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Although combination antiretroviral therapy (ART) has been a landmark achievement for the treatment of human immunodeficiency virus (HIV), an HIV cure has remained elusive. Elimination of latent HIV reservoirs that persist throughout HIV infection is the most challenging barrier to an HIV cure. The progressive HIV infection is marked by the increasing size and diversity of latent HIV reservoirs until an effective immune response is mobilized, which can control but not eliminate HIV infection. The stalemate between HIV replication and the immune response is manifested by the establishment of a viral set point. ART initiation during the early stage limits HIV reservoir development, preserves immune function, improves the quality of life, and may lead to ART-free viral remission in a few people living with HIV (PLWH). However, for the overwhelming majority of PLWH, early ART initiation alone does not cure HIV, and lifelong ART is needed to sustain viral suppression. A critical area of research is focused on determining whether HIV could be functionally cured if additional treatments are provided alongside early ART. Several HIV interventions including Block and Lock, Shock and Kill, broadly neutralizing antibody (bNAb) therapy, adoptive CD8+ T cell therapy, and gene therapy have demonstrated delayed viral rebound and/or viral remission in animal models and/or some PLWH. Whether or not their application during early infection can improve the success of HIV remission is less studied. Herein, we review the current state of clinical and investigative HIV interventions and discuss their potential to improve the likelihood of post-treatment remission if initiated during early infection.

BackgroundWe constructed RediTac, novel biologics designed to selectively activate and expand virus-specific CD8 T cells (CTL) and redirect them to eliminate cancer cells (figure 1A). RediTac utilize an Fc-fusion protein scaffold to dimerize an HLA-A2 pMHC linked to cancer-targeting scFvs (figure 1B). The pMHC presents a tethered virus peptide to target its cognate TCR and selectively stimulate virus-specific CTL. The scFv redirects virus-specific CTLs to eliminate cancer cells. As a proof-of-concept, we developed RediTac with a pMHC presenting a CMV-derived peptide, NLV, capable of expanding CMV-specific CTLs with potent cytotoxic activity.1 This pMHC was linked to a CD19-specific scFv capable of targeting malignant B cells.MethodsWe first confirmed the functionality of the NLV-pMHC domain and CD19-specific scFv domain by demonstrating NLV-CD19 RediTac-mediated expansion of NLV-specific CTLs and selective binding to a CD19 on cells, respectively. The NLV-CD19 RediTac was then evaluated for its capacity to expand and redirect CMV-specific CTLs to eliminate NALM6, a CD19-expressing leukemia cell-line, in vitro and in vivo. To do this, donor PBMC with expanded NLV-specific CTLs were cocultured with NALM6 cells or coinjected with NALM6 cells into spleens of NSG mice. NLV-CD19 RediTac or control treatments were administered and NALM6 cell elimination was measured as a readout for functional activity.ResultsNLV-CD19 was detected binding to the surface of CD19+ NALM6 cells (figure 2A,B). Twelve days after NLV-CD19 RediTac treatment, NLV-specific CTLs expanded by >40-fold as compared to untreated controls (figure 3A). After expansion, treatment with fresh NLV-CD19 RediTac induced IFNγ secretion by these expanded CTLs (figure 3B). Expanded CTLs eliminated ~60% of NALM6 cells when treated with NLV-CD19 RediTac during a two-day coculture, but no significant NALM6 cell elimination was observed when treated with control RediTac, either without a targeting scFv or with a pMHC linked to an irrelevant peptide (figure 4A). Five days after expanded CTLs and NALM6 cells were coinjected into NSG mice and NLV-CD19 was administered intravenously, the NALM6 population in the spleens was reduced by >99% when compared to a vehicle control treatment or a no-effector-cell control (figure 4B).ConclusionsNLV-CD19 RediTac expands CMV-specific CTLs and redirects their cytotoxic activity to eliminate NALM6 leukemia cells. We can use the RediTac modular design to expand and redirect other virus-specific T cells and target other cancers with scFvs. These results support RediTac-mediated virus-specific CTL expansion and redirection as a novel immunotherapy strategy to eliminate cancer cells and an effective platform for future treatments.AcknowledgementsWe would like to acknowledge Dr. Steve Almo and Dr. Scott Garforth for their work in conceiving and developing the RediTac technology.ReferenceLi M, Garforth SJ, O’Connor KE, Su H, Lee DM, Celikgil A, Chaparro RJ, Seidel RD, Jones RB, Arav-Boger R, Almo SC, Goldstein H. T cell receptor-targeted immunotherapeutics drive selective in vivo HIV- and CMV-specific T cell expansion in humanized mice. J Clin Invest. 