Post-immunotherapy CTLA-4 Ig treatment improves antitumor efficacy.

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether CTLA-4 or PD-1 blockade. The frequency of Tregs was significantly decreased with CTLA-4 Ig. The resulting increased CD8/Treg ratio potentially underlies the enhanced efficacy of ICT followed by CTLA-4 Ig. This paradoxical mechanism shows that a CTLA-4 Ig regimen shown to reduce irAE severity does not compromise antitumor efficacy.

Tobacco and nicotine use among active component U.S. military service members: a comparison of 2018 estimates from the Health Related Behaviors Survey and the Periodic Health Assessment.

This study compared estimates of the prevalence of and risk factors for tobacco and nicotine use obtained from the 2018 Health Related Behaviors Survey (HRBS) and Periodic Health Assessment (PHA) survey. The HRBS and the PHA are important Department of Defense sources of data on health behavior collected from U.S. military service members. While their collection methods differ, some survey questions are similar, which provides an opportunity to compare survey estimates. Active duty service members consistently reported a much lower prevalence of all types of tobacco and nicotine use on the PHA compared to the HRBS: cigarettes (11.1% vs. 18.4%), e-cigarettes (7.3% vs. 16.2%), chewing tobacco (9.7% vs. 13.4%), any tobacco or nicotine use (25.3% vs. 37.8%), and use of 2 or more tobacco or nicotine products (5.8% vs. 17.4%). Associations between tobacco and nicotine use as well as demographic and other behavioral variables were fairly similar, including age, sex, education, race and ethnicity, rank, and alcohol use. The associations with service branch, body mass index, and sleep were inconsistent. This results of this study suggest that the PHA can provide timely information on trends in military tobacco and nicotine use over time, but much higher estimates from the confidential, voluntary HRBS reported in this study suggest that the command-directed PHA may substantially underestimate the prevalence of all types of tobacco and nicotine use.

Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis.

Importance: It remains unclear why only a small proportion of individuals infected with the Epstein-Barr virus (EBV) develop multiple sclerosis (MS) and what the underlying mechanisms are. Objective: To assess the serologic response to all EBV peptides before the first symptoms of MS occur, determine whether the disease is associated with a distinct immune response to EBV, and evaluate whether specific EBV epitopes drive this response. Design, Setting, and Participants: In this prospective, nested case-control study, individuals were selected among US military personnel with serum samples stored in the US Department of Defense Serum Repository. Individuals with MS had serum collected at a median 1 year before onset (reported to the military in 2000-2011) and were matched to controls for age, sex, race and ethnicity, blood collection, and military branch. No individuals were excluded. The data were analyzed between September 1, 2022, and August 31, 2023. Exposure: Antibodies (enrichment z scores) to the human virome measured using VirScan (phage-displayed immunoprecipitation and sequencing). Main Outcome and Measure: Rate ratios (RRs) for MS for antibodies to 2263 EBV peptides (the EBV peptidome) were estimated using conditional logistic regression, adjusting for total anti-EBV nuclear antigen 1 (EBNA-1) antibodies, which have consistently been associated with a higher MS risk. The role of antibodies against other viral peptides was also explored. Results: A total of 30 individuals with MS were matched with 30 controls. Mean (SD) age at sample collection was 27.8 (6.5) years; 46 of 60 participants (76.7%) were male. The antibody response to the EBV peptidome was stronger in individuals with MS, but without a discernible pattern. The antibody responses to 66 EBV peptides, the majority mapping to EBNA antigens, were significantly higher in preonset sera from individuals with MS (RR of highest vs lowest tertile of antibody enrichment, 33.4; 95% CI, 2.5-448.4; P for trend = .008). Higher total anti-EBNA-1 antibodies were also associated with an elevated MS risk (top vs bottom tertile: RR, 27.6; 95% CI, 2.3-327.6; P for trend = .008). After adjusting for total anti-EBNA-1 antibodies, risk estimates from most EBV peptides analyses were attenuated, with 4 remaining significantly associated with MS, the strongest within EBNA-6/EBNA-3C, while the association between total anti-EBNA-1 antibodies and MS persisted. Conclusion and Relevance: These findings suggest that antibody response to EBNA-1 may be the strongest serologic risk factor for MS. No single EBV peptide stood out as being selectively targeted in individuals with MS but not controls. Larger investigations are needed to explore possible heterogeneity of anti-EBV humoral immunity in MS.

