Schwerd et al. report a novel homozygous missense substitution in the cytokine co-receptor GP130 encoded by IL6ST. This is associated with defective IL-6, IL-11, OSM, and IL-27 signaling and causes immunodeficiency and skeletal abnormalities with similarities to STAT3 hyper-IgE syndrome.

Transduction of dendritic cells (DC) can result in presenmixed lymphocyte reactions. Mice immunized with Adtation of tumor-associated antigens and induction of transduced DC develop cytotoxic T lymphocytes that are immunity against undefined epitopes. The present studies specific for the ␤-galactosidase or DF3/MUC1 antigens. demonstrate adenovirus (Ad)-mediated transduction of the The results also demonstrate that Ad.MUC1-transduced ␤-galactosidase gene in mouse DC. Similar transductions DC induce a specific response which inhibits the growth have been obtained with the gene encoding the of DF3/MUC1-positive tumors. These findings support the DF3/MUC1 tumor-associated antigen. We show that the usefulness of Ad-transduced DC for in vivo immunization Ad-transduced DC are functional in primary allogeneic against tumor-associated antigens. Results and discussionT cells. 1 Murine DC pulsed with peptides prime antigenspecific CD8 + cytotoxic T lymphocytes (CTLs) in vivo. 2 Flow cytometry was used to define the phenotype of DC Peptides derived from tumor-associated antigens have following transduction with recombinant adenovirus. DC similarly been used to pulse DC and induce antitumor derived from bone marrow expressed MHC class I and II immunity. [3][4][5] Other studies have employed soluble products, costimulatory molecules and ICAM-1 18 (Figure tumor-associated antigens for loading DC and generating 1a). Transduction with Ad.␤gal resulted in a similar patantitumor activity. 6 Whereas peptides pulsed on to DC tern of antigen expression ( Figure 1a). Moreover, transmay dissociate from MHC molecules, CD34 + cells have duction with Ad.MUC1 was associated with DF3/MUC1 been retrovirally transduced to stably express antigens expression and little if any effect on cell surface levels of after differentiation to DC. 7,8 In contrast to pulsing, trans-MHC, costimulatory or adhesion molecules ( Figure 1a). duction of DC can result in longer term antigen presenThe Ad.MUC1-transduced DC exhibited a typical mortation and induction of immunity against undefined phology with veiled dendrites (Figure 1b). Staining with MHC epitopes. Thus, transduced DC may be effective in MAb M5/114 (anti-MHC class II) and MAb DF3 demonimmunizing against known tumor-associated antigens. strated expression of DF3/MUC1 by the transduced DC The human DF3/MUC1 glycoprotein is aberrantly (Figure 1b). Immunoblot analysis of the Ad.MUC1 transoverexpressed in breast and other carcinomas. 9 The DF3 duced DC confirmed DF3/MUC1 expression ( Figure 1c). protein is one member of the MUC1 family of carcinomaWhereas MAb DF3 detects glycosylated MUC1, the findassociated antigens that contain variable numbers of ing that MAb DF3-P reacts with an approximately 55 kDa highly conserved (G+C)-rich 60 base pair tandem protein in the transduced DC also provides support for repeats. 10,11 A C-terminal region includes a transmemdetection of the unglycosylated protein core 19 ( Figure 1c). brane domain that anchors the antigen at the cell sur-DC are potent stimulators ...

AS Th17 cells have a specific miR signature and upregulate miR-10b in vitro. Our data suggest that miR-10b is upregulated by proinflammatory cytokines and may act as a feedback loop to suppress IL-17A by targeting MAP3K7. miR-10b is a potential therapeutic candidate to suppress pathogenic Th17 cell function in patients with AS.

