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This study sought to understand how the programmed death ligand 1 (PD-L1) inhibitor durvalumab and the immunomodulatory agent pomalidomide regulate immune cell activation and function in patients with relapsed/refractory (RR) multiple myeloma (MM). Immunologic changes in peripheral blood and bone marrow of patients treated with durvalumab as monotherapy or in combination with pomalidomide with/without dexamethasone were characterized by assessing subsets of immune cells and gene signatures to understand the immunomodulatory effect of the treatment. Soluble PD-L1 levels were elevated at screening in patients with RRMM but did not correlate with response to durvalumab combination therapy. Immune cell subsets were increased in peripheral blood during treatment with durvalumab and pomalidomide, and combination therapy induced significant gene expression changes in the MM tumor microenvironment versus durvalumab alone. Estimation of cell populations based on RNA sequencing data revealed increased monocytes, neutrophils, and natural killer cells with the combination therapy, but not with durvalumab alone. Additionally, multiplex immunofluorescence of bone marrow demonstrated that immune populations were different in responders versus nonresponders to durvalumab plus pomalidomide with dexamethasone therapy. Overall, durvalumab effectively blocked soluble PD-L1; however, durvalumab monotherapy was not associated with immunologic changes, which were observed with combination therapy.

The RTS,S/AS01 vaccine provides partial protection against Plasmodium falciparum infection but determinants of protection and/or disease are unclear. Previously, anti-circumsporozoite protein (CSP) antibody titers and blood RNA signatures were associated with RTS,S/AS01 efficacy against controlled human malaria infection (CHMI). By analyzing host blood transcriptomes from five RTS,S vaccination CHMI studies, we demonstrate that the transcript ratio MX2/GPR183, measured 1 day after third immunization, discriminates protected from non-protected individuals. This ratiometric signature provides information that is complementary to anti-CSP titer levels for identifying RTS,S/AS01 immunized people who developed protective immunity and suggests a role for interferon and oxysterol signaling in the RTS,S mode of action.