Smoking and multiple sclerosis risk in black people: A nested case-control study.

BACKGROUND: Smoking is a well-established risk factor for MS; however, it is not known whether its effect on disease risk varies by race/ethnicity. METHODS: We conducted a nested case-control study among US military personnel who have serum samples stored at the Department of Defense Serum Repository. We measured serum cotinine levels, a marker of tobacco smoke exposure, in 157 Black and 23 White individuals who developed MS during follow-up. Controls were randomly selected and matched to each case by age, sex, race/ethnicity, dates of sample collection, and branch of military service. RESULTS: Smoking was not associated with an increased risk of MS in Black people (RR: 1.08, 95 % CI: 0.63-1.85). The results remained similar in analyses restricted to smoking status at baseline, to samples collected 5 years before symptom onset, and using different cut-off levels in cotinine to define smoking status. Smoking was not statistically significantly associated with MS risk in White people, but the point estimate was similar to what has previously been reported in other studies (RR: 1.85, 95 % CI: 0.56-6.16). CONCLUSIONS: Smoking was not associated with MS risk in Black people. Given the consistent association between smoking and MS risk in predominantly White populations, this may suggest that the association between smoking and MS varies by race/ethnicity.

Suicidal Behaviors Among Active-Duty US Service Members: Data from the 2018 Health-Related Behaviors Survey.

Background: This study aimed to 1) determine the prevalence of past-year suicidal ideation (SI) and attempts (SA) among active-duty SMs; 2) determine whether differences exist by age, sex, and race; and 3) assess whether prevalence estimates vary by risk profiles of mental health conditions and substance use. Methods: Data were from the 2018 Health-Related Behavior Survey (HRBS), a cross-sectional survey of active-duty SMs (n = 17,166). We used the logistic model to identify the factors of SI and SA and latent class analysis (LCA) to identify the risk profiles. Results: Among active duty SMs, 8.26% had SI and 1.25% had SA in the past year. Gender and age have been shown to influence how race might contribute to suicidal behaviors. Mental health conditions were associated with higher odds of SI and SA, as were younger ages; LGB identity; being separated, divorced, or widowed; use of e-cigarettes, dual use of e-cigarettes and cigarettes, or drugs; and history of deployment of less than 12 months. Frequencies of cigarette and e-cigarette use were also associated with SI and SA, indicating the odds were increasing by 0.3% for every additional cigarette or e-cigarette used. Five risk profiles were identified: class 1 (illegal drug use), class 2 (mental health needs with tobacco and alcohol use), class 3 (mental health conditions only), class 4 ("low risk" SMs with low levels of illegal drug use, mental health visits, tobacco use, and alcohol use), and class 5 (alcohol use). Compared to class 4 ("low risk"), all other risk profiles were associated with increased odds of suicidal behaviors. Conclusion: Despite the resources and increased access provided for mental health support, the prevalence of SI among active-duty SMs is greater than in the general population of the same age, likely due to additional military exposures and stressors.

Spatial and Spatio-Temporal Distribution of Human Respiratory Syncytial Virus, Human Parainfluenza Virus, and Human Adenoviruses Cases in Kenya 2007-2013.