2021 Dec 1;131(23):e141051Ethics ApprovalAll human PBMC samples and animal work was done with ethics approval by the Albert Einstein College of Medicine. All participants gave informed consent. This study was approved by the Albert Einstein College of Medicine institution’s Ethics Board; approval number 2017–8116. Animal use was approved by the AECOM Institute of Animal Studies animal use protocol number 00001105.Abstract 1170 Figure 1RediTac is designed to redirect antigen-specific CTL activity against labeled cancer cells. (A) Graphic depicting the designed function of RediTac. RediTac binds cancer-associated antigen via an antibody-derived single chain variable fragment (scFv), which coats the cancer cell in bivalent peptide-major histocompatibility complex (pMHC) modules. These modules trigger antigen-specific T cell receptor (TCR) activation and facilitate redirection of cytotoxic activity against the cancer cell and proliferation of the effector cell. (B) Components of the complete RediTac dimer.Abstract 1170 Figure 2NLV-CD19 RediTac can bind CD19 on the surface of NALM6 leukemia cells. (A) Methodology for the detection of scFv-mediated RediTac binding to the surface of antigen-expressing cells (B) CD19+ NALM6 cells or CD19- Jurkat cells were incubated with 80nM of either NLV-CD19 RediTac or NLV-gp120 RediTac with an scFv targeting an irrelevant antigen. Following an incubation with a fluorochrome-conjugated anti-His-Tag secondary antibody, RediTac binding was detected using flow cytometry. Representative dot plots depict one of four replicates from two independent experiments using two different batches of NLV-CD19 RediTac.Abstract 1170 Figure 3NLV-CD19 RediTac expands CMV-specific CTLs and activates secretion of IFNy. (A) Donor-derived PBMC with memory for CMV were treated with 1nM NLV-CD19 RediTac or left untreated. Cells were collected and stained before treatment (Day 0) and on days 7 or 12 following treatment. Selective expansion was determined as an increase in the percentage of live CD8+ T cells that were NLV-tetramer+. Data represents mean of N=4 different donor samples depicted as unique shapes. Two-way ANOVA and Sidak’s multiple comparison test was performed. ** = p>0.01. (B) On day 14 following NLV-CD19 RediTac treatment, PBMC with expanded NLV-specific CTLs were treated with 5nM fresh NLV-CD19 RediTac or left untreated in the presence or absence of CD19+ NALM6 cells. IFNy ELISpot was performed two days following secondary treatment of PBMC. Data represents mean and SD of n=3 technical replicates using PBMC from a single donor. One-way ANOVA with Tukey’s multiple comparisons test performed. *** = p> 0.001, *** = p> 0.0001.Abstract 1170 Figure 4NLV-CD19 RediTac redirects expanded NLV-specific CTLs to eliminate NALM6 leukemia cells. (A) PBMC with NLV-specific CTIs that were expanded for seven days were cocultured with PKH26 membrane dyed NALM6 cells at a 1:1 Effector:Target (E:T) ratio and were treated with 1 nM fresh NLV-CD19 RediTac, 1nM SL9-CD19 RediTac with an irrelevant pMHC, 1nM RediTac without a targeting scFV (NLV-no scFv RediTac), or nothing. Flow cytometry was performed after two days to detect live PKH26+ NALM6 cell count per well. Data depicts mean of n=3 technical replicates using PBMC from a single donor. One-way ANOVA with Dunnett’s multiple comparisons test performed. ** = p> 0.01. (B) PBMC with NLV-specific CTIs that were expanded for twelve days were coinjected at a 1:1 E:T ratio with CD24+ CD19+ NALM6 cells into the spleen of immunocompromised NSG mice. Some mice received no effector PBMC (0:1 E:T). Mice received a 1 mg/kg retro-orbital injection of NLV-CD19 RediTac or a PBS vehicle control. Spleens were harvested and processed and splenocytes were stained for human CD3, CD24, and CD19 to detect NALM6 cells by flow cytometry. Data is a representative dot plot for n=2 mice gated on CD3- cells, with the mean count of NALM6 cells depicted.