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Background: Cell cycle inhibition is a target of interest for novel cancer therapeutics. Palbociclib (P) is an orally active inhibitor of CDK4/6 which arrests the cell cycle at the G1-S transition. P has demonstrated efficacy in phase II and III randomized trials for first-line and pre-treated hormone receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancer (MBC), with hazard ratios 0.42-0.49 (Finn et al, Lancet Oncol 2015, Turner et al, NEJM 2015), and is approved in combination with letrozole as first-line therapy for HR+/HER2- MBC. Given confirmed benefits of P and endocrine therapy for MBC, the PALLAS study was designed to determine if the addition of P to adjuvant endocrine therapy (ET) improves outcomes over ET alone in HR+/HER2- early breast cancer. Trial Design: PALLAS is an international open label phase III trial randomizing patients to 2 years of P (125 mg daily, 21 days on 7 days off in a 28-day cycle) combined with at least 5 years of provider choice ET (AI, tamoxifen, +/- LHRH agonist), versus ET alone. The primary objective of the study is to compare invasive disease-free survival (iDFS) for the combination of P and ET versus ET alone. Secondary objectives include comparing iDFS excluding cancer of non-breast origin, DRFS, LRRFS, OS, as well as safety. The principal translational science objective is to determine the predictive or prognostic utility of defined genomic subgroups with respect to iDFS and OS. Additional translation objectives include evaluation of tissue and blood biomarkers predictive of benefit or resistance, cfDNA, pharmacogenomics, adherence, BMI, and patient-reported QOL. Eligible patients (pts) may be pre- or post-menopausal, have stage II-III breast cancer, HR+/HER2- by ASCO CAP guidelines, and have recovered from prior therapies. Pts may have already initiated ET, but randomization must occur within 12 months of diagnosis and 6 months of initiation of ET. An FFPE block must be received at the central sample repository for eligibility. Total planned accrual to the trial is 4600 pts, providing 85% power to detect a 25% risk reduction in iDFS from ET alone using a stratified logrank test with an overall one-sided alpha = 0.025. Pts will be randomized 1:1 stratified by stage, receipt of prior chemotherapy, age, and geographic location. Interim analyses for safety, futility/efficacy and sample size re-estimation are planned. PALLAS will open in 9/2015; current accrual will be updated at time of presentation. Citation Format: Mayer E, DeMichele A, Dubsky P, Barry W, Metzger O, Symmans WF, Burstein H, Miller K, Wolff A, Rastogi P, Loibl S, von Minckwitz G, Goulioti T, Zardavas D, Fesl C, Koehler M, Huang Bartlett C, Chen L, Piccart M, Winer E, Gnant M. PALLAS: PAlbociclib Collaborative Adjuvant Study: A randomized phase 3 trial of palbociclib with adjuvant endocrine therapy versus endocrine therapy alone for HR+/HER2- early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-21.

IL-12 is a heterodimeric immunoregulatory cytokine composed of covalently linked p40 and p35 subunits and exhibits antitumor activity in a variety of laboratory models. The efficacy of systemically administered cytokines for cancer therapy is often limited by toxicity. The gene therapy approach provides a mechanism to achieve temporary and high local concentrations of cytokines within a tumor with less risk of systemic toxicity. We constructed replication-defective adenoviruses containing the murine IL-12 p40 subunit (Ad.mp40) or a bicistronic vector containing cDNAs for the p40 and p35 subunits (Ad.mIL-12). Murine MB49 bladder cancer cells infected with Ad.mIL-12 secrete high concentrations of biologically active IL-12, while those infected with Ad.mp40 produce the p40 homodimer. Tumors injected with Ad.mIL-12 show rapid increases in IL-12 and IFN-gamma expression over 2 to 5 days and a return to baseline by 7 to 14 days. Injection of tumors with Ad.mIL-12 (1 x 10(9) plaque-forming units) results in a complete tumor regression in all mice, while those treated with control adenovirus succumb to their tumor. Efficacy is reduced when studies are performed in mice depleted of CD4+ and CD8+ cells or in nude mice. Mice cured of their tumor by Ad.mIL-12 demonstrate specific protective immunity upon rechallenge. Ad.mp40 does not exhibit antitumor activity and may antagonize the activity of rIL-12 or Ad.mIL-12. In summary, gene therapy strategies for cancer using adenoviral vectors containing IL-12 are highly effective with no significant toxicity in mice.