Introduction: Mutations in TP53 occur in 10% of patients (pts) with AML and HR-MDS and have been associated with worse outcomes and an immunosuppressive phenotype. To define the immune and epigenetic landscape in TP53-M advanced myeloid neoplasms (MN), we compared data from 61 pts with HR-MDS or AML with TP53 mutations (TP53-M) to 143 TP53 wildtype (TP53-WT) pts who were followed prospectively with serial samples in a well-annotated clinical trial in which all pts received hypomethylating agent (HMA)-based therapy. Methods: The FUSION trial (NCT02775903) was a large, randomized phase 2 study comparing azacitidine (AZA) monotherapy with AZA + anti-PD-L1 antibody durvalumab in 2 separate cohorts of previously untreated unfit AML and HR-MDS pts (Zeidan A et al, ASH 2019). Responses were classified by IWG 2003 and 2006 criteria for AML and MDS, respectively. Survival was estimated using Kaplan-Meier techniques. Samples from peripheral blood (PB) and bone marrow (BM) were obtained at baseline and serially on trial. A 38-targeted mutation analysis was performed at Munich Leukemia Laboratory. Only level 1 pathogenic TP53 mutations with variant allele frequency (VAF) ≥2% were included. DNA methylation was assessed using Illumina's Infinium Human Methylation EPIC methylation array. Immunophenotyping and immune checkpoint expression was performed using flow cytometry. Gene expression profiles were studied by RNA-sequencing. Results: Of 129 AML and 84 HR-MDS pts enrolled in FUSION trial, 37 had TP53-M AML, 88 TP53-WT AML, 24 TP53-M HR-MDS, and 55 TP53-WT HR-MDS pts. The average VAF for TP53 mutations were 37%, and 90% had ≥10% VAF. TP53-M AML pts were more likely to have poor-risk cytogenetics, therapy-related disease, and lower BM blast percentage compared to TP53-WT AML pts. TP53-M HR-MDS were more likely to have secondary MDS, very poor risk cytogenetics by IPSS-R, and very high risk IPSS-R score. There were no statistically significant differences in overall response rate (ORR) between TP53-M and TP53-WT pts (AML cohort: ORR: 35.1% [95% CI: 21%-53%] vs. 34.1% [CI: 26%-45%]; HR-MDS cohort: ORR: 41.7% [CI: 23%-63%] vs. 60% [CI: 46%-73%]). Median OS was 8.1 [95% CI: 5.4 - 13] months (mos) among TP53-M AML pts and 16.6 [95% CI: 13 - 21] mos for TP53-WT AML pts [Figure 1A]. Median OS was 9.8 [95% CI: 9.3 - 20+] mos for TP53-M HR-MDS pts and 23.5 [95% CI: 12 - 25+] mos for TP53-WT HR-MDS pts [Figure 1B]. Global DNA methylation was independent of TP53 mutation status in both AML (global methylation score x10^5: TP53-M: 4.9 [SD: 0.23] vs TP53-WT: 4.8 [SD: 0.33]; p=0.35) and HR-MDS pts (global methylation score: TP53-M: 4.8 [SD: 0.20] vs TP53-WT: 4.7 [SD: 0.25]; p=0.24) at baseline. DNA methylation changes after one cycle of AZA treatment were similar in both cohorts (AML: TP53-M:4.4 [SD: 0.38] vs TP53-WT: 4.5 [SD: 0.41, p=0.33]; HR-MDS: TP53-M: 4.3 [SD: 0.35] vs TP53-WT: 4.3 [SD: 0.36]; p=0.52). In RNA sequencing (Figure 2), TP53-M pts had higher expression of T-cell genes (e.g. IL7R) in both AML and HR-MDS compared to TP53-WT pts. Compared to TP53-WT pts, IFN alpha signature genes were reduced only in TP53-M AML pts but were increased in TP53-M HR-MDS pts. PD-L1 (CD274) expression was correlated with the T-cell gene signature and had a higher expression in TP53-M samples. TP53-M pts showed lower expression of tumor associated genes (e.g. CD34) consistent with the tumor cell percentages seen by BM flow cytometry. However, in gene set enrichment analysis, MYC target genes, MTORC1, and E2F were enriched in TP53-M samples consistent with the higher expression of proliferation genes (e.g., MKI67). In the bone marrow flow cytometry of AML pts, more T-cells were seen in TP53-M pts (Figure 3A), and PDL1 positive tumor cells were trending higher in TP53-M pts while the total abundance of tumor cells was slighter higher in TP53-WT (Figure 3B). Discussion: We confirm here that achieving a response to AZA therapy in AML or HR-MDS pts is not impacted by presence of TP53 mutations, however as expected median OS was substantially shorter among TP53-M pts for both AML and HR-MDS. In analyzing the epigenetic landscape, there were no differences in baseline global DNA methylation by TP53 status. RNA sequencing showed enrichment of T-cell genes and PD-L1, and an increase in gene expression of proliferation genes in TP53-M pts. Taken together, these findings support the presence of immunosuppressive microenvironment among TP53-M pts with advanced MN. Figure 1 Figure 1. Disclosures Zeidan: Janssen: Consultancy; Jasper: Consultancy; Epizyme: Consultancy; Acceleron: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Jazz: Consultancy; BioCryst: Other: Clinical Trial Committees; Astex: Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; ADC Therapeutics: Research Funding; Incyte: Consultancy, Research Funding; Agios: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Pfizer: Other: Travel support, Research Funding; BeyondSpring: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Geron: Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Aprea: Consultancy, Research Funding; Ionis: Consultancy; Astellas: Consultancy. Hasle: Bristol Myers Squibb: Current Employment. Thompson: Bristol Myers Squibb: Current Employment. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Boss: Bristol Myers Squibb: Current Employment. Fox: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Introduction: Identifying prior therapy exposures that affect the patient or their peripheral blood mononuclear cell (PBMC) material is one strategy to optimize outcomes to CAR T cell therapy. Alkylating agents commonly used in multiple myeloma management, such as cyclophosphamide, have been reported to impair the proliferative capacity of T lymphocytes and to blunt their functional activity (Ercolini et al. J Exp Med. 2005;201:1591; Banissi et al. Cancer Immunol Immunother. 2009;58:1627; Litterman et al. J Immunol. 2013;190:6259). In the pivotal phase 2 KarMMa trial (NCT03361748) investigating the BCMA-directed CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121) in triple-class exposed patients with RRMM, 80% of patients had a history of prior anticancer treatment with ≥1 alkylating agents. In this retrospective analysis, patient and PBMC characteristics associated with time from last dose of alkylating agent(s) until apheresis of PBMCs for CAR T cell manufacture were identified. Methods: PBMCs isolated from patient apheresis material, which serves as starting material for CAR T cell manufacturing, were immunophenotyped by polychromatic flow cytometry for markers associated with T cell differentiation, memory, senescence, and exhaustion. Data from relevant prespecified clinical and exploratory endpoints were collected, and a novel implementation of left-censored time-to-event analysis (Ware et al. Biometrics. 1976;32:459) was used to identify statistically significant relationships between washout time after prior alkylator exposure (encompassing 14 individual drugs) and patient and PBMC variables. Dose intensity of prior alkylators was not considered due to sparse annotations in the patient histories. Optimal cutpoints were identified for each variable that maximized the proportional hazard of receiving an alkylator between patients above and below the cutpoint, and P values were adjusted for testing multiple cutpoints. Relationships were verified by nonparametric correlation, in which alkylator washout was encoded as 1/log(−washout). Results: More recent exposure to an alkylating agent (after diagnosis but before apheresis) was associated with patients receiving more prior therapies per year to manage their disease (hazard ratio [HR]=2.63, ρ=−0.54, P Conclusions: Associations between patient characteristics and alkylator washout suggest that patients who more recently received alkylating agents to manage their myeloma had a more aggressive disease course, having progressed more quickly through prior regimens, and had lower weight and elevated systemic inflammation. Although these factors suggest a suboptimal patient profile, the depletion of T cells by alkylator therapy may be especially disadvantageous for autologous CAR T cell therapies (Wang et al. Mol Ther Oncolytics. 