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such ‘epigenetic clocks’ appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue ‘counting’ beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared ‘young’ regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.

The purpose of the current study was to investigate the relationship between religious and spiritual identities and the mental health of sexual minorities. This study sought to compare the psychological well-being of sexual minorities who identify as (1) neither religious nor spiritual, (2) spiritual and not religious, (3) religious from an affirming institution, and (4) religious from a non-affirming institution. This study hypothesized there would be significant differences between the psychological well-being, internalized sexual stigma, spiritual well-being, and symptoms of depression between each religious and spiritual classification. Results showed limited support for the hypothesis. Religious participants from the non-affirming religious institutions demonstrated higher levels of internalized homophobia when compared to all other groups. Additionally, both religious groups reported greater spiritual well-being than the spiritual and not religious group, which was also greater than the neither religious nor spiritual participants. These finding suggest that sexual minorities are capable of maintaining rich religious and spiritual lives within the context of both affirming and non-affirming religious institutions and at the same time have minimal levels of depression.

IntroductionDuodenal stenting is an established palliative therapy in malignant gastric outflow obstruction. This can be carried out either endoscopically or via interventional radiology (IR) depending on clinician experience and resources. We sought to assess the efficacy and safety of these two methods in our centre.MethodsPatients who underwent duodenal stenting via endoscopy or IR from July 2014 to November 2020 were retrospectively identified. Unique patient identification numbers were cross referenced with the endoscopy database and electronic record. Patient demographics, procedure indication, success rates and complication rates were recorded. Technical success was defined as safe insertion of the duodenal stent across the stricture. Clinical success was defined as relief of symptoms related to gastric outlet obstruction (Grades; 0 – fail, 1 – liquid diet, 2 – soft diet, 3 – solid diet). Statistical analysis was performed using Fisher’s Test with p value of < 0.05 being significant.Results92 patients underwent 114 procedures. Stenting was carried out via endoscopy in 78 patients (103 stents, age median 69 (32-90)), with 17 patients having stents inserted via IR (27 stents, age median 63 (46-88)). The median survival for both groups was 167.9 days following their first stent insertion.In the endoscopic intervention group, 63 had gastric outlet obstruction secondary to an upper GI cancer and 15 had metastatic disease from a non-upper GI primary. 4 of the patients had a previous Whipple’s procedure and 1 had a gastrojejunostomy. In the IR group, 16 had an upper GI cancer, 1 had metastatic colorectal cancer. 1 of these patients had a previous gastrojejunostomy.There were no immediate serious post procedure complications in either group. 2 patients in the endoscopic group had early stent migration (within 30 days of insertion) and 1 patient’s stent did not fully open and required balloon dilatation. Similarly, in the IR group, 1 patient’s stent did not fully open requiring balloon dilatation of the stent and an additional stent insertion.In the endoscopic group, technical success was achieved in 101 (98.1%) stents compared to 25 (92.6%) in IR (p = 0.19). A patient with previous gastrojejunostomy underwent a combined endoscopic and radiological procedure unsuccessfully. In the endoscopic group, 1 stent was inadvertently deployed through an existing biliary metal stent. On further analysis, we observed that more than one stent was inserted more frequently in the IR group, 13 of 20 procedures (65%), compared to 10 of 93 (10.8%) endoscopic procedures (p= 0.003). Tumour ingrowth and stent obstruction occurred in 12(12.8%) procedures in the endoscopy group vs 2(10%) in IR group within 6 months from insertion.Clinical success was achieved in endoscopic stenting in 95 (92.4%) of the stents vs 23 (85.2%) through IR (p= 0.27). Further analysis comparing the type of diet patients could tolerate was available for 51 (out of 77) of the patients in the endoscopic group and for all 17 patients in the IR group. In the endoscopically inserted group, 22 patients tolerated solid diet (43.1%), 18 tolerated soft diet (35.3%) and 6 tolerated liquid diet (11.8%) vs 3 (17.6%), 10 (58.8%) and 2 (11.8%) in the IR group respectively.ConclusionIn malignant gastric outlet obstruction, duodenal stents inserted endoscopically or radiologically, can be performed safely and allow patients to live with improved symptoms for an extended period of time. In our cohort, it appears that radiologically, 2 overlapping stents are more frequently required to achieve the desired effect. We suspect this is because of endoscopic direct visualisation of the obstruction aids stent position on insertion.

