An overview of systematic reviews(SRs) and network meta-analysis(NMA) were conducted to evaluate the comparative effectiveness of peri-discharge complex interventions for reducing 30-day readmissions among chronic obstructive pulmonary disease(COPD) patients.Five databases were searched for SRs of randomized controlled trials(RCTs). An additional search was conducted for updated RCTs from database inception until Jun 2020. Pooled effect of peri-discharge complex interventions was assessed using random-effect pairwise meta-analyses. Comparative effectiveness across different peri-discharge complex interventions was evaluated using NMA.Nine SRs and 11 eligible RCTs assessing eight different peri-discharge complex interventions were included. For reducing 30-day all-cause readmissions, pairwise meta-analysis showed no significant difference between peri-discharge complex interventions and usual care, while NMA indicated no significant differences among different peri-discharge complex interventions as well as usual care. For reducing 30-day COPD-related readmissions, peri-discharge complex interventions were significantly more effective than usual care .Peri-discharge complex interventions may not differ from usual care in reducing 30-day all-cause readmissions among COPD patients but some are more effective for lowering 30-day COPD-related readmission. Thus, complex intervention comprising core components of patient education, self-management, patient-centred discharge instructions, and telephone follow up may be considered for implementation, but further evaluation is warranted. Chronic obstructive pulmonary disease (COPD) is a progressive and life-limiting disease that imposes a huge clinical and economic burden on health system . In 2019467812Fortunately, it is estimated that up to 37% of 30-day readmissions among COPD patients are preventable . To resp19The key goal of these peri-discharge complex interventions is to ensure a seamless transition from inpatient to outpatient care. Quality of such transition is considered as one of the key factors associated with successful prevention of avoidable 30-day hospital readmissions . These pIn practice, the nature and components of peri-discharge complex interventions vary across health systems. For example, discharge support intervention can be included in both pre-discharge preparation and post-discharge care for COPD patients . For preExisting studies have summarized the effectiveness of various peri-discharge complex interventions for reducing readmissions at different time points 22232728,222327Table 1.This study was reported according to the PRISMA extension statement for NMA . ProtocoSR is defined as an “endeavour to identify, appraise, and synthesize all the evidence that fulfils pre-specified eligibility criteria to answer a specific research question” in the Cochrane Handbook version 6 . AccordiParticipants should be adult patients (≥18 years) admitted from the community to a hospital inpatient ward for 24 hours or more with a diagnosis of COPD. Participants with behavioural health issues, pediatric, or obstetric admission were excluded.Interventions should be any pre-emptive peri-discharge complex interventions for reducing readmissions, which were compared with any types of control as comparisons, including usual care. In this study, peri-discharge complex interventions referred to interventions comprising multiple interacting components delivered during the peri-discharge process . Usual cEligible SRs should report readmission outcomes in both intervention and control groups among the embedded RCTs. Details are listed in the paragraph below.After including all eligible SRs, embedded RCTs were extracted and assessed for eligibility criteria as well. To be included, an embedded RCT should fulfill the same criteria for participants, interventions, and comparisons for SRs as abovementioned. For outcomes, eligible RCTs should report 30-day all-cause or 30-day COPD-related readmissions in both intervention and control groups. Primary and main secondary outcomes are 30-day all-cause and 30-day COPD-related readmissions, respectively. These two outcomes are chosen because they are considered to be modifiable by appropriate peri-discharge complex interventions among policy makers . For ins34Other secondary outcomes included 3-month and 6-month all-cause readmissions, as well as 30-day mortality. The 3-month and 6-month readmission outcomes are selected as they can reflect the medium-term impact of peri-discharge complex interventions. These readmissions are known to be associated with a substantial risk of mortality and adverse impacts on health-related quality of life 37. LowerWe searched for SRs in MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Global Health, and AMED from the databases’ inception till August 2019. We applied specialized filters with balanced sensitivity and specificity for SRs in MEDLINE and EMBASE. No restrictions on publication status were imposed.Table 1.To be more comprehensive, we conducted an updated search for potentially eligible RCTs in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials published from databases’ inception till Jun 2020. Detailed search strategies for SRs and