5.2 , 3.9 and 5.2 months ; median OS of 12.9 , 9.1 and 9.9 months . Overall rates of grade 3/4 irAEs were 17 , 21 and 9 % for phased ipilimumab , concurrent ipilimumab and control , respectively . CONCLUSION : These results suggest further investigation of ipilimumab in ED-SCLC . Phase 2 trial of single agent DB06186 ( anti- P16410 ) for locally advanced or metastatic pancreatic adenocarcinoma . New , effective therapies are needed for pancreatic ductal adenocarcinoma . DB06186 can mediate an immunologic tumor regression in other histologies . This phase II trial evaluated the efficacy of DB06186 for advanced pancreatic cancer . Subjects were adults with locally advanced or metastatic pancreas adenocarcinoma with measurable disease , good performance status , and minimal comorbidities . DB06186 was administered intravenously ( 3.0 mg/kg every 3 wk ; 4 doses/course ) for a maximum of 2 courses . Response rate by response evaluation criteria in solid tumors criteria and toxicity were measured . Twenty-seven subjects were enrolled ( metastatic disease : 20 and locally advanced : 7 ) with median age of 55 years ( 27 to 68 y ) and good performance status ( 26 with Eastern Cooperative Oncology Group performance status =0 to 1 ) . Three subjects experienced ≥ grade 3 immune-mediated adverse events ( colitis:1 , encephalitis:1 , hypohysitis:1 ) . There were no responders by response evaluation criteria in solid tumors criteria but a subject experienced a delayed response after initial progressive disease . In this subject , new metastases after 2 doses of DB06186 established progressive disease . But continued administration of the agent per protocol resulted in significant delayed regression of the primary lesion and 20 hepatic metastases . This was reflected in tumor markers normalization , and clinically significant improvement of performance status . Single agent DB06186 at 3.0 mg/kg/dose is ineffective for the treatment of advanced pancreas cancer . However , a significant delayed response in one subject of this trial suggests that immunotherapeutic approaches to pancreas cancer deserve further exploration . Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . DB01656 , a phosphodiesterase (PDE)4-selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up-regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA-Cβ phosphorylates p65 in a DB02527 -dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor . DB06186 administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection : a multicenter , retrospective case series . DB06186 is a fully human , monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 ( P16410 ) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma . DB06186 is associated with potentially serious immune-related adverse events , including autoimmune hepatitis . Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection , there is a paucity of data on the safety of ipilimumab administration to that patient population . Here , we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma . Two of the nine patients described in this case series experienced fluctuations in their liver function tests ( LFTs ) and were subsequently treated with corticosteroids . Although this is a small series , the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab , and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection . The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options . Immune Checkpoint Blockade in Cancer Therapy . Immunologic checkpoint blockade with antibodies that target cytotoxic T lymphocyte-associated antigen 4 ( P16410 ) and the programmed cell death protein 1 pathway ( P18621 / Q9NZQ7 ) have demonstrated promise in a variety of malignancies . DB06186 ( P16410 ) and pembrolizumab ( P18621 ) are approved by the US Food and Drug Administration for the treatment of advanced melanoma , and additional regulatory approvals are expected across the oncologic spectrum for a variety of other agents that target these pathways . Treatment with both P16410 and P18621 / Q9NZQ7 blockade is associated with a unique pattern of adverse events called immune-related adverse events , and occasionally , unusual kinetics of tumor response are seen . Combination approaches involving P16410 and P18621 / Q9NZQ7 blockade are being investigated to determine whether they enhance the efficacy of either approach alone . Principles learned during the development of P16410 and P18621 / Q9NZQ7 approaches will likely be used as new immunologic checkpoint blocking antibodies begin clinical investigation . Review : anti- P16410 antibody ipilimumab : case studies of clinical response and immune-related adverse events . The immune system is a powerful natural agent against cancer . Cytotoxic T lymphocyte antigen 4 ( P16410 ) , a key negative regulator of T-cell responses , can restrict the antitumor immune response . DB06186 ( DB06186 ) is a fully human , monoclonal antibody that overcomes P16410 -mediated T-cell suppression to enhance the immune response against tumors . Preclinical and early clinical studies of patients with advanced melanoma show that ipilimumab promotes antitumor activity as monotherapy and in combination with treatments such as chemotherapy , vaccines , or cytokines . Emerging data on the kinetics of response to ipilimumab and associated adverse events are increasing our understanding about how to manage patients treated with this therapy . For example , short-term tumor progression prior to delayed regression has been observed in ipilimumab-treated patients , and objective responses may be of prolonged duration . In some patients clinical improvement manifests as stable disease , which may also extend for months or years . Immune-related adverse events ( IRAEs ) have been observed in patients after P16410 blockade and most likely reflect the drug mechanism of action and corresponding effects on the immune system . Early clinical data suggest a correlation between IRAEs and response to ipilimumab treatment . This paper briefly reviews the results from several ongoing and completed ipilimumab clinical trials , provides a synopsis of current trials , and presents several cases that demonstrate the kinetics of antitumor responses and the relationship to IRAEs in patients receiving ipilimumab . DB01016 -induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 (M1289T) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 -sensitive K+ channel ( K( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta-cells or beta-cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea-induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 (M1289T) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase-3-like activity , we observed a Q09428 -specific enhancement of glibenclamide-induced apoptosis that was not seen in SUR2B , Q09428 (M1289T) , or control cells . Coexpression with the pore-forming Kir6.2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 (M1289T) , renders cells more susceptible to glibenclamide-induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta-cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 -mediated apoptosis . This effect does not require the presence of functional Kir6.2-containing K( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 . Differential expression and function of phosphodiesterase 4 ( DB05876 ) subtypes in human primary P01730 + T cells : predominant role of Q08499 . Type 4 phosphodiesterases ( DB05876 ) are critical regulators in TCR signaling by attenuating the negative constraint of DB02527 . In this study , we show that anti-CD3/ P10747 stimulation of human primary P01730 (+) T cells increases the expression of the DB05876 subtypes P27815 , Q07343 , and Q08499 in a specific and time-dependent manner . P27815 and Q08499 mRNAs as well as enzyme activities were up-regulated within 5 days , Q07343 showed a transient up-regulation with highest levels after 24 h . The induction was shown to be independent of different stimulation conditions and was similar in naive and memory T cell subpopulations . To elucidate the functional impact of individual DB05876 subtypes on T cell function , we used DB05876 subtype-specific short-interfering RNAs ( siRNAs ) . Knockdown of either Q07343 or Q08499 inhibited P60568 release 24 h after stimulation ( time point of maximal P60568 concentrations ) to an extent similar to that observed with the panPDE4 inhibitor RP73401 ( piclamilast ) . Substantial amounts of P01579 or P05113 were measured only at later time points . siRNA targeting Q08499 showed a predominant inhibitory effect on these cytokines measured after 72 h . However , the inhibition of all cytokines was most effective when DB05876 siRNAs were applied in combination . Although the effect of DB05876 inhibition on T cell proliferation is small , the Q08499 -targeting siRNA alone was as effective as the panPDE4 inhibitor , whereas P27815 or Q07343 siRNAs had hardly an effect . In summary , individual DB05876 subtypes have overall nonredundant , but complementary , time-dependent roles in propagating various T cell functions and Q08499 is the form likely playing a predominant role . Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti-inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( DB00605 ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U.S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers . DB06186 -induced acute severe colitis treated by infliximab . DB06186 ( anti- P16410 antibody ) is a new tool for the treatment of metastatic melanoma patients that has led to an improvement in survival rates worldwide . New types of toxicities have been described with ipilimumab called ' immune-related adverse events ' or irAEs . Here , we report an acute and steroid resistant case of ipilimumab-induced colitis treated with infliximab in a melanoma stage IV AJCC patient . The patient presented with acute grade 3 diarrhea after the second perfusion of ipilimumab . After the administration of intravenous steroids , the patient continued to have grade 2 diarrhea with erythematous mucous with several ulceration sites on rectosigmoidoscopy . DB00065 perfusion ( 5 mg/kg ) was performed and resulted in resolution of symptoms within 2 days with complete healing was observed by rectal sigmoidoscopy on day 7 . After failure of two further lines of chemotherapy , the patient died 10 months after the diagnosis of stage IVM1C melanoma . Treatment algorithms exist for the management of these digestive adverse events ; however , some points remain unclear . No predictive marker for the occurrence of this digestive toxicity has been validated to date . Modes of administration of steroids and dosage are not clearly defined , except in cases of acute abdomen ; surgery is difficult to propose for patients with a poor prognosis . DB00065 is another option for the treatment of steroid-resistant ipilimumab-induced colitis but its use in metastatic melanoma raises questions of its possible impact on the evolution of cancer . We reviewed at least 19 cases published of infliximab administration for ipilimumab-mediated colitis . Unfortunately , tolerance and cancer evolution have scarcely been reported . Thus , because more patients are being treated with P16410 blockade , management of ipilimumab-induced colitis requires further studies . Expression of cyclooxygenase-2 ( P35354 ) in tumour and stroma compartments in cervical cancer : clinical implications . This study aims at investigating the relationship between cyclooxygenase-2 expression in tumour vs stroma inflammatory compartment and its possible clinical role . The study included 99 stage IB-IV cervical cancer patients : immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase-2 . CD3 , P01730 , CD8 , CD25 , Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours . An inverse relation was found between cyclooxygenase-2 levels ( cyclooxygenase-2 IDV ) of tumour vs stroma compartment ( r=-0.44 , P < 0.0001 ) . The percentage of cases showing high tumour/stromal cyclooxygenase-2 IDV ratio was significantly higher in patients who did not respond to treatment ( 93.3 % ) with respect to patients with partial ( 60.5 % ) , and complete ( 43.7 % ) response ( P= 0.009 ) . Cases with a high tumour/stroma cyclooxygenase-2 IDV ratio had a shorter overall survival rate than cases with a low tumour/stroma cyclooxygenase-2 IDV ( P < 0.0001 ) . In the multivariate analysis advanced stage and the status of tumour/stroma cyclooxygenase-2 IDV ratio retained an independent negative prognostic role . The proportion of CD3(+) , P01730 (+) , and CD25(+) cells was significantly lower in tumours with high tumour/stroma cyclooxygenase-2 IDV ratio , while a higher percentage of mast cells was detected in tumours showing high tumour/stroma cyclooxygenase-2 IDV ratio . Our study showed the usefulness of assessing cyclooxygenase-2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis . P16410 blockade by a human MAb enhances the capacity of AML-derived DC to induce T-cell responses against AML cells in an autologous culture system . BACKGROUND : Cells from AML patients can differentiate into the phenotype of DC when cultured with GM- P04141 and P05112 . Such cytokine-treated AML-derived DC ( AML-DC ) can stimulate autologous T cells . In this study we examined whether an anti- P16410 MAb ( DB06186 ) could enhance the generation of autologous anti-AML T cells . METHODS : MAb DB06186 was added to AML PBMC cultures in the presence of GM- P04141 and P05112 , a previously reported AML-DC culture method of generating anti-AML T cells . T-cell activation and proliferation were examined thereafter . RESULTS : Addition of DB06186 to GM- P04141 / P05112 -conditioned AML-DC cultures induced a mean seven-fold increase in the numbers of autologous T cells compared with cultures without DB06186 ( P < 0.007 ) . T cells stimulated by AML-DC with P16410 blockade were significantly more cytotoxic towards autologous AML cells than those without DB06186 ( 42 +/- 23 % vs. 26 +/- 15 % , E:T ratio of 20 ) . T cells stimulated by AML-DC with P16410 blockade had significantly greater proportions of T cells producing P01579 in response to autologous AML cells than those cultured with AML-DC alone ( 10.7 +/- 4.7 % vs. 4.5 +/- 2.4 % for P01730 + P01579 + Q07108 + and 9.8 +/- 4.1 % vs. 4 +/- 2.1 % for CD8+ P01579 + Q07108 + with or without DB06186 ; n = 7 ; P < 0.007 , P < 0.003 , respectively ) . DISCUSSION : P16410 blockade enhances the activity and numbers of AML-reactive T cells that can be stimulated by autologous AML-DC and may enhance the efficacy of adoptive immunotherapy of AML . Sulfonylureas inhibit cytokine-induced eosinophil survival and activation . Eosinophils play a key role in the pathogenesis of asthma and other allergic inflammatory diseases . We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits P05113 -induced survival . This inhibition can not be overcome by increasing concentrations of P05113 and is not due to the blocking of Na+ channels by lidocaine . Here we report that one class of K+ channel blockers , the sulfonylureas , inhibits eosinophil survival in a manner similar to lidocaine . The sulfonylurea glyburide inhibits eosinophil survival even at high concentrations of P05113 . In contrast , increasing concentrations of P08700 or granulocyte-macrophage P04141 overcome glyburide inhibition . Glyburide also blocks cytokine-induced eosinophil superoxide production . Similar results were seen with the sulfonylureas tolbutamide and glipizide . Interestingly , the effects of glyburide are not antagonized by the DB00171 -sensitive K+ channel openers cromakalim , pinacidil , or diazoxide . Although Scatchard analysis of [3H]glyburide binding to eosinophil membranes indicated that the high affinity sulfonylurea receptor ( Q09428 ) is not present on eosinophils , human eosinophils do express mRNA homologous to the sulfonylurea receptor family , in keeping with the presence of a sulfonylurea receptor . Finally , coculture of eosinophils with combinations of glyburide , lidocaine , and dexamethasone resulted in synergistic inhibition of cytokine-mediated eosinophil survival and superoxide production . These results have intriguing clinical implications for the treatment of eosinophil-associated diseases . Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors . We have recently shown that the mu-opioid receptor [ P35372 , also termed mu-opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid-specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co-expressing P35372 and O14939 , treatment with ( D-Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C-terminal splice variant of the mu-opioid receptor ( MOR1D , also termed MOP(1D) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist-independent ( constitutive ) O14939 -activation facilitating agonist-induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over-expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta-opioid receptor [ Q8IXH6 , also termed delta-opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 -dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist-dependent and agonist-independent G protein-coupled receptor ( GPCR ) endocytosis . Intracellular capture of P33681 in antigen-presenting cells reduces costimulatory activity . P16410 gene constructs were designed to express P16410 exclusively in the endoplasmic reticulum ( ER ) . Four different P16410 gene constructs were transfected into P29320 293 ( human embryonic kidney ) and A20 ( Balb/c mouse B lymphoma ) cells . All constructs contained an ER retention signal and coded for P16410 expression in the ER . One of the constructs , which contained the membrane part of P16410 , coded for an expression both on the cell surface and in the ER . Three of the expressed P16410 types ( including the ER-membrane-expressed form ) caused a reduced surface expression of P33681 in the A20 cells . Only constructs which allow dimerization of P16410 showed this effect . It is assumed that intracellular P16410 bound P33681 and inhibited therefore the transport of P33681 to the surface . The binding obviously caused also an enhanced degradation of the complexes because both proteins showed a low concentration in the transfected cell lines . P16410 -transfected and P33681 -reduced A20 cells showed a diminished costimulating activity upon T cells . This was demonstrated by a reduced proliferation of T cells from ovalbumin-immunized Balb/c mice , incubated with ovalbumin peptide-primed P16410 -transfected A20 cells . Single-center experience with ipilimumab in an expanded access program for patients with pretreated advanced melanoma . DB06186 , a P16410 -blocking monoclonal antibody , improved the overall survival ( OS ) of advanced melanoma patients treated in prospective clinical trials . We here report a study on the outcome of patients with pretreated advanced melanoma offered ipilimumab ( at its licensed dose of 3 mg/kg , every 3 wk for a total of 4 doses ) in an expanded access program at a single-center university hospital . Of the 50 patients initiating ipilimumab , 31 patients completed induction therapy and 9 patients were offered reinduction therapy . Most immune-related adverse events were mild and reversible . The best objective response rate by mWHO-criteria included 1 complete response and 4 partial responses ( best objective response rate of 10 % ) . Two additional patients obtained a partial response by immune-related response criteria . Median OS was 7 months , with a 1- and 2-year survival rate of 45.2 % and 28.8 % , respectively . Long-term disease control with ipilimumab was observed in 7 patients of which 4 received reinduction . Baseline serum P02741 ( CRP ) and the absolute lymphocyte count ( ALC ) measured on week 6 significantly correlated with OS . In conclusion , in this single-center experience with ipilimumab for advanced pretreated melanoma patients , clinical outcome was comparable with the results of published prospective studies . Reinduction therapy was of importance for maintaining long-term disease control in the majority of responding patients . Baseline CRP and ALC at week 6 deserve further prospective evaluation as prognostic and/or predictive ( surrogate ) markers . New-onset mediastinal and central nervous system sarcoidosis in a patient with metastatic melanoma undergoing P16410 monoclonal antibody treatment . BACKGROUND : DB06186 , a cytotoxic monoclonal antibody that inhibits cytotoxic T lymphocyte-associated antigen-4 ( P16410 ) , has been established as an effective therapy in the management of advanced melanoma . Immune-mediated adverse events are a common side effect . CASE REPORT : A 37-year-old male patient was diagnosed with nodal and osseous metastatic melanoma 15 months after the initial surgical treatment for lower limb melanoma . Therapy with the anti- P16410 antibody , ipilimumab , was started . Follow-up staging imaging after treatment initiation showed symmetrical bihilar adenopathy . Transbronchial biopsy showed sarcoidosis . The patient had associated systemic symptoms of fatigue , joint pains , anorexia and weight loss . Brain magnetic resonance imaging ( Q9BWK5 ) , which was performed for the investigation of headaches , showed abnormal enhancing tissue in the sella turcica and adjacent to the pituitary infundibulum , consistent with neurosarcoidosis . The condition was successfully treated with corticosteroids . CONCLUSIONS : We report a case of immunotherapy-induced mediastinal/hilar sarcoidosis , with pituitary involvement , mimicking tumour progression . This highlights the need for awareness amongst radiologists and oncologists of the mechanism of action and potential side effects of new immunotherapies . Chemical coding of the human gastrointestinal nervous system : cholinergic , VIPergic , and catecholaminergic phenotypes . The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal ( GI ) tract . For this purpose , antibodies against the vesicular monoamine transporters ( P54219 /2 ) , the vesicular acetylcholine transporter ( Q16572 ) , tyrosine hydroxylase ( TH ) , dopamine beta-hydroxylase ( P09172 ) , serotonin ( 5-HT ) , vasoactive intestinal peptide ( P01282 ) , and protein gene product 9.5 ( P09936 ) were used . For in situ hybridization (35)S-labeled P54219 , Q05940 , and Q16572 riboprobes were used . In all regions of the human GI tract , 50-70 % of the neurons were cholinergic , as judged by staining for Q16572 . The human gut unlike the rodent gut exhibits a cholinergic innervation , which is characterized by an extensive overlap with VIPergic innervation . Neurons containing Q05940 constituted 14-20 % of all intrinsic neurons in the upper GI tract , and there was an equal number of TH-positive neurons . In contrast , P09172 was absent from intrinsic neurons . Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes . In conclusion , the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species , but also significant differences . P01282 is a cholinergic cotransmitter in the intrinsic innervation of the human gut . The substantial overlap between Q05940 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life . The absence of P09172 from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype . [ Molecular-target therapy for advanced malignant melanoma ] . Malignant melanoma is insensitive to chemotherapy , and standard therapy for metastatic melanoma has been dacarbazine for years . Molecular abnormalities of malignant melanoma , mainly of Q96HU1 kinase signals such as P15056 mutation , have been clarified , and molecular target therapy for melanoma has been developed recently . DB08881 , an inhibitor for mutated P15056 , has shown its efficacy for the first time , with response rate of more than 50 % , and an overall improvement in survival compared with dacarbazine in a phase III study . Skin toxicities including squamous cell carcinoma , are the most severe adverse events . Another P15056 inhibitor , dabrafenib , and a MEK inhibitor , trametinib , have shown excellent efficacy in clinical studies . Melanoma also has high immunogenicity , and cytokines or cell immunotherapy have shown some efficacy . Recently , the importance of immune checkpoints which adjust T-cell activation , such as the cytotoxic T-lymphocyte-associated antigen 4 ( P16410 ) , - P33681 or the programmed cell death protein-1(PD1)-PD1 ligand( Q9NZQ7 ) , have been clarified . Targeting those immune checkpoints is expected to be effective for enhancing tumor immunity . P16410 antibody ipilimumab has been reported to improve overall survival in two phase III studies . Major adverse events were autoimmune response such as colitis , eruption , liver dysfunction and endocrineopathies . Antibodies to PD1 or Q9NZQ7 have shown a higher response rate than those of ipilimumab , and seem to accompany fewer autoimmune responses in phase I studies . These two types of targeting therapy are expected to be standard therapies for melanoma . Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels . Vasoactive intestinal peptide ( P01282 ) is a potent anti-inflammatory neuropeptide that , by inhibiting Th1-driven responses and inducing the emergence of regulatory T cells ( T(reg) ) , has been proven successful in the induction of tolerance in various experimental models of autoimmune disorders . Here , we investigate the molecular mechanisms involved in P01282 -induced tolerance . P01282 treatment in the presence of T-cell receptor ( TCR ) signaling and P10747 costimulation induced cell cycle arrest in human T cells . P01282 blocked G(1)/S transition and inhibited the synthesis of cyclins D3 and E and the activation of the cyclin-dependent kinases ( CDKs ) cdk2 and cdk4 . This effect was accompanied by maintenance of threshold levels of the CDK inhibitor p27(kip1) and impairment of phosphatidylinositol 3-kinase ( PI3K ) -Akt signaling . Inhibition of interleukin 2 ( P60568 ) transcription and downregulation of signaling through NFAT , AP-1 , and Ras-Raf paralleled the P01282 -induced cell cycle arrest . Noteworthy from a functional point of view is the fact that P01282 -treated T cells show a regulatory phenotype characterized by high expression of CD25 , cytotoxic-T-lymphocyte-associated protein 4 ( P16410 ) , and Forkhead box protein 3 ( FoxP3 ) and potent suppressive activities against effector T cells . P16410 appears to be critically involved in the generation and suppressive activities of P01282 -induced T(reg) . Finally , cyclic AMP ( DB02527 ) and protein kinase A ( PKA ) activation seems to mediate the P01282 -induced cell cycle arrest and T(reg) generation . Hypophysitis caused by ipilimumab in cancer patients : hormone replacement or immunosuppressive therapy . DB06186 is besides the P15056 inhibitor vemurafenib the first officially approved medical treatment for metastatic melanoma , which results in improved survival . DB06186 leads to a release of a P16410 -mediated inhibition of T-cell immunoreactions . Therefore , patients may also suffer from immune-related adverse events affecting different organs , which are typically treated by high-dose corticosteroids . DB06186 -induced hypophysitis ( iH ) has been reported in up to 17 % of melanoma patients in clinical trials.Here we present 5 patients with metastatic melanoma and 2 patients with prostate cancer who developed hypophysitis after ipilimumab therapy . Patients were treated by high-dose corticosteroid therapy resulting in the resolution of local inflammation but not of pituitary deficiencies . Partial or complete hypopituitarism remained in all patients . Pharmacotherapy with high-dose corticosteroids caused complications in 5 patients , necessitating hospitalization in 4 . 2 of the 3 patients with progressive disease died , while 3 patients had stable disease and 1 patient showed tumor regression after discontinuation of ipilimumab.In summary , with regard to safety and simplicity of hormonal substitution therapy we have to scrutinize high-dose corticosteroid therapy , though it only improves inflammation but not neuro-endocrine function and may cause further morbidity . Regression of the tumor depends on the ipilimumab-mediated immune events , in which high-dose and long-term corticosteroid therapy for iH appears to be counter-intuitive . Herein , we discuss screening and the diagnostic as well as therapeutic management of iH in metastatic cancer patients from an endocrinologic perspective . [ Endocrinologic side effects of oncologic treatment with anti- P16410 -antibodies ] . New immune-modulating treatments like the anti- P16410 -antibodies-based therapies are increasingly used in medical oncology . The action of DB06186 , a monoclonal anti- P16410 -antibody used for the treatment of metastasized melanoma and other solid tumors , is well documented . Blocking the P16410 -receptors on lymphocytes leads to T-cell activation and hence reduction of the tumor-mediated immunotolerance . This mechanism constitutes the basis of the antiproliferative effects but is also responsible for a spectrum of specific adverse events ( immune-related adverse events , IRAE ) . IRAE of the endocrine system comprise hypophysitis , thyroiditis and adrenalitis . Especially adrenal insufficiency can be fatal when not diagnosed and treated . Symptoms often are unspecific and early diagnosis and targeted treatment are crucial . We present a case report and summarize - based upon the current literature - the diagnosis and treatment of endocrinologic IRAEs . A Patient with HIV Treated with DB06186 and Stereotactic Radiosurgery for Melanoma Metastases to the Brain . Cancers , such as melanoma , that are associated with immune deficiencies are a major cause of morbidity and mortality in HIV-infected patients . Once patients develop melanoma metastases to the brain , treatment is often limited to palliative surgery and/or radiation . DB06186 , a P16410 antagonist , has been shown to improve the median survival of patients with metastatic melanoma . However , available data regarding the safety and efficacy of ipilimumab in HIV-infected patients who develop intracranial melanoma metastases is limited . Here we report our experience administering ipilimumab to a patient with HIV-AIDS who developed multiple intracranial melanoma metastases . Following treatment , our patient showed improvement in systemic tumor control without any apparent interference with antiretroviral treatment . Gene transfer of GM- P04141 , P33681 and CD154 cDNA enhances survival in a murine model of acute leukemia with persistence of a minimal residual disease . Gene transfer of various cytokines and co-stimulatory molecules has been reported to induce a potent antileukemic immunity in murine models , however , the relative efficiency and possible synergistic effects between candidate genes have not been extensively investigated . We analyzed in a murine model of P11274 / P00519 acute leukemia whether gene transfer of CD154 , P33681 or GM- P04141 as a single agent or combination of CD154 + GM- P04141 , P33681 + CD154 and GM- P04141 + P33681 in leukemic cells could enhance survival . We observed that CD154 gene transfer induced a marked inhibition of leukemogenicity , and also that CD154 and combination of GM- P04141 and P33681 gene transfer protected mice against subsequent challenge with leukemic cells and had a therapeutic effect for a pre-established leukemia disease . We also found minimal residual leukemic disease by RT-PCR for 6 to 12 months in 0 to 25 % of animals injected with transduced leukemic cells and surviving the challenge without evidence of disease , except in the control empty plasmid group where very few mice survived the challenge but all of those were positive by RT-PCR . These findings suggest that leukemic cell vaccination by gene transfer can induce a tumor dormancy phenomenon compatible with long-term survival . Advances in immunotherapy of chronic myeloid leukemia CML . Tyrosine kinase inhibitors induce sustained disease remissions in chronic myeloid leukemia by exploiting the addiction of this type of leukemia to the activity of the fusion oncogene P11274 - P00519 . However , these agents fail to eradicate CML stem cells which are ultimately responsible for disease relapses upon treatment discontinuation . Evidence that the immune system can effectively reject CML stem cells potentially leading to patient cure is provided by the experience with patients receiving allogeneic bone marrow transplantations . Compelling evidence indicates that more modern , antigen-specific immunotherapeutic approaches are also feasible and hold strong potential to be clinically effective . Amongst these , particularly promising is the use of autologous dendritic cells pulsed with antigens or direct application of in vitro transcribed RNA encoding for leukemia-associated antigens , since this approach allows to circumvent HLA-restriction of the leukemia-associated T cell epitopes that have been eventually identified . Combining these strategies with monoclonal antibodies , such as anti- P16410 or anti- P18621 , may help to obtain even stronger immune responses and better clinical results . This narrative review addresses this topic by focusing in particular on the cell-based immunotherapeutic strategies for CML and on the issue of the leukemia-associated antigens to be selected for targeting . [ Current status and prospects of immunotherapy for castration-resistant prostate cancer ] . Surgery , radiation and chemotherapy are three major therapies for cancer . But now , hope is being gathered in immunotherapy as a treatment for fourth . Immunotherapy has been done than before , but they are non-specific immunotherapy . Those that have become hot topics are specific immunotherapies targeting certain molecules or antigens . In this chapter , current status and prospects of immunotherapy for castration-resistant prostate cancer ( CRPC ) are described . As concrete examples , Sipuleucel-T(Provenge) , GVAX , PROSTVAC-VF , DB06186 ( anti- P16410 mAb ) , anti- P18621 mAb and anti- Q04609 mAb are cited . As a result , it is not obtained results which therapy also satisfactory at present . Because of its uncertainties we are in the developmental stages of this therapy and improved outcomes might be achievable . DB06186 augments antitumor activity of bispecific antibody-armed T cells . BACKGROUND : DB06186 is an antagonistic monoclonal antibody against cytotoxic T-lymphocyte antigen-4 ( P16410 ) that enhances antitumor immunity by inhibiting immunosuppressive activity of regulatory T cells ( Treg ) . In this study , we investigated whether inhibiting Treg activity with ipilimumab during ex vivo T cell expansion could augment anti-CD3-driven T cell proliferation and enhance bispecific antibody ( BiAb ) -redirected antitumor cytotoxicity of activated T cells ( ATC ) . METHODS : PBMC from healthy individuals were stimulated with anti-CD3 monoclonal antibody with or without ipilimumab and expanded for 10-14 days . ATC were harvested and armed with anti-CD3 x anti- P00533 BiAb ( EGFRBi ) or anti-CD3 x anti- P11836 BiAb ( CD20Bi ) to test for redirected cytotoxicity against COLO356/FG pancreatic cancer cell line or Burkitt 's lymphoma cell line ( Daudi ) . RESULTS : In PBMC from healthy individuals , the addition of ipilimumab at the initiation of culture significantly enhanced T cell proliferation ( p = 0.0029 ) . ATC grown in the presence of ipilimumab showed significantly increased mean tumor-specific cytotoxicity at effector:target ( E:T ) ratio of 25:1 directed at COLO356/FG and Daudi by 37.71 % ( p < 0.0004 ) and 27.5 % ( p < 0.0004 ) , respectively , and increased the secretion of chemokines ( P13500 , P10147 , P13236 , P13501 , Q07325 , and granulocyte-macrophage colony stimulating factor(GM- P04141 ) ) and cytokines ( IFN-γ , IL-2R , IL-12 , and P35225 ) , while reducing P22301 secretion . CONCLUSIONS : Expansion of ATC in the presence of ipilimumab significantly improves not only the T cell proliferation but it also enhances cytokine secretion and the specific cytotoxicity of T cells armed with bispecific antibodies . A DNA vaccine against cytotoxic T-lymphocyte associated antigen-4 ( P16410 ) prevents tumor growth . Co-stimulatory signaling pathway triggered by the binding of P33681 .1/ P33681 .2 ( P33681 /86 ) of antigen-presenting cells ( APCs ) to P10747 of T cells is required for optimal T-cell activation . Cytotoxic T lymphocyte-associated antigen-4 ( P16410 ) is a negative regulator of T cell activation , which competes with P10747 for P33681 .1/ P33681 .2 binding with a greater affinity . DB06186 , a monoclonal antibody against P16410 , has shown positive efficacy in a pivotal clinical trial for the treatment of metastatic melanoma and was approved by FDA . However , the cost of monoclonal antibody-based therapeutics might limit the number of patients treated . To develop a novel therapeutics specifically targeting P16410 , we constructed a DNA vaccine by cloning the sequence of P16410 fused with a transmembrane domain sequence of placental alkaline phosphatase ( PLAP ) into a mammalian expression plasmid , pVAC-1 . Immunization with the resulting construct , pVAC-1-hCTLA-4 , elicited antibody specific to human P16410 with cross reactivity to murine P16410 , which was sufficient for inhibiting B16F10 tumor growth in c57BL/6 mice in the absence of measurable toxicity . Coupling liposome with pVAC-1-mCTLA-4 could break tolerance to self-antigen in BALB/c mice and induce potent immunity against murine P16410 , and suppress growth of subcutaneous renal cell carcinoma ( Renca ) . New therapeutical strategies in the treatment of metastatic disease . Metastatic melanoma is a very aggressive cancer . For decades , although dacarbazine has been the standard of care as first-line therapy , new therapies have now been shown their superiority either alone or in association with dacarbazine . DB06186 ( anti- P16410 monoclonal antibody ) and vemurafenib ( P15056 V600E inhibitor ) have been recently approved by the Food and Drugs Association and European Medicine Agency for their use in metastatic melanoma patients . Other compounds targeting the Q96HU1 kinase pathway ( anti-MEK , anti- P29323 , other anti- P15056 ) are under clinical evaluation as well as molecules targeting alternate pathways . Along with the development of these targeted agents , an initial molecular characterization of each patient melanoma has become the first step to define the best therapeutic options . The recent published data shed the light on advanced melanoma management . Herein we review the latest development of these molecules and their impact on the treatment strategy . Phosphodiesterase 4B2 is the predominant phosphodiesterase species and undergoes differential regulation of gene expression in human monocytes and neutrophils . The type 4 phosphodiesterase ( DB05876 ) is the predominant PDE isozyme in various leukocytes and plays a key role in the regulation of inflammatory cell activation . There are four DB05876 subtypes ( A , B , C , and D ) , and within each subtype , there are multiple variants . Very recently , we found in monocytes that Q07343 gene expression is selectively induced by lipopolysaccharide ( LPS ) and that the induction is inhibited by interleukin ( IL ) -10 and P05112 . In this study , we show that the Q07343 gene is constitutively expressed in neutrophils and that this expression remains unaffected by LPS or P22301 . Q07343 is the predominant subtype in neutrophils and in unstimulated or LPS-stimulated monocytes , and in these cells , the PDE4B2 variant is the only detectable molecular species of Q07343 . Therefore , PDE4B2 is the predominant PDE isoform in human neutrophils and monocytes , and its expression is regulated differently by these two cell types . Furthermore , leukocytes are the most dominant source of PDE4B2 , suggesting that PDE4B2 is a relatively specific target for discovering anti-inflammatory drugs . Organizing pneumonia as a side effect of ipilimumab treatment of melanoma . DB06186 is one of the newly developed human monoclonal antibodies used in the treatment of metastatic melanoma . Its primary mechanism of action is a specific blockade of cytotoxic T-lymphocyte-associated antigen 4 ( P16410 ) , a T-cell receptor responsible for inhibition of lymphocyte activation . By blocking P16410 , ipilimumab enhances immune responses against tumor cells , but also exposes normal tissues to an increased risk of autoimmune phenomena as a potential side effect . In this report , we describe the case of a 58-year-old woman with metastatic melanoma who was treated with ipilimumab in the weeks prior to the onset of severe nonresolving dyspnea and cough . Extensive workup revealed organizing pneumonia as the cause of her hypoxemic respiratory failure and treatment with steroids led to a resolution of her pulmonary disease . To our knowledge , this is the first report of pulmonary toxicity caused by ipilimumab , which manifested on pathology as organizing pneumonia . Immune-mediated adverse events associated with ipilimumab ctla-4 blockade therapy : the underlying mechanisms and clinical management . Immunomodulation with the anti- P16410 monoclonal antibody ipilimumab has been shown to extend overall survival ( OS ) in previously treated and treatment-naive patients with unresectable stage III or IV melanoma . Blockade of P16410 signaling with ipilimumab prolongs T-cell activation and restores T-cell proliferation , thus amplifying T-cell-mediated immunity and the patient 's capacity to mount an effective antitumor immune response . While this immunostimulation has unprecedented OS benefits in the melanoma setting , it can also result in immune-mediated effects on various organ systems , leading to immune-related adverse events ( irAEs ) . DB06186 -associated irAEs are common and typically low grade and manageable , but can also be serious and life threatening . The skin and gastrointestinal tract are most frequently affected , while hepatic , endocrine , and neurologic events are less common . With proper management , most irAEs resolve within a relatively short time , with a predictable resolution pattern . Prompt and appropriate management of these irAEs is essential and treatment guidelines have been developed to assist oncologists and their teams . Implementation of these irAE management algorithms will help ensure that patients are able to benefit from ipilimumab therapy with adequate control of toxicities . DB01016 exerts an antitumor activity through reactive oxygen species-c-jun NH2-terminal kinase pathway in human gastric cancer cell line MGC-803 . DB01016 , a blocker of DB00171 -sensitive potassium ( K( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC-803 cells expressed the K( DB00171 ) channels composed of Kir6.2 and Q09428 subunits . DB01016 induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC-803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91(phox) expression and superoxide anion ( O2- ) generation , and caused mitochondrial respiration dysfunction in MGC-803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . DB01016 could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis-inducing factor ( O95831 ) , and activation of c-jun NH2-terminal kinase ( JNK ) in MGC-803 cells . Pretreatment with antioxidant N-acetyl-l-cysteine ( Q9C000 ) prevented glibenclamide-induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild-type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC-803 cells by activating ROS-dependent , JNK-driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer . Investigation of the binding of