Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages.

Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.

Demographic diversity of US-based participants in GSK-sponsored interventional clinical trials.

BACKGROUND: Demographic diversity among clinical trials is required for representing the real-world populations intended for treatment and disease prevention. Moreover, genetic and environmental differences between ethnic and racial groups necessitate appropriately powered trials for relevant subgroups. We investigate the racial and ethnic demographic diversity of US-based participants in GSK-sponsored interventional trials. We also assess the evaluation of demographic diversity against US Census and epidemiologic data. METHODS: GSK-sponsored interventional phase I-IV clinical trials conducted from 2002 to 2019 across three areas were analyzed: pharmaceutical (includes therapeutic medicines except for vaccines and human immunodeficiency virus (HIV)), vaccine (includes prophylactic and therapeutic vaccines), and ViiV (includes HIV therapies). A total of 1005 global trials encompassing 460,707 global participants were identified, of which 495 had US-based sites with a total of 108,261 (23.5% of global) US participants (pharmaceutical, n = 357 trials; vaccine, n = 45 trials; and ViiV, n = 93 trials). We evaluated how GSK US-based trial recruitment compares with US Census (in line with previously published studies from other groups) and with epidemiologic data. RESULTS: GSK participant data for race and ethnicity combined across areas were generally similar to US Census levels (e.g. GSK versus census: White, 76.5% versus 76.3%; Black or African American, 15.1% versus 13.4%; Asian, 1.8% versus 5.9%; Hispanic or Latino, 14.0% versus 18.5%; Non-Hispanic White, 63.5% versus 60.1%). However, this was not the case for the individual pharmaceutical, vaccine, and ViiV data sets; least represented groups were Asian individuals for pharmaceutical and ViiV trials and American Indian or Alaskan Native individuals for vaccine trials (6.2%, 11.8%, and 11.1% of trials met/exceeded census level representation, respectively). The percentage of trials reaching/exceeding census levels also varied per trial phase for race and ethnicity. Furthermore, disparities in the percentage of trials reaching/exceeding census levels versus epidemiology-based prevalence levels have revealed opportunities to improve industry success metrics; in HIV trials, the proportion of Black or African American individuals (35.1%) exceeded census (13.4%) but not epidemiologic levels (55.3%). CONCLUSION: Further work is required to achieve demographic diversity across clinical trials. We conclude that US Census data are an inappropriate universal benchmark. A shift to epidemiology benchmarking will enable the consideration of global participants into US analyses for highly intrinsic (i.e. influenced by ancestry) diseases and more firm requirements for US-based participants into US analyses for extrinsic (i.e. influenced by location or culture) diseases. Benchmarking in line with epidemiologic data will allow us to set better trial enrollment goals, with the aim of conducting more demographically balanced, diverse, and representative clinical trials and enabling a better understanding of drug safety and efficacy per demographic group.

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function.

Regulatory T (Treg) cells have a critical role in the control of immunity, and their diverse subpopulations may allow adaptation to different types of immune responses. In this study, we analyzed human Treg cell subpopulations in the peripheral blood by performing genome-wide expression profiling of 40 Treg cell subsets from healthy donors. We found that the human peripheral blood Treg cell population is comprised of five major genomic subgroups, represented by 16 tractable subsets with a particular cell surface phenotype. These subsets possess a range of suppressive function and cytokine secretion and can exert a genomic footprint on target effector T (Teff) cells. Correlation analysis of variability in gene expression in the subsets identified several cell surface molecules associated with Treg suppressive function, and pharmacological interrogation revealed a set of genes having causative effect. The five genomic subgroups of Treg cells imposed a preserved pattern of gene expression on Teff cells, with a varying degree of genes being suppressed or induced. Notably, there was a cluster of genes induced by Treg cells that bolstered an autoinhibitory effect in Teff cells, and this induction appears to be governed by a different set of genes than ones involved in counteracting Teff activation. Our work shows an example of exploiting the diversity within human Treg cell subpopulations to dissect Treg cell biology.

Take Heart America: A comprehensive, community-wide, systems-based approach to the treatment of cardiac arrest.