Background: Human Respiratory Syncytial Virus (HRSV), Human Parainfluenza Virus (HPIV), and Human Adenovirus (HAdV) epidemics differ in geographical location, time, and virus type. Regions prone to infections can be identified using geographic information systems (GIS) and available methods for detecting spatial and time clusters. We sought to find statistically significant spatial and time clusters of HRSV, HPIV, and HAdV cases in different parts of Kenya. Methods: To analyse retrospective data, we used a geographical information system (GIS) and the spatial scan statistic. The information was gathered from surveillance sites and aggregated at the county level in order to identify purely spatial and Spatio-temporal clusters. To detect the presence of spatial autocorrelation, the local Moran's I test was used. To detect the spatial clusters of HRSV, HPIV, and HAdV cases, we performed the purely spatial scan statistic. Furthermore, space-time clusters were identified using space-time scan statistics. Both spatial and space-time analyses were based on the discrete Poisson model with a pre-specified statistical significance levelof p<0.05. Results: The findings showed that HRSV, HPIV, and HAdV cases had significant autocorrelation within the study areas. Furthermore, in the Western region of the country, the three respiratory viruses had local clusters with significant positive autocorrelation (p<0.05). Statistically, the Western region had significant spatial clusters of HRSV, HPIV, and HAdV occurrence. Furthermore, the space-time analysis revealed that the HPIV primary cluster persisted in the Western region from 2007 to 2013. However, primary clusters of HRSV and HAdV were observed in the Coastal region in 2009-11 and 2008-09, respectively. Conclusion: Human respiratory syncytial virus (HRSV), human parainfluenza virus (HPIV), and human adenovirus (HAdV) hotspots (clusters) occurred in Kenya's Western and Coastal regions from 2007 to 2013. The Western region appeared to be more prone to the occurrence of allthree respiratory viruses throughout the study period. Strategic mitigation should focus on these locations to prevent future clusters of HRSV, HPIV, and HAdV infections that could lead to epidemics.

Diagnosis of hepatitis C infection and cascade of care in the active component, U.S. Armed Forces, 2020.

Hepatitis C virus (HCV) infection rates are rising in the U.S. despite widely available tools to identify and effectively treat nearly all of these cases. This cross-sectional study aimed to use laboratory data to evaluate the prevalence of HCV diagnoses among active component U.S. military service members, describe the characteristics of those diagnosed with HCV, and evaluate the adherence of their care to current standards of practice. All service members in the active component U.S. military between 1 January and 31 December 2020 were included in the study population. The primary outcome was an HCV diagnosis at any time during military service, with secondary outcomes of HCV treatment and sustained virologic response (SVR). The initial case-finding algorithm used laboratory data to identify HCV patients seen in infectious disease and gastrointestinal disease clinics in military treatment facilities (MTFs) (direct care); this was supplemented with additional data to assess and correct for undercounting from cases occurring outside MTFs (purchased care). Thirty active component service members in 2020 had been diagnosed with HCV infection during their military service via direct care, or an estimate of 68 cases after correcting for additional cases from purchased care; this number represents only 12% of the expected number of infections based on previous studies. Of the 30 cases treated via direct care, 28 (93%) received HCV treatment, with 27 of those 28 (96%) achieving SVR. Changes to HCV screening policy for military accessions should be considered in order to effectively identify and treat asymptomatic HCV infections that would otherwise go undetected.

Cigarette smoking patterns among U.S. military service members before and after separation from the military.

U.S. military Service members have consistently smoked more than the general population and the prevalence of smoking is even higher among U.S. veterans. Our study examined cigarette smoking patterns among Service members before and after military separation to better understand the disproportionate rate of smoking among veterans. Data from the Millennium Cohort Study were used. All study participants were in the military at baseline and some transitioned from the military to civilian life during the observation period. We investigated any impact of military separation on smoking, as well as other potential risk factors for smoking. Overall, we observed higher smoking prevalence among veterans than Service members. Additionally, we found that Service members smoked more while approaching their separation from the military. Longitudinal analysis revealed military separation was not a risk factor for smoking, as we had hypothesized. Baseline smoking was the most influential predictor of current smoking status. Other significant factors included alcohol consumption, life stressors, and mental health conditions, among others. Military separation was not a risk factor for smoking. However, Service members in the process of transitioning out of the military, as well as high alcohol consumers and Service members with mental health conditions, may be at higher risk of smoking. Including smoking prevention/cessation programs in pre-separation counseling sessions and developing smoking screening and cessation programs targeting specific high-risk subgroups may reduce smoking among Service members and veterans.

E-cigarette and dual product use as an emerging health threat to the US military.