MEG and EEG data contain additive correlated noise generated by environmental and physiological sources. To suppress this type of spatially coloured noise, source estimation is often performed with spatial whitening based on a measured or estimated noise covariance matrix. However, artifacts that span relatively small noise subspaces, such as cardiac, ocular, and muscle artifacts, are often explicitly removed by a variety of denoising methods (e.g., signal space projection) before source imaging. Here, we introduce a new approach, the spectral signal space projection (S 3P) algorithm, in which time–frequency (TF)-specific spatial projectors are designed and applied to the noisy TF-transformed data, and whitened source estimation is performed in the TF domain. The approach can be used to derive spectral variants of all linear time domain whitened source estimation algorithms. The denoised sensor and source time series are obtained by the corresponding inverse TF-transform. The method is evaluated and compared with existing subspace projection and signal separation techniques using experimental data. Altogether, S 3P provides an expanded framework for MEG/EEG data denoising and whitened source imaging in both the time and frequency/scale domains. ► MEG and EEG data are corrupted by frequency-specific (FS) spatially coloured noise. ► S 3P suppresses this noise with FS spatial projections and whitened source imaging. ► S 3P performs better than other methods because the noise spatial patterns are FS. ► S 3P provides a new expanded framework for imaging denoised brain oscillations.

Biomarkers and Immune MonitoringO1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumabSonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia Li2, Li Shi2, Xiaoping Jin2, Joyce Antal2, Ashok Gupta2, Koustubh Ranade2, Gerd Binning11Definiens AG, Munich, Bayern, Germany; 2MedImmune, Gaithersburg, MD, USACorrespondence: Brandon Higgs (higgsb@medimmune.com) Background Immunotherapies have improved patient responses and survival, though not all patients benefit. Effective biomarkers may help to improve outcomes. Durvalumab is a human IgG1 monoclonal antibody that inhibits PD-L1 binding to PD-1 and CD80, restoring antitumor immunity [1, 2]. PD-L1 expression on tumor or tumor-infiltrating immune cells measured manually with different immunohistochemistry (IHC) assays can enrich for patients responding to anti-PD-1/PD-L1 agents. Tumor-infiltrating cytotoxic CD8+ T cells may also have potential predictive utility for therapeutic response. We explored automated image analysis and pattern recognition of tumor biopsies to determine whether CD8+ and PD-L1+ cell densities could better identify patients most likely to respond to durvalumab than PD-L1 IHC alone. Methods CP1108/NCT01693562 was a nonrandomized phase I/II trial evaluating durvalumab in advanced NSCLC and other solid tumors [3]. By 29APR2016, 304 previously treated NSCLC patients, median 3 prior lines, received 10 mg/kg of durvalumab q2w ≤12 months. Baseline archived or fresh tumor biopsies were analyzed for PD-L1 (Ventana/SP263) and CD8 (Ventana/SP239) by IHC. For the marker combination, slides were scored using the product of PD-L1+ and CD8+ cell densities with Definiens’ Developer XD 2.1.4 software. For PD-L1 alone, ≥25% tumor cells stained for PD-L1 at any intensity were scored positive. Clinical outcomes (ORR, PFS and OS) were analysed based on CD8+ and PD-L1+ densities (n = 163 available) and PD-L1 alone in pre-treatment biopsies using a discovery (n = 84) and validation (n = 79) set. Datasets were matched on baseline PD-L1 status, histology, ECOG, lines of therapy, and