2016;3:16015; Perica et al. Biol Blood Marrow Transplant. 2018;24:1135). Our analysis found that the use of alkylators prior to CAR T cell therapy exhibits a detrimental effect on the apheresis PBMC material up to 6-9 months after the last dose. Figure 1 Disclosures Rytlewski: Adaptive Biotechnologies: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Madduri:Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria. Fuller:BMS: Current Employment. Campbell:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mashadi-Hossein:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; NanoString Technologies: Ended employment in the past 24 months. Thompson:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Jiang:Bristol Myers Squibb: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol Myers Squibb company: Current Employment. Martin:BMS: Current Employment, Current equity holder in publicly-traded company. Sangurdekar:bluebird bio: Current Employment, Current equity holder in publicly-traded company; Biogen: Ended employment in the past 24 months. Finney:bluebird bio: Current Employment, Current equity holder in publicly-traded company; Seattle Childrens Research Institute: Ended employment in the past 24 months. Bitter:Novartis: Ended employment in the past 24 months; Novartis AG: Patents & Royalties; bluebird bio: Current Employment, Current equity holder in publicly-traded company; F Hofmann-La Roche: Patents & Royalties; Predicant Biosciences: Patents & Royalties; Biospect: Patents & Royalties. Agarwal:BMS: Current Employment, Current equity holder in publicly-traded company. Kaiser:BMS: Current Employment, Current equity holder in publicly-traded company. Hege:Arcus Biosciences (Former Board of Directors): Divested equity in a private or publicly-traded company in the past 24 months; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Celgene (acquired by Bristol Myers Squibb): Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding. Hause:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Background: Patients (pts) with relapsed and refractory multiple myeloma (RRMM) experience unsatisfactory outcomes with established treatment modalities. In the pivotal phase 2 KarMMa study (NCT03361748), idecabtagene vicleucel (ide-cel, bb2121) demonstrated frequent, deep, and durable responses in triple-class exposed pts with RRMM, with an overall response rate (ORR) of 73% and a complete response rate of 33% (Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). The overall safety profile of ide-cel was also manageable. The median time to onset and duration of cytokine release syndrome (CRS) were 1 d and 5 d, respectively, and the median time to onset and duration of neurotoxicity (NT) were 2 d and 3 d; the frequencies of higher-grade CRS and NT were low. Evaluated here are the T cell phenotypes, soluble factors, and cytokines associated with ide-cel activation, CRS, NT, and tumor responses over time in pts who received ide-cel in the KarMMa study. Methods: After longitudinal sampling of peripheral blood post-ide-cel infusion in the KarMMa study (N=128), plasma was analyzed for levels of proinflammatory cytokines and inflammation-related soluble factors; serum was evaluated for soluble BCMA (sBCMA) as a peripheral surrogate measure of tumor burden, and peripheral blood mononuclear cells were assessed by flow cytometry for memory phenotypes of CAR T cells. Associations between these features over time after ide-cel infusion were evaluated in the context of ORR, ongoing response at 9 mo, and grade ≥2 CRS and NT. Response at 9 mo was selected for analysis because this visit was proximal to the median progression-free survival (PFS) reported in all ide-cel-treated pts in KarMMa. The 9-mo responders were defined as pts with assessments >8 mo postinfusion and no progression before 10 mo postinfusion. Results: The levels of both CD4+ and CD8+ populations of CAR T cells increased to a greater degree postinfusion in responders and were skewed towards a higher fraction of CD8+ cells through peak expansion. Cell expansion in responders was characterized by an increased proportion of TEM in CAR T cells (CCR7−/CD45RA−) for both CD4+ and CD8+ subsets. Congruent with dominant TEM expansion, characteristic TEM-associated proinflammatory cytokines, such as IFN-ɣ and IL-6, were consistently upregulated early after infusion. Peak IFN-ɣ and IL-6 levels occurred a median of 4 d postinfusion, and 90% of pts (5th−95th percentile) had IFN-ɣ and IL-6 peaks 21 d and 15 d postinfusion, respectively, which was in line with the observed early onset of CRS and NT. Pharmacodynamic responses, shown by decreases in sBCMA after infusion, also occurred consistently early after infusion, and the sBCMA nadir occurred in 90% of pts 7 d−85 d postinfusion (5th−95th percentile; median, 31 d). Early sBCMA clearance below the limit of detection of the assay was associated with longer responses, and median PFS was significantly longer in pts with undetectable sBCMA vs detectable sBCMA at 2 mo (12.3 mo [95% CI, 11.6−17.7] vs 2.9 mo [95% CI, 1.9−3.1]; P Conclusions: Postinfusion expansion of ide-cel was characterized by a TEM-dominant phenotype with expansion of both CD4+ and CD8+ CAR T cell populations. The relative magnitudes of the increase in both populations were substantially greater in responders vs nonresponders, with a bias toward a higher proportion of CD8+ CAR T cells in responders. The induction of effector cytokines followed by return to baseline levels occurred predictably and early after infusion and was consistent with both the observed early onset and resolution of CRS and early sBCMA clearance in pts who received ide-cel in the KarMMa study. Disclosures Martin: BMS: Current Employment, Current equity holder in publicly-traded company. Thompson:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Brown:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Finney:bluebird bio: Current Employment, Current equity holder in publicly-traded company; Seattle Childrens Research Institute: Ended employment in the past 24 months. Rytlewski:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Adaptive Biotechnologies: Current equity holder in publicly-traded company. Jiang:Juno Therapeutics, a Bristol Myers Squibb company: Current Employment; Bristol Myers Squibb company: Current equity holder in publicly-traded company. Sangurdekar:bluebird bio: Current Employment, Current equity holder in publicly-traded company; Biogen: Ended employment in the past 24 months. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bitter:Novartis AG, Predicant Biosciences, Biospect, F Hofmann-La Roche: Ended employment in the past 24 months; bluebird bio: Current Employment, Current equity holder in publicly-traded company; Novartis: Ended employment in the past 24 months, Patents & Royalties. Hause:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hege:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding; Celgene (acquired by Bristol Myers Squibb): Ended employment in the past 24 months; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences (Former Board of Directors): Divested equity in a private or publicly-traded company in the past 24 months. Kaiser:BMS: Current Employment, Current equity holder in publicly-traded company.