INTRODUCTION: Cigarette and e-cigarette use are threats to the health and readiness of the US military. The study objective was to determine the prevalence and factors associated with e-cigarette, cigarette, and dual use among active duty service members (SMs). METHODS: We used data from the 2015 Health Related Behaviors Survey-a crosssectional survey weighted to represent the US military (n=16699). Weighted prevalence and odds ratios assessed associations between risk factors and e-cigarette/cigarette use via weighted multinomial logistic models. RESULTS: The prevalence of cigarette use in the US military declined from 24% in 2011 to 13.8% in 2015. However, e-cigarette use (12.4%) and dual product use (4.7%) increased during this period. Additionally, prevalence of e-cigarette use was higher in the military compared to the general population (12.4% vs 3.5%), particularly among those aged 17-24 years (22.8% vs 5.2%); cigarette use was also higher in the military in this age group (19.3% vs 13.0%). After adjustment, SMs who were enlisted, lacked a Bachelor's degree, and/or had probable alcohol use disorder had significantly greater odds of cigarette, e-cigarette, and dual use. While SMs aged 17-24 years had the highest prevalence of all types of product use, only being aged ≥45 years was significantly associated with decreased odds of product use in adjusted models. CONCLUSIONS: Military efforts to control cigarette use among SMs seem to have been successful, as demonstrated by the dramatic declines in its use and the lower prevalence seen in the military compared to the general population. However, the concurrent increases in e-cigarette use are concerning, particularly among the youngest members of the military. The US military must continue to monitor emerging trends in e-cigarette, cigarette, and dual use and rapidly take steps to address them as threats to health and readiness.

Prevalence of human respiratory syncytial virus, parainfluenza and adenoviruses in East Africa Community partner states of Kenya, Tanzania, and Uganda: A systematic review and meta-analysis (2007-2020).

BACKGROUND: Viruses are responsible for a large proportion of acute respiratory tract infections (ARTIs). Human influenza, parainfluenza, respiratory-syncytial-virus, and adenoviruses are among the leading cause of ARTIs. Epidemiological evidence of those respiratory viruses is limited in the East Africa Community (EAC) region. This review sought to identify the prevalence of respiratory syncytial virus, parainfluenza, and adenoviruses among cases of ARTI in the EAC from 2007 to 2020. METHODS: A literature search was conducted in Medline, Global Index Medicus, and the grey literature from public health institutions and programs in the EAC. Two independent reviewers performed data extraction. We used a random effects model to pool the prevalence estimate across studies. We assessed heterogeneity with the I2 statistic, and Cochran's Q test, and further we did subgroup analysis. This review was registered with PROSPERO under registration number CRD42018110186. RESULTS: A total of 12 studies met the eligibility criteria for the studies documented from 2007 to 2020. The overall pooled prevalence of adenoviruses was 13% (95% confidence interval [CI]: 6-21, N = 28829), respiratory syncytial virus 11% (95% CI: 7-15, N = 22627), and parainfluenza was 9% (95% CI: 7-11, N = 28363). Pooled prevalence of reported ARTIs, all ages, and locality varied in the included studies. Studies among participants with severe acute respiratory disease had a higher pooled prevalence of all the three viruses. Considerable heterogeneity was noted overall and in subgroup analysis. CONCLUSION: Our findings indicate that human adenoviruses, respiratory syncytial virus and parainfluenza virus are prevalent in Kenya, Tanzania, and Uganda. These three respiratory viruses contribute substantially to ARTIs in the EAC, particularly among those with severe disease and those aged five and above.

Morbidity burden, seasonality and factors associated with the human respiratory syncytial virus, human parainfluenza virus, and human adenovirus infections in Kenya.