RCTs are shown in Appendix 1a-1b, respectively. Their eligibility criteria were the same as illustrated in Literature selection, data extraction, methodological quality assessments , risk of40We used the validated AMSTAR 2 instrument  to appraIn each included RCTs, peri-discharge complex interventions for reducing readmissions consisted of different components. To facilitate analysis, we coded components of different peri-discharge complex interventions based on a published classification framework   high certainty category containing interventions supported by moderate or high quality of evidence; and ii) low certainty category containing interventions supported by low or very low quality of evidence. Finally, we checked consistency between the network estimates among all possible pairs of comparisons and SUCRA rankings, so as to finalize the classification of all interventions.Figure 1.A total of nine SRs were identified and considered to be eligible (Appendix 5a). These nine SRs synthesized 76 primary studies, of which 71 were excluded due to the following: being duplicates (n = 13); no intervention for reducing readmission evaluated, or no data on 30-day readmission rate reported (n = 52); not RCTs (n = 4); written in languages other than English/Chinese (n = 2). The additional literature search identified six RCTs that were considered eligible (Appendix 4). Therefore, a total of 11 RCTs were included (Appendix 5b). Details of the literature search and selection process are presented in Table 2. They included a total of 1,422 COPD patients, with sample sizes varying from 30 to 253. The mean age range was 64.4 to 75.3 years.Characteristics of the included RCTs are presented in Table 3 and Appendix 3.There were five peri-discharge complex interventions evaluated in the intervention group: discharge coordinator intervention (n = 2), discharge rehabilitation (n = 2), early discharge intervention (n = 2), home based telemedicine (n = 2), and supported self-management program (n = 3). Components of each peri-discharge complex intervention and their definitions are presented in Table 3. The remaining five studies reported the use of usual care as control, which was defined as routine care provided by the hospital. Detailed contents of usual care were not mentioned in these five studies.Different peri-discharge complex interventions were evaluated as controls among the included studies: discharge education (n = 2), follow up appointment (n = 2), rehabilitation education (n = 2). Components of peri-discharge complex interventions serving as controls are presented in Amongst the nine included SRs, methodological quality of six SRs was moderate (66.7%). Two (22.2%) were appraised as low, and one (11.1%) as critically low (Appendix 6). For the 11 included RCTs, we judged the overall risk of bias of four (36.4%) RCTs as low, one (9.1%) as high, and the remaining six (54.5%) as having some concerns (Appendix 7a). Detailed results of the risk of bias assessment on each domain are presented in Appendix 7b.2 = 0%, 9 RCTs) (Appendix 8a). The overall quality of evidence was high (Table 4).For the reduction of 30-day all-cause readmissions, there was no significant difference between peri-discharge complex interventions and controls from pairwise meta-analyses  (Appendix 8b), and 3-month all-cause readmissions  (Appendix 8c), as supported by high quality evidence (Table 4). For other secondary outcomes, moderate quality evidence showed that there was no significant difference between peri-discharge complex interventions and controls in reducing 6-month all-cause readmissions  , and 30-day mortality  .For secondary outcomes, peri-discharge complex interventions were significantly more effective than controls in reducing 30-day COPD-related readmissions . Results are presented in Appendix 10 and Table 4.Results of sensitivity analysis focusing on three RCTs with low risk of bias showed no significant difference between peri-discharge complex interventions and controls for reducing 30-day all-cause readmissions ; ii) peri-discharge complex interventions vs. usual care . Quality of evidence ratings for subgroup analysis are also presented in Table 4.Results of subgroup analysis based on different comparisons in the control groups were presented in Appendix 11. There was no significance difference in the following subgroups comparisons for reducing 30-day all-cause readmissions: i) peri-discharge complex interventions vs. rehabilitation education . Size of nodes indicated that usual care was the most common comparator across the included studies. NMA results showed no significant difference among these eight different peri-discharge complex interventions and usual care (Appendix 12).For the primary outcome of reducing 30-day all-cause readmissions, the network included nine two-arm trials . Results on inconsistency evaluation using the SIDE approach were shown in Appendix 16. As the difference between direct and indirect estimates for each comparison was statistically insignificant, it can be considered that there is no significant inconsistency in this network.For all secondary outcomes, peri-discharge complex interventions of the included studies did not share a common comparator, hence