OBJECTIVES: To determine out-of-hospital cardiac arrest survival rates before and after implementation of the Take Heart America program (a community-based initiative that sequentially deployed all of the most highly recommended 2005 American Heart Association resuscitation guidelines in an effort to increase out-of-hospital cardiac arrest survival). PATIENTS: Out-of-hospital cardiac arrest patients in Anoka County, MN, and greater St. Cloud, MN, from November 2005 to June 2009. INTERVENTIONS: Two sites in Minnesota with a combined population of 439,692 people (greater St. Cloud and Anoka County) implemented: 1) widespread cardiopulmonary resuscitation and automated external defibrillator skills training in schools and businesses; 2) retraining of all emergency medical services personnel in methods to enhance circulation, including minimizing cardiopulmonary resuscitation interruptions, performing cardiopulmonary resuscitation before and after single-shock defibrillation, and use of an impedance threshold device; 3) additional deployment of automated external defibrillators in schools and public places; and 4) protocols for transport to and treatment by cardiac arrest centers for therapeutic hypothermia, coronary artery evaluation and treatment, and electrophysiological evaluation. MEASUREMENTS AND MAIN RESULTS: More than 28,000 people were trained in cardiopulmonary resuscitation and automated external defibrillator use in the two sites. Bystander cardiopulmonary resuscitation rates increased from 20% to 29% (p = .086, odds ratio 1.7, 95% confidence interval 0.96-2.89). Three cardiac arrest centers were established, and hypothermia therapy for admitted out-of-hospital cardiac arrest victims increased from 0% to 45%. Survival to hospital discharge for all patients after out-of-hospital cardiac arrest in these two sites improved from 8.5% (nine of 106, historical control) to 19% (48 of 247, intervention phase) (p = .011, odds ratio 2.60, confidence interval 1.19-6.26). A financial analysis revealed that the cardiac arrest centers concept was financially feasible, despite the costs associated with high-quality postresuscitation care. CONCLUSIONS: The Take Heart America program doubled cardiac arrest survival when compared with historical controls. Study of the feasibility of generalizing this approach to larger cities, states, and regions is underway.

Implementing the 2005 American Heart Association guidelines, including use of the impedance threshold device, improves hospital discharge rate after in-hospital cardiac arrest.

OBJECTIVE: To determine the impact of the 2005 American Heart Association cardiopulmonary resuscitation (CPR) guidelines, including use of an impedance threshold device (ITD), on survival after in-hospital cardiac arrest. METHODS: Two community hospitals that tracked outcomes after in-hospital cardiac arrest pooled and compared their hospital discharge rate before and after implementing the 2005 American Heart Association CPR guidelines (including ITD) in standardized protocols. In CPR we used the proper ventilation rate, allowed full chest-wall recoil, conducted continuous CPR following intubation, and used an ITD. We compared historical control data from a 12-month period at St Cloud Hospital, St Cloud, Minnesota, to data from a subsequent 18-month intervention phase. We compared historical control data from a 12-month period at St Dominic Hospital, Jackson, Mississippi to a subsequent 12-month intervention phase. 507 patients received CPR during the study period. Patient age and sex were similar in the control and intervention groups. RESULTS: The combined hospital discharge rate for patients with an in-hospital cardiac arrest was 17.5% in the control group (n=246 patients), which is similar to the national average, versus 28% in the intervention group (n=261 patients) (P=.006, odds ratio 1.83, 95% CI 1.17-2.88). The greatest benefit of the intervention was in patients with an initial rhythm of pulseless electrical activity: 14.4% versus 29.7% (P=.014, odds ratio 2.50, 95% CI 1.15, 5.58). Neurological function (as measured with the Cerebral Performance Category scale) in survivors at hospital discharge was similar between the groups. CONCLUSIONS: Implementation of improved ways to increase circulation during CPR increased the in-hospital discharge rate by 60%, compared to historical controls in 2 community hospitals. These data demonstrate that immediate care with improved means to circulate blood during CPR significantly reduces hospital mortality from inhospital sudden cardiac arrest.

Awakening after cardiac arrest and post resuscitation hypothermia: are we pulling the plug too early?

BACKGROUND: Time to awakening after out-of-hospital cardiac arrest (OHCA) and post-resuscitation therapeutic hypothermia (TH) varies widely. We examined the time interval from when comatose OHCA patients were rewarmed to 37°C to when they showed definitive signs of neurological recovery and tried to identify potential predictors of awakening. METHODS: With IRB approval, a retrospective case study was performed in OHCA patients who were comatose upon presentation to a community hospital during 2006-2010. They were treated with TH (target of 33°C) for 24h, rewarmed, and discharged alive. Comatose patients were generally treated medically after TH for at least 48h before any decision to withdraw supportive care was made. Pre-hospital TH was not used. Data are expressed as medians and interquartile range. RESULTS: The 89 patients treated with TH in this analysis were divided into three groups based upon the time between rewarming to 37°C and regaining consciousness. The 69 patients that regained consciousness in ≤48h after rewarming were termed "early-awakeners". Ten patients regained consciousness 48-72h after rewarming and were termed "intermediate-awakeners". Ten patients remained comatose and apneic >72h after rewarming but eventually regained consciousness; they were termed "late-awakeners". The ages for the early, intermediate and late awakeners were 56 [49,65], 62 [48,74], and 58 [55,65] years, respectively. Nearly 67% were male. Following rewarming, the time required to regain consciousness for the early, intermediate and late awakeners was 9 [2,18] (range 0-47), 60.5 [56,64.5] (range 49-71), and 126 [104,151]h (range 73-259), respectively. Within 90 days of hospital admission, favorable neurological function based on a Cerebral Performance Category (CPC) score of 1 or 2 was reported in 67/69 early, 10/10 intermediate, and 8/10 late awakeners. CONCLUSION: Following OHCA and TH, arbitrary withdrawal of life support <48h after rewarming may prematurely terminate life in many patients with the potential for full neurological recovery. Additional clinical markers that correlate with late awakening are needed to better determine when withdrawal of support is appropriate in OHCA patients who remain comatose >48h after rewarming.