response. Results Patients with high pretreatment CD8+ and PD-L1+ densities (prevalence = 36%) had better ORR, OS, and PFS compared to those with low CD8+ and PD-L1+ densities (Fig. 1), as well as high PD-L1 expression alone. Conclusions Automated image analysis of CD8+ and PD-L1+ cell densities in baseline tumor biopsies may identify patients with improved outcomes to durvalumab. Trial Registration ClinicalTrials.gov identifier NCT01693562. References 1. MedImmune/AstraZeneca. Data on file.2. Ibrahim R, Stewart R, Shalabi A: PD-L1 blockade for cancer treatment: MEDI4736.Semin Oncol 2015,42:474–483.3. Rizvi NA, Brahmer JR, Ou SHI, Segal NH, Khleif S, Hwu WJ, et al:Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1 antibody, in patients with non-small lung cancer (NSCLC).J Clin Oncol 2015,33(Suppl.):Abstract 8032.Fig. 1 (abstract O1).Clinical outcomes in CD8+/PD-L1+ or PD-L1 NSCLC patient subsetsClinical Trials: Cutting-Edge (Completed Trials)O2 Keynote-045: open-label, phase III study of pembrolizumab versus investigator’s choice of paclitaxel, docetaxel, or vinflunine for previously treated advanced urothelial cancerJoaquim Bellmunt,1 Ronald de Wit,2 David J Vaughn,3 Yves Fradet,4 Jae Lyun Lee,5 Lawrence Fong,6 Nicholas J Vogelzang,7 Miguel A Climent,8 Daniel P Petrylak,9 Toni K Choueiri,1 Andrea Necchi,10 Winald Gerritsen,11 Howard Gurney,12 David I Quinn,13 Stéphane Culine,14 Cora N Sternberg,15 Yabing Mai,16 Markus Puhlmann,16 Rodolfo F Perini,16 Dean F Bajorin171Dana-Farber Cancer Institute, Boston, MA, USA; 2Erasmus MC Cancer Institute, Rotterdam, Netherlands; 3Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; 4CHU de Québec-Université Laval, Québec, QC, Canada; 5Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; 6University of California, San Francisco, San Francisco, CA, USA; 7Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA; 8Fundación Instituto Valenciano de Oncología, Valencia, Spain; 9Smilow Cancer Hospital at Yale University, New Haven, CT, USA; 10Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 11Radboud University Medical Center, Nijmegen, Netherlands; 12Westmead Hospital and Macquarie University, Sydney, NSW, Australia; 13Univeristy of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA, USA; 14Hôpital Saint-Louis, Paris, France; 15San Camillo Forlanini Hospital, Rome, Italy; 16Merck & Co., Inc., Kenilworth, NJ, USA; 17Memorial Sloan Kettering Cancer Center, New York, NY, USA Background There is no standard second-line therapy for advanced urothelial cancer. Although paclitaxel, docetaxel, and vinflunine are commonly used, they provide limited clinical benefit. KEYNOTE-045 compared the efficacy and safety of the anti–PD-1 antibody pembrolizumab versus investigator-choice chemotherapy as second-line therapy for advanced urothelial cancer that progressed or recurred following first-line platinum-based chemotherapy. Methods Eligible patients were enrolled regardless of PD-L1 expression and randomized 1:1 to pembrolizumab 200 mg Q3W for 24 months or investigator’s choice of paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. Randomization was stratified by ECOG PS (0/1 vs 2), liver metastases (yes vs no), hemoglobin level (<10 vs ≥10 g/dL), and time from last chemotherapy dose (<3 vs ≥3 months). The study had a group sequential design to control for type I error. Primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review). ORR was a key secondary endpoint. Differences in OS and PFS were assessed in the intention-to-treat population using the stratified log-rank test Results Between November 5, 2014 and November 13, 2015, 542 patients from 29 countries were enrolled: 