BackgroundTofacitinib is an oral Janus kinase inhibitor under investigation for treatment of psoriatic arthritis (PsA). The safety and efficacy of tofacitinib for the treatment of PsA has been investigated in two Phase 3 randomised controlled trials (RCTs: OPAL Broaden [12 months; NCT01877668]; OPAL Beyond [6 months; NCT01882439]).ObjectivesTo evaluate patient-reported outcomes (PROs) in patients (pts) with active PsA enrolled in OPAL Broaden (N=422) and OPAL Beyond (N=394). OPAL Broaden pts had an inadequate response (IR) to ≥1 conventional synthetic disease-modifying antirheumatic drug and were naïve to tumour necrosis factor inhibitors (TNFi) whilst OPAL Beyond pts had an IR to ≥1 TNFi.MethodsPts were randomised to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, placebo (PBO)→ tofacitinib 5 mg BID, PBO→ tofacitinib 10 mg BID and, in OPAL Broaden, also to adalimumab 40 mg subcutaneously every two weeks (active comparator). Pts receiving PBO advanced to either tofacitinib 5 mg BID or 10 mg BID at month 3 (M3) in both RCTs. Least squares mean changes from baseline in: Patient's Global Assessment of Arthritis (PtGA; Visual Analogue Scale [VAS]); Arthritis Pain (Pain; VAS); Short Form-36 Health Survey (SF-36); Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F); Dermatology Life Quality Index (DLQI) and Ankylosing Spondylitis Quality of Life (ASQOL) questionnaires are reported. Nominal p values are reported without adjustments for multiple comparisons.ResultsPatients with active PsA in OPAL Broaden and OPAL Beyond RCTs receiving tofacitinib 5 mg and 10 mg BID reported improved PROs compared with PBO (Table 1). Greater improvements in PtGA and Arthritis Pain were observed as early as Week 2 through M3 with both tofacitinib doses compared with PBO in both studies (p≤0.05). Greater improvements were also reported in SF-36 Physical Component Summary, DLQI and ASQOL scores at M1 and M3 with both tofacitinib doses compared with PBO (p≤0.05). There were greater improvements in SF-36 physical functioning, bodily pain and vitality domains with both tofacitinib doses compared with PBO in both studies (p≤0.05) at M3. SF-36 social functioning domain showed greater improvement with tofacitinib 5 mg BID in OPAL Broaden and both tofacitinib doses in OPAL Beyond compared with PBO at M3 (p≤0.05). SF-36 role-physical domain showed greater improvement with tofacitinib 10 mg BID in OPAL Beyond at M3 compared with PBO (p≤0.05). FACIT-F showed a greater improvement in both studies at M3 with both tofacitinib doses compared with PBO (p≤0.05). In OPAL Broaden, improvements in PROs were similar between tofacitinib and adalimumab.ConclusionsPts with active PsA receiving tofacitinib reported greater improvements in PROs compared with PBO at M3 that were maintained throughout both RCTs.AcknowledgementsTo be presented at AAD 2017 and reproduced with permission. This study was sponsored by Pfizer Inc. Editorial support was provided by S. Morgan of CMC and was funded by Pfizer Inc.Disclosure of InterestV. Strand Consulta...

BackgroundInfection with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility.MethodsHuman challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (n=176) and/or transcriptionally profiled by RNA-sequencing (n=178).ResultsTwo SNPs within CAPN14 and MIATNB were identified with p<10−5 for association with development of symptoms or bacteraemia following oral S. Typhi or S. Paratyphi A challenge. Imputation of classical human leukocyte antigen (HLA) types from genomic and transcriptomic data identified HLA-B*27:05, previously associated with non-typhoidal Salmonella-induced reactive arthritis, as the HLA type most strongly associated with enteric fever susceptibility (p=0.012). Genes related to the unfolded protein response and heat shock were over-represented in HLA-B*27:05+ participants following challenge (p=0.01). Furthermore, intracellular replication of S. Typhi is higher in C1R cells transfected with HLA-B*27:05 (p=0.02).ConclusionThese data suggest that activation of the unfolded protein response by HLA-B*27:05 misfolding may create an intracellular environment conducive to S. Typhi replication, increasing susceptibility to enteric fever.