Background: Human respiratory syncytial viruses (HRSV), human parainfluenza viruses (HPIV), and human adenoviruses (HAdVs) cause a substantial morbidity burden globally. Objective: We sought to estimate morbidity burden, assess seasonality, and determine factors associated with these respiratory viruses in Kenya. Methods: The data were obtained from Kenyan sites included in the Köppen-Geiger climate classification system. We defined the proportion of morbidity burden by descriptive analysis and visualized time-series data for January 2007-December 2013. Logistic regression was used to identify factors associated with infection outcomes. Results: The morbidity burden for HRSV was 3.1%, HPIV 5.3% and HAdVs 3.3%. Infants were more likely to be infected than other age groups. HRSV exhibited seasonality with high occurrence in January-March (odds ratio[OR] = 2.73) and April-June (OR = 3.01). Hot land surface temperature (≥40 °C) was associated with HRSV infections (OR = 2.75), as was warmer air temperature (19-22.9 °C) (OR = 1.68), compared with land surface temperature (<30) and cooler air temperature (<19 °C) respectively. Moderate rainfall (150-200 mm) areas had greater odds of HRSV infection (OR = 1.32) than low rainfall (<150 mm). Conclusion: HRSV, HPIV and HAdVs contributed to morbidity burden, and infants were significantly affected. HRSV had a clear seasonal pattern and were associated with climate parameters, unlike HPIV and HAdVs.

Checkpoint Blockade + Chemotherapy: the Right Combination for AML?

An emerging strategy to enhance the efficacy of immune checkpoint blockade in relapsed/refractory cancers is increasing immunogenic cell death via combination with cytotoxic therapies. Understanding the effects of cytotoxic and immunotherapeutic agents on immune cell populations will enable improved mechanism-based design of combination therapies to maximum efficacy and minimum toxicity.See related article by Zeidner et al., p. 616.

A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention.

Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of Ctla4 in the context of complete genetic absence of Pdcd1 leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4-Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. SIGNIFICANCE: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4-Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies.See related commentary by Young and Bluestone, p. 537.This article is highlighted in the In This Issue feature, p. 521.

Safety of Ertugliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Seven Phase 3 Randomized Controlled Trials.

INTRODUCTION: The sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin is approved for the treatment of adults with type 2 diabetes mellitus (T2DM). This analysis was conducted on safety data pooled from phase 3 studies using ertugliflozin 5 mg or 15 mg versus placebo or an active comparator. METHODS: The placebo pool (n = 1544) comprised data from three similarly designed 26-week placebo-controlled studies. The broad pool (n = 4849) comprised these three placebo-controlled studies plus four placebo- or active-controlled studies with treatment durations of up to 104 weeks. RESULTS: In the placebo pool, there were no notable differences across groups in the incidence of adverse events (AEs), serious AEs, or AEs resulting in discontinuation from study medication, while associations were observed with genital mycotic infection in both females (3.0%, 9.1%, and 12.2% in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively) and males (0.4%, 3.7%, 4.2%), thirst (0.2%, 1.3%, 1.0%), and increased urination (1.0%, 2.7%, 2.4%). In the broad pool, volume depletion was increased with ertugliflozin in patients with estimated glomerular filtration rate < 60 ml/min/1.73 m2, aged ≥ 65 years, or who were taking diuretics. Ertugliflozin was not associated with increased urinary tract infection, fracture, hypoglycemia, pancreatitis, renal or hepatic injury, hypersensitivity, malignancy, or venous thromboembolism. Small numbers of patients were reported with lower limb amputation [0.1% (non-ertugliflozin group), 0.2% (ertugliflozin 5 mg), 0.5% (ertugliflozin 15 mg)]. There were three cases of ketoacidosis (all ertugliflozin 15 mg) and no cases of Fournier's gangrene. CONCLUSION: This pooled analysis showed that ertugliflozin was generally well tolerated in a large population of patients with T2DM with and without moderate renal impairment who were taking a range of background diabetes medications including insulin and insulin secretagogs, with results that are generally consistent with those for other SGLT2 inhibitors. TRIAL REGISTRATION: Clinicaltrials.gov indentifier, NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218.

Analyzing outcomes of neoadjuvant and adjuvant treatment for borderline-resectable pancreatic adenocarcinoma in the perioperative period at an academic institution.