isoform-selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform-selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time-resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped-flow kinetic studies reveal that the rate of quenching is limited by a first-order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange . Immunotherapy for metastatic melanoma . Melanoma has traditionally been considered an immunogenic tumor . A number of approaches have been studied for enhancement of antitumor immunity . The first cytokine approved for the treatment of metastatic melanoma , interleukin-2 , has resulted in prolonged responses in a small subset of patients , providing hope that immunotherapy might be useful for this disease . DB06186 , a monoclonal antibody to P16410 , was recently approved and a number of other promising investigational approaches are currently being pursued . This manuscript discusses more recent advances in the treatment of melanoma employing a variety of immune-enhancing approaches . DB00877 induces Q8NHJ6 (high) Q8N423 (high) dendritic cells promoting a new immunoregulatory pathway . Q8NHJ6 (high) Q8N423 (high) dendritic cells ( DCs ) may cause anergy in P01730 (+)CD45RO(+)CD25(+) T cells transforming them into regulatory T cells ( Tregs ) . Here , we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients . Forty renal transplant patients with biopsy-proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction . At conversion and 2 years thereafter , we measured the rapamycin effects on circulating DCs ( BDCA1/ Q8WTT0 and Q8NHJ6 / Q8N423 expression ) , P01730 (+)/CD25(high)/Foxp3(+) Tregs , CD8(+)/ P10747 (-) T cells , and the Th1/Th2 balance in graft biopsies . In rapamycin-treated patients , peripheral Q8WTT0 (+) cells were significantly increased along with Q8NHJ6 / Q8N423 (+) DCs . The number of circulating P01730 (+)/CD25(high)/Foxp3(+)/ P16410 (+) Tregs , CD8(+) P10747 (-) T cells , and P17693 serum levels were higher in the rapamycin-treated group . The number of Q8NHJ6 / Q8N423 (+) Q8WTT0 (+) DC was directly and significantly correlated with circulating Tregs and CD8(+) P10747 (-) T cells . Q8NHJ6 / Q8N423 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin-treated patients . Thus , rapamycin induces the upregulation of Q8NHJ6 and Q8N423 on the DC surface , and this effect is associated with an increase in the number of Tregs and expansion of the CD8(+) P10747 (-) T cell population . This suggests that P42345 inhibition may promote a novel immunoregulatory pathway . The monoclonal antibody to cytotoxic T lymphocyte antigen 4 , ipilimumab , in the treatment of melanoma . BACKGROUND : Cytotoxic T lymphocyte antigen 4 ( P16410 ) is an inhibitory regulator of the T-cell immune response against tumor cells . DB06186 is a monoclonal antibody directed against P16410 . OBJECTIVE : This review describes the basic mechanism of ipilimumab and discusses data available to date with regards to its safety and efficacy profile . METHODS : Data from clinical trials including abstracts was reviewed using the PubMed Database , as well as the American Society of Clinical Oncology Abstract Database . CONCLUSION : P16410 inhibition with a monoclonal antibody is usually well tolerated and has efficacy as a therapeutic agent in a variety of cancers . The classical response interpretation has changed because of the delayed mechanism of action . The toxicities are autoimmune events and guidelines for treatment of these effects are discussed . Therapy with ipilimumab leads to durable responses . The first two Phase III randomized studies showed an improvement of survival at 1 , 2 , and 3 years . Other studies are currently underway to better understand the optimal treatment administration of ipilimumab in melanoma . Novel anti-melanoma immunotherapies : disarming tumor escape mechanisms . The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth . However , continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system . Here , we focus on metastatic melanoma , a highly immunogenic tumor , and on anti-melanoma immunotherapies , which recently , especially following the FDA approval of DB06186 , gained interest from drug development companies . We describe new immunomodulatory approaches currently in the development pipeline , focus on the novel P13688 immune checkpoint , and compare its potential to the extensively described targets , P16410 and PD1 . This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular , medical , and business angles . Immune modulation for cancer therapy . BACKGROUND : Immune modulation in cancer refers to a range of treatments aimed at harnessing a patient 's immune system to achieve tumour control , stabilisation , and potential eradication of disease . A novel therapeutic drug class called immune checkpoint-blocking antibodies modulate T-cell pathways that regulate T cells and have the potential to reinvigorate an antitumour immune response . DB06186 was the first FDA-approved immune checkpoint antibody licensed for the treatment of metastatic melanoma ( MM ) and blocks a checkpoint molecule called cytotoxic T-lymphocyte antigen 4 ( P16410 ) . METHODS : Herein we review the preclinical and clinical development of ipilimumab . We outline the mode of action of these agents and other immune checkpoint inhibitors , the management of their toxicities , and how to adequately assess response to treatment . RESULTS : As a result of these data , a number of other antibodies that block novel checkpoint molecules including programmed death-1 ( P18621 ) , and corresponding ligands such as programmed death ligand-1 ( Q9NZQ7 ) are under preclinical and clinical development , and have demonstrated activity in multiple tumour types . CONCLUSIONS : This review will summarise the mechanism of action and clinical development of immune checkpoint antibodies , as well as lessons learned in the management and assessment of patients receiving these agents . Regulation of P33681 .1 costimulatory molecule is mediated by the IFN regulatory factor-7 through the activation of JNK in lipopolysaccharide-stimulated human monocytic cells . The engagement of P10747 or P16410 with P33681 .1 provides the essential second costimulatory signal that regulates the development of immune responses , including T cell activation , differentiation , and induction of peripheral tolerance . The signaling molecules and the transcription factors involved in P33681 .1 regulation are poorly understood . In this study we investigated the role of MAPKs in the regulation of LPS-induced P33681 .1 expression in human monocytes and the promonocytic THP-1 cells . Our results show that LPS-induced P33681 .1 expression in monocytic cells did not involve the activation of either p38 or ERKs . Using the JNK-specific inhibitor SP600125 , small interfering RNAs specific for P45983 and P45984 , and agents such as dexamethasone that inhibit JNK activation , we determined that LPS-induced P33681 .1 expression was regulated by JNK MAPK in both monocytes and THP-1 cells . In addition , we identified a distinct P33681 .1-responsive element corresponding to the IFN regulatory factor-7 ( Q92985 ) binding site in the P33681 .1 promoter responsible for the regulation of LPS-induced P33681 .1 transcription . Furthermore , SP600125 and dexamethasone inhibited LPS-induced Q92985 activity . Taken together , these results suggest that LPS-induced P33681 .1 transcription in human monocytic cells may be regulated by JNK-mediated activation of the Q92985 transcription factor . P16410 polymorphisms and P48444 . 5-Hydroxytryptamine induces cyclooxygenase-2 in rat vascular smooth muscle cells : Mechanisms involving Src , PKC and MAPK activation [ corrected ] . Considering the importance of 5-hydroxytryptamine ( 5-HT ) and cyclooxygenase ( P36551 ) products in vascular pathology , we investigated the effects of 5-HT on P36551 expression in rat vascular smooth muscle cells ( VSMCs ) , and to provide mechanistic insights into these effects . VSMCs were enzymatically isolated from aortic media of Wistar rats . Incubation of VSMCs with 5-HT for 24h stimulated prostaglandin I(2) production , but this stimulation was completely suppressed by NS-398 , a selective P35354 inhibitor . 5-HT induced transient P35354 , but not P23219 , protein and mRNA expression in concentration- and time-dependent manners . This effect of 5-HT was completely inhibited by sarpogrelate , a 5-HT(2A) receptor antagonist . 5-HT-induced P35354 expression was markedly blunted by Ca(2+) depletion ; GF 109203X , a protein kinase C ( PKC ) inhibitor ; Q99463 , an inhibitor of Src-family tyrosine kinase ( Src ) ; PD 98059 , an inhibitor of extracellular signal-regulated kinase ( P29323 ) activation ; SB 203580 , an inhibitor of p38 mitogen-activated protein kinase ( MAPK ) ; and SP 600125 , an inhibitor of c-Jun N-terminal kinase ( JNK ) . 