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts.Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.

HIV-infected individuals are at high risk of tuberculosis disease and those with prior tuberculosis episodes are at even higher risk of disease recurrence. A non-sputum biomarker that identifies individuals at highest tuberculosis risk would allow targeted microbiological testing and appropriate treatment and also guide need for prolonged therapy. We determined the utility of a previously developed whole blood transcriptomic correlate of risk (COR) signature for (1) predicting incident recurrent tuberculosis, (2) tuberculosis diagnosis and (3) its potential utility for tuberculosis treatment monitoring in HIV-infected individuals. We retrieved cryopreserved blood specimens from three previously completed clinical studies and measured the COR signature by quantitative microfluidic real-time-PCR. The signature differentiated recurrent tuberculosis progressors from non-progressors within 3 months of diagnosis with an area under the Receiver-operating characteristic (ROC) curve (AUC) of 0.72 (95% confidence interval (CI), 0.58–0.85) amongst HIV-infected individuals on antiretroviral therapy (ART). Twenty-five of 43 progressors (58%) were asymptomatic at microbiological diagnosis and thus had subclinical disease. The signature showed excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94–1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81–0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.

BackgroundCurrent diagnostics are inadequate to meet the challenges presented by coinfection with Mycobacterium tuberculosis (Mtb) and HIV, the leading cause of death for HIV-infected individuals. Improved characterisation of Mtb/HIV coinfection as a distinct disease state may lead to better identification and treatment of affected individuals.MethodsFour previously published TB and HIV co-infection related datasets were used to train and validate multinomial machine learning classifiers that simultaneously predict TB and HIV status. Classifier predictive performance was measured using leave-one-out cross validation on the training set and blind predictive performance on multiple test sets using area under the ROC curve (AUC) as the performance metric. Linear modelling of signature gene expression was applied to systematically classify genes as TB-only, HIV-only or combined TB/HIV.ResultsThe optimal signature discovered was a single 10-gene random forest multinomial signature that robustly discriminates active tuberculosis (TB) from other non-TB disease states with improved performance compared with previously published signatures (AUC: 0. 87), and specifically discriminates active TB/HIV co-infection from all other conditions (AUC: 0.88). Signature genes exhibited a variety of transcriptional patterns including both TB-only and HIV-only response genes and genes with expression patterns driven by interactions between HIV and TB infection states, including the CD8+ T-cell receptor LAG3 and the apoptosis-related gene CERKL.ConclusionsBy explicitly including distinct disease states within the machine learning analysis framework, we developed a compact and highly diagnostic signature that simultaneously discriminates multiple disease states associated with Mtb/HIV co-infection. Examination of the expression patterns of signature genes suggests mechanisms underlying the unique inflammatory conditions associated with active TB in the presence of HIV. In particular, we observed that disregulation of CD8+ effector T-cell and NK-cell associated genes may be an important feature of Mtb/HIV co-infection.

New biomarkers of tuberculosis (TB) risk and disease are critical for the urgently needed control of the ongoing TB pandemic. In a prospective multisite study across Subsaharan Africa, we analyzed metabolic profiles in serum and plasma from HIV-negative, TB-exposed individuals who either progressed to TB 3–24 months post-exposure (progressors) or remained healthy (controls). We generated a trans-African metabolic biosignature for TB, which identifies future progressors both on blinded test samples and in external data sets and shows a performance of 69% sensitivity at 75% specificity in samples within 5 months of diagnosis. These prognostic metabolic signatures are consistent with development of subclinical disease prior to manifestation of active TB. Metabolic changes associated with pre-symptomatic disease are observed as early as 12 months prior to TB diagnosis, thus enabling timely interventions to prevent disease progression and transmission., The tuberculosis pandemic requires new methods for diagnosing and containing infections prior to active disease. Here, the authors performed a multi-site observational study within sub-Saharan Africa and present serum and plasma metabolic signatures that can predict the onset of active TB with a high degree of sensitivity and specificity.

Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease. Objectives: We investigated bio-signatures with predictive ability for incident TB. Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated. Measurements and Main Results: A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-a variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events. Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs.

The cynomolgus macaque model of low-dose Mycobacterium tuberculosis infection recapitulates clinical aspects of human tuberculosis pathology, but it is unknown whether the 2 systems are sufficiently similar that host-based signatures of tuberculosis will be predictive across species. By blind prediction, we demonstrate that a subset of genes comprising a human signature for tuberculosis risk is simultaneously predictive in humans and macaques and prospectively discriminates progressor from controller animals 3-6 weeks after infection. Further analysis yielded a 3-gene signature involving PRDX2 that predicts tuberculosis progression in macaques 10 days after challenge, suggesting novel pathways that define protective responses to M. tuberculosis.

Biomarkers for tuberculosis treatment outcome will assist in guiding individualized treatment and evaluation of new therapies. To identify candidate biomarkers, RNA sequencing of whole blood from a well-characterized TB treatment cohort was performed. Application of a validated transcriptional correlate of risk for TB revealed symmetry in host gene expression during progression from latent TB infection to active TB disease and resolution of disease during treatment, including return to control levels after drug therapy. The symmetry was also seen in a TB disease signature, constructed from the TB treatment cohort, that also functioned as a strong correlate of risk. Both signatures identified patients at risk of treatment failure 1–4 weeks after start of therapy. Further mining of the transcriptomes revealed an association between treatment failure and suppressed expression of mitochondrial genes before treatment initiation, leading to development of a novel baseline (pre-treatment) signature of treatment failure. These novel host responses to TB treatment were integrated into a five-gene real-time PCR-based signature that captures the clinically relevant responses to TB treatment and provides a convenient platform for stratifying patients according to their risk of treatment failure. Furthermore, this 5-gene signature is shown to correlate with the pulmonary inflammatory state (as measured by PET-CT) and can complement sputum-based Gene Xpert for patient stratification, providing a rapid and accurate alternative to current methods.