BACKGROUND: Only 15-20% of pancreatic ductal adenocarcinoma (PDAC) patients are upfront surgical candidates at presentation, and for this cohort of patients, the 5-year survival is a mere 20% despite adjuvant therapy. Previous data indicate that in clinical practice most of these cases are "borderline-resectable," and there is currently no mature data on perioperative treatment. METHODS: We performed a retrospective electronic chart review of patients with "borderline-resectable"PDAC treated at an academic comprehensive cancer center, dividing them into groups based on surgery alone, surgery plus neoadjuvant, adjuvant, or neoadjuvant plus adjuvant perioperative treatment groups. The objectives were to determine the median overall survival (mOS), progression-free survival (PFS) and disease-free survival (DFS). Statistical analysis was performed to assess the association of demographic, tumor traits, and interventions with OS, PFS and DFS. RESULTS: Only surgery followed by adjuvant therapy showed an increase in mOS [hazard ratio (HR) 0.22; 95% CI, 0.09-0.51; P<0.001), after adjustment for radiation (yes vs. no), resection margins (R0 vs. R1 or R2), and tumor location (head vs. body or tail). Patients who received adjuvant therapy after surgery had 2.1 times greater odds to be alive at 24 months after diagnosis than those who had surgery alone (P=0.015). PFS and DFS were not statistically significantly different among treatment groups after adjustment. Those whose disease was located in the head of the pancreas had a significantly improved OS (HR =0.27; 95% CI, 0.11-0.64; P=0.003), PFS (HR =0.40; 95% CI, 0.17-0.94; P=0.035), and DFS (HR =0.30; 95% CI, 0.13-0.67; P=0.004). Negative margins led to a significant improvement in PFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001) and DFS (HR =0.30; 95% CI, 0.16-0.57; P<0.001). Those who received radiation had a non-significantly improved OS, PFS, and DFS (P>0.05). CONCLUSIONS: Our study corroborated that patients treated with adjuvant therapy after surgical resection had an mOS benefit as reported on prior phase III clinical trials. Patients with "borderline-resectable" pancreatic cancer are encouraged to participate in a clinical trial or clinically be treated with adjuvant therapy until more mature results from the ongoing perioperative prospective study are available.

HIV Care Continuum and Meeting 90-90-90 Targets: Cascade of Care Analyses of a U.S. Military Cohort.

INTRODUCTION: The new initiative by the Department of Health and Human Services (DHHS) aims to decrease new HIV infections in the U.S. by 75% within 5 years and 90% within 10 years. Our objective was to evaluate whether the U.S. military provides a good example of the benefits of such policies. MATERIALS AND METHODS: We conducted an analysis of a cohort of 1,405 active duty military personnel with HIV enrolled in the Natural History Study who were diagnosed between 2003 and 2015 at six U.S. military medical centers. The study was approved by institutional review boards at the Uniformed Services University of the Health Sciences and each of the sites. We evaluated the impact of Department of Defense (DoD) HIV care policies, including screening, linkage to care, treatment eligibility, and combined antiretroviral therapy (cART) initiation on achieving viral suppression (VS) within 3 years of diagnosis. As a secondary outcome, we evaluated the DoD's achievement of UNAIDS 90-90-90 targets. RESULTS: Nearly all (99%) were linked to care within 60 days. Among patients diagnosed in 2003-2009, 77.5% (95% confidence intervals (CI) 73.9-80.6%) became eligible for cART within 3 years of diagnosis, 70.6% (95% CI 66.6-74.1%) overall initiated cART, and 64.2% (95% CI 60.1-68.0%) overall achieved VS. Among patients diagnosed in 2010-2015, 98.7% (95% CI 96.7-99.5%) became eligible for cART within 3 years of diagnosis, 98.5% (95% CI 96.4-99.4%) overall initiated cART, and 89.8% (95% CI 86.0-92.5%) overall achieved VS. CONCLUSIONS: U.S. military HIV policies have been highly successful in achieving VS goals, exceeding the UNAIDS 90-90-90 targets. In spite of limitations, including generalizability, this example demonstrates the feasibility of the DHHS initiative to decrease new infections through testing, early treatment, and retention in care.

STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer.