5-HT activated P29323 and p38 MAPK , followed by JNK activation . Q99463 inhibited these activations , while GF 109203X inhibited only JNK activation . Furthermore , PD 98059 inhibited JNK activation . These results suggest that 5-HT induces P35354 expression in rat VSMCs , and that PKC , Src , and MAPK activation are each essential for the full expression of P35354 pathways . DB06186 : an anti- P16410 antibody for metastatic melanoma . DB06186 ( DB06186 , Yervoy ; Bristol-Myers Squibb ) , a fully human monoclonal antibody against CTL antigen 4 ( P16410 ) , was recently approved by the U.S . Food and Drug Administration ( FDA ) for the treatment of metastatic melanoma . In both early- and late-phase trials , ipilimumab has shown consistent activity against melanoma . For example , in a randomized phase III trial that enrolled patients with previously treated metastatic disease , ipilimumab , with or without a peptide vaccine , improved overall survival : Median overall survival was 10.1 and 10.0 months in the ipilimumab and ipilimumab plus vaccine arms , respectively , versus 6.4 months in the vaccine-alone group ( hazard ratio , 0.68 ; P ≤ 0.003 ) . Serious ( grade 3-5 ) immune-related adverse events occurred in 10 % to 15 % of patients . Thus , although it provides a clear survival benefit , ipilimumab administration requires careful patient monitoring and sometimes necessitates treatment with immune-suppressive therapy . Here , we review the mechanism of action , preclinical data , and multiple clinical trials that led to FDA approval of ipilimumab for metastatic melanoma . Irritable bowel syndrome : methods , mechanisms , and pathophysiology . Genetic epidemiology and pharmacogenetics in irritable bowel syndrome . The objectives of this review are twofold . Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome ( IBS ) . Specific examples of the associations of genetic variation and symptoms , syndromes , and intermediate phenotypes , including neurotransmitter ( serotonergic , α(2)-adrenergic , and cannabinoid ) mechanisms , inflammatory pathways ( P22301 , TNFα , GNβ3 , and susceptibility loci involved in Crohn 's disease ) , and bile acid metabolism , are explored . The second objective is to review pharmacogenetics in IBS , with the focus on cytochrome P-450 metabolism of drugs used in IBS , modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine ( 5-HT ) transporter-linked polymorphic region ( 5-HTTLPR ) and 5-HT(3) genetic variants , responses to a nonselective cannabinoid agonist ( dronabinol ) based on cannabinoid receptor ( P21554 ) and fatty acid amide hydrolase ( FAAH ) variation , and responses to a bile acid ( sodium chenodeoxycholate ) and bile acid binding ( colesevelam ) based on klothoβ ( Q86Z14 ) and fibroblast growth factor receptor 4 ( P22455 ) variation . Overall , there is limited evidence of a genetic association with IBS ; the most frequently studied association is with 5-HTTLPR , and the most replicated association is with P01375 superfamily member 15 . Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials , and confirmation in large clinical trials using validated clinical end points is still required . No published genome-wide association studies in functional gastrointestinal or motility disorders have been published . [ Major therapeutic advances in the treatment of metastatic melanoma ] . The treatment of metastatic melanoma is presently in complete revolution . Two molecules have recently been authorized for this indication . These treatments have a very different mechanism of action compared to previous chemotherapies . DB08881 is a targeted therapy , which blocks P15056 selectively . This molecule induces objective responses in more than 50 % of the patients with V600E mutated melanoma and a benefit in terms of overall survival . However , many patients relapse after about 6 to 8 months of treatment . Many mechanisms are evoked to explain these secondary resistances to therapy . DB06186 is an immunotherapy that blocks P16410 , a physiological brake of lymphocyte activation . With ipilimumab , the objective responses are less frequent than with vemurafenib but are more prolonged over time . Two phases III have demonstrated that ipilimumab treatment is effective on the overall survival of patients with metastatic melanoma . New combination therapies and additional targeted and immunotherapy agents are exciting perspectives that make us more optimistic for the future of metastatic melanoma treatment . Synergism between bosutinib ( DB06616 ) and the Chk1 inhibitor ( PF-00477736 ) in highly imatinib-resistant P11274 /ABL⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib-resistant cells , including those with the T315I mutation . Bosutinib blocked PF-00477736-induced P27361 /2 activation and sharply increased apoptosis in association with Mcl-1 inhibition , p34(cdc2) dephosphorylation , BimEL up-regulation , and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF-0047736 lethality . Bosutinib/PF-00477736 co-treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL . DB06186 : unleashing the power of the immune system through P16410 blockade . Malignant melanoma is rising faster in incidence than any other malignancy . Long-term remission or " cure " is rare and is almost exclusively limited to therapies that stimulate an immune antitumor response . DB06186 is a novel targeted human immunostimulatory monoclonal antibody that blocks cytotoxic T-lymphocyte antigen4 ( P16410 ) , an immune-inhibitory site expressed on activated T cells . DB06186 is well tolerated as an outpatient infusion therapy . Multiple studies have confirmed significant antimelanoma activity . A randomized trial has documented a survival benefit when ipilimumab was compared to a gp-100 vaccine only arm . The unique mechanism of action of ipilimumab makes assessment of response by conventional criteria difficult . Benefit from ipilimumab can occur after what would be considered progression with World Health Oganization ( WHO ) or Response Evaluation Criteria in Solid Tumors ( RECIST ) criteria . New immune response criteria have been proposed . Therapeutic responses peak between 12 and 24 weeks , with slow responses continuing up to and beyond 12 months . The major drug- related adverse side effects ( 10 % -15 % grade 3 or above ) are immune-related and consist most commonly of rash , colitis , hypophysitis , thyroiditis , and hepatitis . Colonic perforation can occur and patients with diarrhea have to be monitored carefully with strict adherence to treatment algorithms . Algorithms for the treatment of other adverse side effects have been developed . The treatment of immune-related side effects with immunosuppressive agents , such as corticosteroids , does not appear to impair antitumor response . With proper monitoring and management of side effects , ipilimumab is an extremely safe drug to administer . The benefits of ipilimumab will most certainly extend to other malignancies in the near future . DB06186 -induced orbital inflammation resembling Graves disease with subsequent development of systemic hyperthyroidism from P16410 receptor suppression . AM2389 , a high-affinity , in vivo potent P21554 -receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( DB00486 (®) ) . OBJECTIVE : To characterize the novel , high-affinity cannabinoid receptor 1 ( CB(1)R ) HHC-ligand AM2389 [ 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol in two rodent pre-clinical assays . MATERIALS AND METHODS : CB(1)R mediation of AM2389-induced hypothermia in mice was evaluated with AM251 , a CB(1)R-selective antagonist/inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0.18 and 0.56 mg/kg ) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1 % saccharin/water . Generalization/substitution tests were conducted with AM2389 , AM5983 , and Δ(9)-tetrahydrocannabinol ( Δ(9)-THC ) . RESULTS : Δ(9)-THC (30 mg/kg)-induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0.1 and 0.3 mg/kg ) . AM251 ( 3 and 10 mg/kg ) attenuated/blocked hypothermia induced by 0.3 mg/kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ(9)-THC with ED(50) values of 0.0025 , 0.0571 , and 0.2635 mg/kg , respectively , in the low-dose condition . The corresponding ED(50) values in the high-dose condition were 0.0069 , 0.1246 , and 0.8438 mg/kg , respectively . Onset of the effects of AM2389 was slow with a protracted time-course ; the functional , perceptual in vivo half-life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation . Human lung fibroblasts increase P01730 (+)CD25(+)Foxp3(+) T cells in co-cultured P01730 (+) lymphocytes . Aim of this study was to evaluate functional modifications induced by human lung fibroblasts in co-cultured P01730 (+) T lymphocytes . P01730 (+) T cells , resting or stimulated with ionomycin/PMA for 6h , were co-cultured with fibroblasts isolated from pulmonary biopsies , in contact or separated by a semi-permeable membrane . The expression of CD25 , P16410 , TGF-β , IFNγ , P60568 , P05112 , P22301 and Foxp3 was evaluated by flow cytometric analysis . Fibroblasts induced a significant increment in CD25(+) cells in co-cultured activated P01730 (+) T lymphocytes separated by a membrane . Moreover , fibroblasts treatment with a P35354 inhibitor abrogated the increment in CD25(+) cells whereas exogenous DB00917 restored it . The CD25(+) subpopulation was characterized by increased presence of Fox- P09131 , P16410 , P22301 and TGF-β positive cells while IFN-γ and P60568 positive cells were diminished . Proliferative response of P01730 (+) to the anti CD3/ P10747 -Abs was abrogated in P01730 (+) co-cultured with fibroblasts thus demonstrating a suppressive feature of the expanded CD25(+) subpopulation . Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation . DB06186 is a first-in-class immunological checkpoint blockade agent and monoclonal antibody against Cytotoxic T-Lymphocyte Antigen 4 ( P16410 ) that has demonstrated survival benefit and durable responses in patients with metastatic melanoma . To date , solid organ transplant recipients have been excluded from clinical trials with cancer immunotherapies on the basis of their concurrent treatment with immunosuppressive agents . We present the first case to our knowledge of a patient with advanced cutaneous melanoma receiving ipilimumab status post orthotopic liver transplantation with a partial response . Transaminitis was observed 4 months after administration of ipilimumab that resolved with close observation . No evidence of graft rejection has been observed to date . This case advocates for further investigation of the safety and efficacy of cancer immunotherapies in solid organ transplant recipients . [ DB00988 -beta-hydroxylaseaktivität im Plasma von Dialysepatienten ( author 's transl ) ] . Plasma dopamin-b-hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50.0 +/- 29.3 IU . There was was no significant difference between males ( 53.9 +/1 33.8 IU ) and females ( 47.4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0.01 ) decreased ( 32.5 % /- 17.6 IU ) , suggesting lowered sympathetic activity and/or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients . Update on immune checkpoint inhibitors in lung cancer . BACKGROUND : The immune checkpoint proteins , including the P33681 / P10747 receptor superfamily , have become increasingly important targets for pharmacologic blockade . Several classes of new agents have impressive clinical activity , and their eventual approval for treatment of lung cancer seems likely . METHODS : This article discusses the current development of these agents , including the P16410 , P18621 , and Q9NZQ7 inhibitory pathways , killer immunoglobulin receptor ( P55040 ) inhibition , and other checkpoint proteins . RESULTS : DB06186 in combination with chemotherapy has exhibited encouraging results in small-cell and non-small-cell lung cancer alike . Reported phase I trials of the monoclonal antibodies nivolumab , MK-3475 , MEDI4736 , and MPDL3280A are demonstrating durable overall radiological response rates in the 20 % to 25 % range in lung cancer . This exceptional activity includes squamous lung cancers , a population historically bereft of significant therapeutic advances . Retrospective examination of tumor Q9NZQ7 expression suggests that Q9NZQ7 may eventually be evaluable as a predictive biomarker . Dual checkpoint blockade strategies , such as those combining anti- P16410 , anti- P18627 , or anti- P55040 , are being tested to increase the proportion and durability of tumor responses . Examination of acquired immune resistance and post-immunotherapy relapse strategies are underway . CONCLUSIONS : These emerging antibodies hold great potential for the systemic control of epithelial cancers such as lung cancer . Detection of early onset of hypophysitis by (18)F- DB09150 PET-CT in a patient with advanced stage melanoma treated with ipilimumab . DB06186 is a human monoclonal antibody directed against a receptor expressed on activated T-lymphocytes ( P16410 ) . Binding to this receptor induces T-cell activation against tumor cells . A 77-year-old man with a stage IV metastatic melanoma was treated with ipilimumab . F- DB09150 PET-CT performed for response evaluation revealed intense uptake in the pituitary gland . Two weeks later , biochemical parameters altered confirming hypophysitis . Treatment of the hypophysitis was started , and shortly thereafter , biochemical parameters normalized . Follow-up PET-CT revealed normalization of F- DB09150 uptake in the pituitary gland . In this case , we present a patient with ipilimumab-induced hypophysitis initially diagnosed on F- DB09150 PET-CT . Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . DB00784 ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose-dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy . Pituitary expression of P16410 mediates hypophysitis secondary to administration of P16410 blocking antibody . Hypophysitis is a chronic inflammation of the pituitary gland of unknown ( primary forms ) or recognizable ( secondary forms ) etiology , such as the use of ipilimumab in cancer immunotherapy . DB06186 , which blocks the T cell inhibitory molecule P16410 ( cytotoxic T lymphocyte antigen-4 ) , induces hypophysitis in about 4 % of patients through unknown mechanisms . We first established a model of secondary hypophysitis by repeated injections of a P16410 blocking antibody into SJL/J or C57BL/6J mice , and showed that they developed lymphocytic infiltration of the pituitary gland and circulating pituitary antibodies . We next assessed the prevalence of pituitary antibodies in a cohort of 20 patients with advanced melanoma or prostate cancer , 7 with a clinical diagnosis of hypophysitis , before and after ipilimumab administration . Pituitary antibodies , negative at baseline , developed in the 7 patients with hypophysitis but not in the 13 without it ; these antibodies predominantly recognized thyrotropin- , follicle-stimulating hormone- , and corticotropin-secreting cells . We then hypothesized that the injected P16410 antibody could cause pituitary toxicity if bound to P16410 antigen expressed " ectopically " on pituitary endocrine cells . Pituitary glands indeed expressed P16410 at both RNA and protein levels , particularly in a subset of prolactin- and thyrotropin-secreting cells . Notably , these cells became the site of complement activation , featuring deposition of C3d and C4d components and an inflammatory cascade akin to that seen in type II hypersensitivity . In summary , the study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab , and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis . Identification and characterization of a tumor infiltrating CD56(+)/CD16 ( - ) NK cell subset with specificity for pancreatic and prostate cancer cell lines . In a recent clinical trial , a patient exhibited regression of several pancreatic cancer metastases following the administration of the immune modulator DB06186 ( anti- P16410 antibody ) . We sought to characterize the immune cells responsible for this regression . Tumor infiltrating lymphocytes ( Q15399 -2742 ) and an autologous tumor line ( TC-2742 ) were expanded from a regressing metastatic lesion excised from this patient . Natural killer ( NK ) cells predominated in the Q15399 ( 92 % CD56(+) ) with few T cells ( 12 % CD3(+) ) . A majority ( 88 % ) of the NK cells were CD56(bright)CD16(-) . Q15399 -2742 secreted IFN-γ and GM- P04141 following co-culture with TC-2742 and major histocompatibility complex mismatched pancreatic tumor lines . After sorting Q15399 -2742 , the purified CD56(+)CD16(-)CD3(-) subset showed reactivity similar to Q15399 -2742 while the CD56(-)CD16(-)CD3(+) cells exhibited no tumor recognition . In co-culture assays , Q15399 -2742 and the NK subset expressed high reactivity to several pancreatic and prostate cancer cell lines and could lyse the autologous tumor as well as pancreas and prostate cancer lines . Reactivity was partially abrogated by blockade of P50591 . We thus identified a unique subset of NK cells ( CD56(bright)CD16(dim) ) isolated from a regressing metastatic pancreatic cancer in a patient responding to DB06186 . This represents the first report of CD56(+)CD16(-) NK cells with apparent specificity for pancreatic and prostate cancer cell lines and associated with tumor regression following the treatment with an immune modulating agent .