†These authors contributed equally. Introduction Ide-cel, an anti-BCMA CAR T cell therapy, has demonstrated promising efficacy in the phase I CRB-401 trial in relapsed/refractory multiple myeloma (MM) (objective response rate, 85%; median progression-free survival [PFS], 11.8 months [95% CI: 6.2, 17.8]), but a subset of patients failed to respond and the duration of response varied across patients (Raje et al, N Engl J Med. 2019). A systematic examination of patient, product, and post-infusion correlates of overall and long-term response could offer biological insight into heterogeneous efficacy as well as provide biomarkers to guide post-CAR T disease management and future CAR T manufacturing and patient enrollment efforts. Soluble BCMA was of particular interest due to its expression on malignant and healthy plasma cells and its role as a composite measure of disease burden in MM. Methods We performed a retrospective analysis of 33 patients from the phase I CRB-401 study of ide-cel. The concentrations of ten immune-related factors in the blood (GMCSF, IFN-γ, IL-10, IL-1b, IL-2, IL-6, IL-8, MCP-1, TNF-α) and soluble BCMA were measured by ELISA before and after infusion with ide-cel along with 290 ide-cel CAR T-cell drug product attributes measured by flow cytometry and immunoassays. The absolute concentrations and fold-changes from baseline were assessed for correlation with overall and long-term response using univariate and multivariate (random forests) approaches. Results Several CAR T-cell drug product covariates nominally associated with longer PFS included reduced senescence phenotype in CD4 CAR T-cells and increased IL-2 and TNF-α production (P < 0.05). Pre-infusion levels of soluble BCMA correlated with serum monoclonal protein (M-protein) levels in 20 of 33 patients for whom M-protein levels were measurable (ρ = .49; P = 0.03) and with concentrations of the involved free light chain (ρ = .59; P = 0.005) in 23 of 33 patients with measurable levels. Our investigation of soluble BCMA levels in patients achieving a partial response (PR) or better confirmed significant decreases in soluble BCMA levels relative to nonresponders (NR) as early as seven days post-infusion (median reduction of 50% for ≥ PR vs. median increase of 27% for NR, P = 0.02). The fold-change in soluble BCMA 1 month after infusion stratified patients who achieved a PR or better from those who did not (P = 0.0001). Notably, patients who maintained a response to ide-cel for ≥ 18 months (M18 R) experienced a greater depth of clearance of soluble BCMA at month 2 (median concentration of 1835 ng/L for M18 R vs. 6299 ng/L for M18 NR, P = 0.002). The induction of IL-6 and TNF-α in blood on days 1-9 post-infusion was also higher in patients with a PR or better in response to ide-cel (e.g. IL-6 median fold change increase at day 2 of 2.9 for ≥ PR vs. 0.7 for NR, P = 0.001), consistent with an active inflammatory response and higher levels of CAR T expansion. Conclusions These data from CRB-401 identify candidate drug product attributes and soluble factors that correlate with response to ide-cel and potentially MM-directed cellular therapies in general. These data suggest that changes in soluble BCMA may be a robust biomarker of both early and durable responses to ide-cel and the depth of clearance of soluble BCMA at 2 months post-infusion may identify patients at risk of progression before standard markers of myeloma progression have emerged. Further molecular characterization of drug product attributes, including CyTOF and RNA sequencing, is ongoing to identify additional biomarkers associated with clinical outcomes following ide-cel treatment. These data will help inform future strategies to improve the efficacy of ide-cel and validation in a larger cohort is ongoing. Disclosures Thompson: Celgene Corporation: Employment, Equity Ownership. Jiang:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Campbell:Celgene Corporation: Employment, Equity Ownership. Fuller:Celgene Corporation: Employment, Equity Ownership. Kaiser:Celgene Corporation: Employment. Mashadi-Hossein:Celgene Corporation: Employment, Equity Ownership. Rytlewski:Adaptive Biotechnologies: Equity Ownership; Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Martin:Celgene Corporation: Employment, Equity Ownership. Finney:bluebird bio Inc.: Employment. Kleinsteuber:bluebird bio Inc.: Employment, Equity Ownership. Alonzo:bluebird bio Inc.: Employment, Equity Ownership. Pandya:bluebird bio Inc.: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Raje:Merck: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy; Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy. Munshi:Celgene: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy. Hause:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. OffLabel Disclosure: ide-cel /bb2121 is an investigational agent and not yet approved in the US