Conventional dendritic cells (cDCs) are a critical immune population, composed of multiple subsets, and responsible for controlling adaptive immunity and tolerance. Although migratory type 1 cDCs (CD103+ cDC1s in mice) are necessary to mount CD8+ T cell-mediated anti-tumor immunity, whether and how tumors modulate CD103+ cDC1 function remain understudied. Signal Transducer and Activator of Transcription 3 (STAT3) mediates the intracellular signaling of tumor-associated immunosuppressive cytokines, such as interleukin (IL)-10; thus, we hypothesized that STAT3 restrained anti-tumor immune responses elicited by CD103+ cDC1s. Herein, we show that in vitro-derived STAT3-deficient (Stat3∆/∆) CD103+ cDC1s are refractory to the inhibitory effects of IL-10 on Toll-like receptor 3 (TLR3) agonist-induced maturation responses. In a tumor vaccination approach, we found Stat3∆/∆ CD103+ cDC1s restrained mammary gland tumor growth and increased mouse survival more effectively than STAT3-sufficient CD103+ cDC1s. In addition, vaccination with Stat3∆/∆ CD103+ cDC1s elicited increased amounts of tumor antigen-specific CD8+ T cells and IFN-γ+ CD4+ T cells in tumors and tumor-draining lymph nodes versus phosphate-buffered saline (PBS)-treated animals. Furthermore, IL-10 receptor-deficient CD103+ cDC1s controlled tumor growth to a similar degree as Stat3∆/∆ CD103+ cDC1s. Taken together, our data reveal an inhibitory role for STAT3 in CD103+ cDC1 maturation and regulation of anti-tumor immunity. Our results also suggest IL-10 is a key factor eliciting immunosuppressive STAT3 signaling in CD103+ cDC1s in breast cancer. Thus, inhibition of STAT3 in cDC1s may provide an important strategy to improve their efficacy in tumor vaccination approaches and cDC1-mediated control of anti-tumor immunity.

Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies.

Immune checkpoint blockade therapy targets T cell-negative costimulatory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). Combination anti-CTLA-4 and anti-PD-1 blockade therapy has enhanced efficacy, but it remains unclear through what mechanisms such effects are mediated. A critical question is whether combination therapy targets and modulates the same T cell populations as monotherapies. Using a mass cytometry-based systems approach, we comprehensively profiled the response of T cell populations to monotherapy and combination anti-CTLA-4 plus anti-PD-1 therapy in syngeneic murine tumors and clinical samples. Most effects of monotherapies were additive in the context of combination therapy; however, multiple combination therapy-specific effects were observed. Highly phenotypically exhausted cluster of differentiation 8 (CD8) T cells expand in frequency following anti-PD-1 monotherapy but not combination therapy, while activated terminally differentiated effector CD8 T cells expand only following combination therapy. Combination therapy also led to further increased frequency of T helper type 1 (Th1)-like CD4 effector T cells even though anti-PD-1 monotherapy is not sufficient to do so. Mass cytometry analyses of peripheral blood from melanoma patients treated with immune checkpoint blockade therapies similarly revealed mostly additive effects on the frequencies of T cell subsets along with unique modulation of terminally differentiated effector CD8 T cells by combination ipilimumab plus nivolumab therapy. Together, these findings indicate that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy.

A Multidisciplinary Evaluation of Barriers to Enrolling Cancer Patients into Early Phase Clinical Trials: Challenges and Patient-centric Recommendations.

Introduction: Early phase clinical trials are the first clinical research step to bringing new cancer therapeutics to patients. At this stage, a new drug's safety, dosing, and scheduling profiles are established as the main endpoints. However, excellent responses due to biomarker-guided and immune checkpoint trials in early phase have resulted in direct approvals of new anti-cancer drugs. Despite doubling of the success rate of new drug approvals, many barriers exist to expeditiously bring active new drugs to the clinic. Areas covered: This review covers roles of members of the early phase program and the challenges they face in enrolling advanced cancer patients to trials. Practical solutions are provided from the perspective of the investigators, regulatory, investigational pharmacy, research nurses, clinical research coordinators, budgets, contracts, and data management. Expert opinion: We are witnessing a burgeoning era in drug development with rapid approval of efficacious drugs. This is achieved by a strong collaboration between investigators, academic institutions, pharmaceutical sponsors, scientists, Food and Drug Administration (FDA), and community practices. Herein, we discuss some of the challenges faced by early phase clinical trials programs and discuss methods of improvement.