270 in the pembrolizumab arm, 272 in the chemotherapy arm. As of September 7, 2016, median follow-up was 9.0 months; 49 (18.4%) patients remained on pembrolizumab and 3 (1.2%) patients remained on chemotherapy. Baseline characteristics were generally balanced between arms, with 87.3% with visceral disease, 34.3% with liver metastases, 1.1% with ECOG PS 2, 81.5% with hemoglobin ≥10 g/dL, and 38.2% with <3 months since most recent chemotherapy. Pembrolizumab significantly improved OS over chemotherapy (HR 0.73, P = 0.0022; median 10.3 vs 7.4 months) (Table 1). There was no difference in PFS (HR 0.98, P = 0.42) (Table 1). ORR was significantly improved with pembrolizumab (21.1% vs 11.4%) (Table 1). Pembrolizumab was associated with fewer any-grade (60.9% vs 90.2%) grade 3-5 treatment-related AEs (15.0% vs 49.4%). 4 patients in each arm died due to treatment-related AEs. Conclusions Pembrolizumab demonstrated a statistically significant OS benefit over chemotherapy in the second-line advanced urothelial cancer setting, making it the first therapy to demonstrate a survival benefit over an active comparator in this population. The superior OS combined with the lower rate of any-grade and high-grade treatment-related AEs support pembrolizumab as a new standard of care for advanced urothelial cancer that progressed on/after platinum-based chemotherapy. Trial registration ClinicalTrials.gov identifier: NCT02256436Efficacy in KEYNOTE-045End pointPembrolizumabN = 270ChemotherapyN = 272OS, no. of events155179 Median (95 % CI), months10.3 (8.0-11.8)7.4 (6.1-8.3) HR (95 % CI)0.73 (0.59-0.91); P = 0.0022PFS, no. of events218219 Median (95 % CI), months2.1 (2.0-2.2)3.3 (2.3-3.5) HR (95 % CI)0.98 (0.81-1.19); P = 0.42ORR (95 % CI)21.1 % (16.4-26.5)11.4 % (7.9-15.8) Treatment difference, % (95 % CI)9.6 (3.5-15.9); P = 0.0011O3 Efficacy and safety of nivolumab plus ipilimumab in metastatic urothelial carcinoma: first results from the phase I/II CheckMate 032 studyPadmanee Sharma1, Margaret K Callahan2, Emiliano Calvo3, Joseph W Kim4, Filipo de Braud5, Patrick A Ott6, Petri Bono7, Rathi N Pillai8, Michael Morse9, Dung T Le10, Matthew Taylor11, Pavlina Spilliopoulou12, Johanna Bendell13, Dirk Jaeger14, Emily Chan15, Scott J Antonia16, Paolo A Ascierto17, Delphine Hennicken18, Marina Tschaika18, Alex Azrilevich18, Jonathan Rosenberg21University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain; 4Yale Cancer Center, New Haven, CT, USA; 5Istituto Nazionale dei Tumori-Università degli Studi di Milano, Milano, Lombardia, Italy; 6Dana-Farber Cancer Institute, Boston, MA, USA; 7Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; 8Emory Winship Cancer Institute, Atlanta, GA, USA; 9Duke University Medical Center, Durham, NC, USA; 10Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA; 11Oregon Health & Science University, Portland, OR, USA; 12Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; 13Sarah Cannon Research Institute and Department of Medical Oncology, Tennessee Oncology, Nashville, TN, USA; 14Heidelberg University Hospital, Heidelberg, Baden-Wurttemberg, Germany; 15Vanderbilt-Ingram University Medical Center, Nashville, TN, USA; 16H. Lee Moffitt Cancer Center, Tampa, FL, USA; 17Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy, Napoli, Italy; 18Bristol-Myers Squibb, Princeton, NJ, USACorrespondence: Padmanee Sharma (padsharma@mdanderson.org) Background Nivolumab is a programmed death-1 (PD-1) immune checkpoint inhibitor associated with clinical benefit in previously treated patients with metastatic urothelial carcinoma [1]. Preclinical and clinical data indicate that the combination of nivolumab plus ipilimumab,