BACKGROUND: Loss of immune surveillance is critical in the pathogenesis of multiple myeloma (MM) and the progression from smoldering to symptomatic MM. To date, no clear efficacy signal has been observed with programmed-death 1 and programmed death ligand-1 inhibitors in patients with MM. General immune dysfunction in MM is well documented, but the evolving immune landscape in relapsed/refractory MM (RRMM) vs newly diagnosed MM (NDMM) is less well characterized. This study aimed to characterize immune profiles in peripheral blood and bone marrow from patients with NDMM and RRMM. METHODS: Peripheral blood samples were collected from 35 NDMM and 146 RRMM patients and 36 age-matched healthy volunteers (HVs). Cell surface and intracellular antigen staining using fluorochrome labeled antibodies was performed on a BD FACSCanto II flow cytometer. Bone marrow aspirates were collected from 26 NDMM and 73 RRMM patients, and the transcriptome was assessed by mRNA-Seq. RESULTS: In peripheral blood, T-cell populations differed between HVs and NDMM and RRMM patients. Absolute numbers of lymphocytes were higher in HVs than in NDMM and RRMM, regardless of the MM disease state. Absolute numbers of total CD4+ T cells and naïve CD4+ T cells were lower in RRMM patients, whereas CD4+ effector memory T cells as a proportion of total CD4+ T cells were increased in RRMM patients. Blood from RRMM patients also contained increased levels of proliferating CD4+ T cells, as evidenced by Ki67, ICOS, and HLA-DR, compared with blood from NDMM patients; HVs had values much closer to those from NDMM than from RRMM patients, suggesting a trend influenced by disease state or therapeutic intervention. In bone marrow, immunologic gene expression signatures were elevated in NDMM vs RRMM patients; the differences were similar to those in peripheral blood. Using limma to model the differential expression of all measured genes between NDMM and RRMM, we identified 367 genes that were elevated in NDMM patients vs 52 in RRMM patients. Gene set analyses using Molecular Signatures Database immunologic signatures (C7) applied to those 367 genes showed that naïve T-cell genes were increased in the bone marrow of NDMM vs RRMM patients. Gene set enrichment analysis with limma, using 489 gene sets from xCell representing 64 cell types and controlling for differences in tumor burden, indicated that macrophage, monocyte, and neutrophil genes were upregulated and T cells, particularly naïve CD4+ T cells, were downregulated in RRMM patients. Immunohistochemistry results from bone marrow biopsies showed increased programmed death-ligand 1 expression on tumor and infiltrating immune cells and increased CD8 infiltration into bone marrow in RRMM vs NDMM patients. Multiparameter immunofluorescence is underway to confirm these findings and further understand the tumor immune microenvironment in patient subsets. As expected, baseline RRMM immune cell populations depended on prior lines of therapy. Daratumumab-exposed RRMM patients had elevated total CD8+ T cells in peripheral blood but decreased CD38+, CD4+, and CD8+ T cells, as well as decreased total natural killer cells, compared with the daratumumab-naïve patients. Transcriptome analyses of bone marrow from daratumumab-exposed RRMM patients revealed increased T-cell gene expression signatures relative to marrow from daratumumab-naïve patients. Additionally, pomalidomide-exposed RRMM patients had increased activated CD4+ and CD8+ T cells vs pomalidomide-naïve patients. CONCLUSIONS: These data indicate that RRMM patients have peripheral blood and bone marrow environments with highly differentiated T-cell populations, whereas NDMM patients show elevated T-cell levels with proliferative capacity. Furthermore, the bone marrow of RRMM patients is enriched with neutrophils and macrophages; investigation is ongoing to determine if these cell types contribute to an immunosuppressive tumor microenvironment. Understanding immune system function based on disease progression, patient segments, and prior lines of therapy is imperative as treatment of MM improves, and it may inform the administration and sequence of next generation immunotherapeutics and identify predictive biomarkers for optimal treatment selection. Disclosures Pietz: Celgene Corporation: Employment. Tometsko:Celgene Corporation: Employment, Equity Ownership. Copeland:Celgene Corporation: Employment, Equity Ownership. Whalen:Celgene Corporation: Employment, Equity Ownership. Schmitz:Celgene Corporation: Employment, Equity Ownership. Thompson:Celgene Corporation: Employment, Equity Ownership. Agarwal:Celgene Corporation: Employment, Equity Ownership. Foy:Celgene Corporation: Employment, Equity Ownership. Buchholz:Celgene Corporation: Employment. Komashko:Celgene Corporation: Employment. Dell'Aringa:Celgene Corporation: Employment, Equity Ownership. Fox:Celgene Corporation: Employment, Equity Ownership. Newhall:Celgene Corporation: Employment.

Introduction Relapsed and refractory multiple myeloma (RRMM) remains a challenging disease to treat due to its heterogeneity and complexity. There is an urgent need for novel combination strategies, including immunotherapy. The study of the tumour and immune microenvironment before and after treatment with combination therapy is a crucial part of understanding the underpinning of disease response. Methods Longitudinal samples of bone marrow aspirates and whole blood were collected from a phase II clinical trial, MEDI4736-MM-003 (NCT02807454) where daratumumab and durvalumab naïve patients were exposed simultaneously to both these drugs. A combination of mass cytometry (CyTOF), RNAseq and flow cytometry were performed on a subset of samples from these subjects. Specifically, paired bone marrow mononuclear cells (BMMC) samples from nine patients taken at screening and six weeks post-treatment were analysed by mass cytometry (CyTOF) using a 37-marker pan-immune panel that included both lineage and functional intracellular/extracellular markers. In addition, whole blood sample specimens were collected at screening and on treatment (8, 15, 30, and 45 days after treatment) and analysed by flow cytometry. Flow cytometry panels were designed to allow interrogation of the abundance and activation status of immune cell subsets. Finally, RNA from bone marrow aspirates at screening and C2D15 were analysed by RNA sequencing. Expression profiles from the aspirates were used to estimate cell proportions by computational deconvolution. Individual cell types in these microenvironments were estimated using the DCQ algorithm and a gene expression signature matrix based on the published LM22 leukocyte matrix (Newman et al., 2015) augmented with 5 bone marrow- and myeloma-specific cell types. Results In a heavily pre-treated population with RRMM, treatment with durvalumab and daratumumab leads to shifts in a number of key immunological populations when compared to pre-treatment. In the bone marrow, CD8 and CD4 populations rise (by CyTOF and RNAseq), while NK, DC and B cell populations fall (by CyTOF). In the bone marrow within CD8+ T lymphocyte populations, we observed a post-treatment rise in markers of degranulation (granzyme p=0.0195, perforin p=0.0078, Wilcoxon signed-rank test). This is also accompanied by a fall in PD1 expression (p=0.0078) and rise in the co-stimulatory receptor DNAM1 (p=0.0273). These changes are most marked on cells with an effector memory CD45RA+ CD8+ T cell phenotype. In the blood, similar to the bone marrow, CD8+ T cells proliferate over the course of treatment (flow cytometry). A fall in both naïve and active NK cell populations is seen following treatment in bone marrow. NK cells express high levels of CD38 and are therefore depleted by daratumumab. Those NK cells which remain have an active phenotype with increased expression of TNFa (p=0.0039) and IFNg (p=0.0195) following treatment. Across the time points sampled in peripheral blood, NK cells were also decreased and those that remained were proliferating. Dendritic cells with a tolerogenic phenotype can be identified prior to treatment and are seen to fall in abundance following treatment with durvalumab and daratumumab. Conclusions The combination of durvalumab and daratumumab leads to several immune microenvironment changes that biologically portend clinical effect. We see increases in the abundance of cell populations with functional anti-tumour activity, including granzyme B+ CD8 T cells and a reduction in PD1high T cells. Despite the treatment expectedly reducing NK cell numbers, many functionally competent NK cells remain, as evidenced by the presence of anti-tumour cytokines. This combination strategy also reduces immunosuppressive tolerogenic DCs, which suppress CD4 and CD8 T cell activity. Taken together, this suggests that this chemotherapy free, doublet treatment has the potential to up-regulate anti-tumour immunological responses, which may restore immunosurveillance mechanisms critically needed in these highly refractory patients. Disclosures Seymour: Celgene: Research Funding. Young:Celgene Corporation: Employment, Equity Ownership. Tometsko:Celgene Corporation: Employment, Equity Ownership. Cavenagh:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thompson:Celgene Corporation: Employment, Equity Ownership. Whalen:Celgene Corporation: Employment, Equity Ownership. Danziger:Celgene Corporation: Employment, Equity Ownership. Fitch:Celgene Corporation: Employment, Equity Ownership. Fox:Celgene Corporation: Employment, Equity Ownership. Dervan:Celgene Corporation: Employment, Equity Ownership. Foy:Celgene Corporation: Employment, Equity Ownership. Newhall:Celgene Corporation: Employment, Equity Ownership. Gribben:Acerta Pharma: Honoraria, Research Funding; Cancer Research UK: Research Funding; TG Therapeutics: Honoraria; Roche: Honoraria; NIH: Research Funding; Medical Research Council: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Kite: Honoraria; Pharmacyclics: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Wellcome Trust: Research Funding; Unum: Equity Ownership.

Loss of IL-27R on T cells results in increased protection from Mycobacterium tuberculosis. Torrado et al. demonstrate that IL-27R−/− T cells show improved fitness that is associated with decreased expression of cell death molecules, maintenance of IL-2 production, and preferential accumulation in the lung parenchyma and around infected macrophages., CD4+ T cells mediate protection against Mycobacterium tuberculosis (Mtb); however, the phenotype of protective T cells is undefined, thereby confounding vaccination efforts. IL-27 is highly expressed during human tuberculosis (TB), and absence of IL-27R (Il27ra) specifically on T cells results in increased protection. IL-27R deficiency during chronic Mtb infection does not impact antigen-specific CD4+ T cell number but maintains programmed death-1 (PD-1), CD69, and CD127 expression while reducing T-bet and killer cell lectin-like receptor G1 (KLRG1) expression. Furthermore, T-bet haploinsufficiency results in failure to generate KLRG1+, antigen-specific CD4+ T cells, and in improved protection. T cells in Il27ra−/− mice accumulate preferentially in the lung parenchyma within close proximity to Mtb, and antigen-specific CD4+ T cells lacking IL-27R are intrinsically more fit than intact T cells and maintain IL-2 production. Improved fitness of IL-27R–deficient T cells is not associated with increased proliferation but with decreased expression of cell death–associated markers. Therefore, during Mtb infection, IL-27R acts intrinsically on T cells to limit protection and reduce fitness, whereas the IL-27R–deficient environment alters the phenotype and location of T cells. The significant expression of IL-27 in TB and the negative influence of IL-27R on T cell function demonstrate the pathway by which this cytokine/receptor pair is detrimental in TB.

We find the first example of a quantum Berenzinskii-Kosterlitz-Thouless (BKT) phase transition in two spatial dimensions via holography. This transition occurs in the D3/D5 system at nonzero density and magnetic field. At any nonzero temperature, the BKT scaling is destroyed and the transition becomes second order with mean-field exponents. We go on to conjecture about the generality of quantum BKT transitions in two spatial dimensions., Comment: 4 pages, 1 figure

We analyze the phase diagram of N=4 supersymmetric Yang-Mills theory with fundamental matter in the presence of a background magnetic field and nonzero baryon number. We identify an isolated quantum critical point separating two differently ordered finite density phases. The ingredients that give rise to this transition are generic in a holographic setup, leading us to conjecture that such critical points should be rather common. In this case, the quantum phase transition is second order with mean-field exponents. We characterize the neighborhood of the critical point at small temperatures and identify some signatures of a new phase dominated by the critical point. We also identify the line of transitions between the finite density and zero density phases. The line is completely determined by the mass of the lightest charged quasiparticle at zero density. Finally, we measure the magnetic susceptibility and find hints of fermion condensation at large magnetic field., Comment: 29 pages, 8 figures

We consider the operator product expansions for unitarity fermions. We compute the dynamic structure factor S(q,w) at large frequency and wavenumber away from the one-particle peak. The overall normalization of S(q,w) is determined by Tan's contact parameter, and the dependence on q and w is obtained in closed analytic form. We also find energy deposited into the system by small, rapid variations of the inverse scattering length., 11 pages, 8 figures

We investigate the properties of the Sakai-Sugimoto model at finite magnetic field and baryon chemical potentials. We show that in a finite magnetic field, there exists a spatially homogeneous configuration carrying finite baryon number density. At low magnetic field and baryon chemical potential the equation of state of the matter coincides with that obtained from the chiral perturbation theory Lagrangian with an anomalous term. We discuss the behavior of the system at larger magnetic fields., 13 pages

We show that the recently constructed holographic duals of conformal non-relativistic theories behave hydrodynamically at long distances, and construct the gravitational dual of fluid flows in a long-wavelength approximation. We compute the thermal conductivity of the holographic conformal non-relativistic fluid. The corresponding Prandtl number is equal to one., Comment: 29 pages, latex. v2 added refs

The holographic description of Pomeron exchange in a strongly-coupled gauge theory with an AdS dual is extended to the case of two to three scattering. We study the production event of a central particle via hadron-hadron scattering in the double Regge kinematic regime of large center-of-momentum energy and fixed momentum transfer. The computation reduces to the overlap of a holographic wave function for the central particle with a source function for the Pomerons. The formalism is applied to scalar glueball production and the resulting amplitude is studied in various kinematic limits., Comment: 35 pages, 8 figures, uses JHEP3.cls

A salient feature of String/Gauge duality is an extra 5th dimension. Here we study the effect of confining deformations of AdS5 and compute the spectrum of a string stretched between infinitely massive quarks and compare it with the quantum states of the QCD flux as determined by Kuti, Juge and Morningstar in lattice simulations. In the long flux tube limit the AdS string probes the metric near the IR cutoff of the 5th dimension with a spectrum approximated by a Nambu-Goto string in 4-d flat space, whereas at short distance the string moves to the UV region with a discrete spectrum for pure AdS5. We also review earlier results on glueballs states and the cross-over between hard and soft diffractive scattering that support this picture., Comment: 12 pages, 4 figures, invited talk by Brower and Tan at the Eighth Workshop on Non-Perturbative Quantum Chromodynamcis, June (2004)

The human bronchial epithelial cell is one of the first cell types to be exposed to the irritants and toxins present in inhaled cigarette smoke. The ability of the bronchial epithelium to modulate inflammatory and immune events in response to cigarette smoke is important in the pathogenesis of smoke-induced airway injury. We have shown that cigarette smoke extract and the complement anaphylatoxin C5a both independently induce increased expression of intercellular adhesion molecule (ICAM)-1 on airway epithelial monolayers compared with unstimulated cells in vitro. This enhanced ICAM-1 expression is associated with a greater capacity of the airway epithelial cells to bind mononuclear cells, a process that appears to require the proinflammatory cytokine tumor necrosis factor-alpha and protein kinase C intracellular signaling. Exposure of epithelial monolayers to the combination of cigarette smoke followed by C5a results in an additive response for ICAM-1 expression and mononuclear cell adhesion compared with smoke or C5a challenge alone. Inhibiting C5a receptor expression can attenuate these responses. These findings suggest that smoke exposure in some way enhances the functional responsiveness of the C5a receptor expressed on these airway epithelial cells for subsequent C5a-mediated increases in ICAM-1 expression and mononuclear cell adhesion. Our results may help explain the initiation and propagation of inflammatory events in vivo induced by chronic airway exposure to cigarette smoke.

We study defects in non-relativistic conformal field theories. As in the well-studied case of relativistic conformal defects, we find that a useful tool to organize correlation functions is the defect operator expansion (dOPE). We analyze how the dOPE is implemented in theories with a holographic dual, highlighting some interesting aspects of the operator/state mapping in non-relativistic holography., 20 pages

We use the AdS/CFT correspondence to study the transport properties of massive N=2 hypermultiplet fields in an N=4 SU(Nc) super-Yang-Mills theory plasma in the large Nc, large 't Hooft coupling limit, and in the presence of a baryon number chemical potential and external electric and magnetic fields. In particular, we compute the flavor fields' contribution to the stress-energy tensor. We find infrared divergences in the stress-energy tensor, arising from the flavor fields' constant rate of energy and momentum loss. We regulate these divergences and extract the energy and momentum loss rates from the divergent terms. We also check our result in various limits in which the divergences are absent. The supergravity dual is a system of D7-branes, with a particular configuration of worldvolume fields, probing an AdS-Schwarzschild background. The supergravity calculation amounts to computing the stress-energy tensor of the D7-branes., Comment: 32 pages; v2, added one footnote in section 2.2, added one reference, version published in JHEP

We use the holographic proposal for calculating entanglement entropies to determine the boundary entropy of defects in strongly coupled two-dimensional conformal field theories. We study several examples including the Janus solution and show that the boundary entropy extracted from the entanglement entropy as well as its more conventional definition via the free energy agree with each other. Maybe somewhat surprisingly we find that, unlike in the case of a conformal field theory with boundary, the entanglement entropy for a generic region in a theory with defect carries detailed information about the microscopic details of the theory. We also argue that the g-theorem for the boundary entropy is closely related to the strong subadditivity of the entanglement entropy., 21 pages, 3 figures