we could not conduct NMA and evaluate their comparative effectiveness.In this overview of SRs, pairwise meta-analyses showed that there was no significant difference between peri-discharge complex interventions and controls on reducing 30-day all-cause readmissions, 30-day mortality, and 6-month all-cause readmissions among COPD patients. Peri-discharge complex interventions were significantly more effective than controls in reducing 30-day COPD-related readmissions and 3-month all-cause readmissions. As shown in the NMA for 30-day all-cause readmissions, there was no significant difference among the eight peri-discharge complex interventions and usual care. The final classification of complex interventions indicated that discharge rehabilitation was not different from usual care with high certainty of evidence, while the remaining seven peri-discharge complex interventions might be no different from usual care with low certainty of evidence.For the primary outcome of reducing 30-day all-cause readmissions, low certainty of evidence indicated that most complex interventions might be no different from usual care. Nevertheless, our pairwise meta-analysis showed that peri-discharge complex interventions were significantly more effective than controls on reducing 30-day COPD-related readmissions, as supported by high quality evidence. Indeed, COPD-related readmissions accounted for majority of the hospital readmissions within 30 days among COPD patients . TherefoFour component peri-discharge complex interventions hereafter) is likely to be context-sensitive. The decision of implementing such interventions in different health system contexts requires careful deliberations. In the following discussion, we consider selected criteria listed in GRADE Evidence to Decision (EtD) framework [These effective peri-discharge complex interventions included discharge rehabilitation, supported self-management program, and discharge coordinator intervention. There are several common components among these three peri-discharge complex interventions, namely patient education, self-management, patient-centred discharge instructions, and telephone follow up. These four components might be the core effective elements that play a significant role in contributing to the reduction of 30-day COPD-related readmission. However, potential effectiveness of this four-component package (peri-discharge complex interventions comprising patient education, self-management, patient-centred discharge instructions, and telephone follow up, abbreviated as ramework , which mAs a chronic, long-term, and complex illness with multiple systemic effects and co-morbidities, COPD requires a multi-disciplinary and multi-modality approach for optimal management. As suggested by COPD patients, patient education could improve their overall satisfaction with healthcare providers , while sPatient education and self-management are widely accepted by both COPD patients and health professionals. Patients were eager to learn more information about the disease and the self-management approaches . Evaluat646566Four component peri-discharge complex interventions could be challenging. Potential barriers towards adopting self-management among COPD patients may include feeling of fear towards increased incidence of exacerbation; perceived lack of capacity to manage exacerbation; and insufficient knowledge on the consequences of inadequate treatment [72Four component peri-discharge complex interventions among COPD patients [75Despite positive views on benefits and acceptability described above, the implementation of the reatment 7273. To atment 72 in impropatients 7576. TheThere are several existing models of integrated care , includiTable 3.Peri-discharge complex interventions synthesized in this systematic review have more focus on Models 1, 3 and 4. For example, home based telemedicine for COPD patients would feature elements from both IT-integrated health care model and patient integrated health care model. This is because this intervention component involves online monitoring of COPD patients’ physiological data, and such data is used to devise individualized education to patients for enhancing self-care. Further information on different peri-discharge complex interventions components is presented in Four component peri-discharge complex interventions or usual care should be tailored to address the needs of local health system [The GRADE-ADOLOPMENT approach provides an explicit framework for guiding localized recommendation development process . Future h system . In thisOur study showed that most complex interventions might be no different from usual care in reducing 30-day all-cause readmissions, but this conclusion is only supported by low certainty evidence. More trials might therefore be conducted in the future to strengthen the evidence base in this field. However, as a complex intervention, evaluating the effectiveness of peri-discharge complex interventions is known to be challenging . The firStrengths of this overview included a comprehensive electronic literature search to identify eligible SRs with an updated search for RCTs; independent literature selection and data extraction; methodological quality and risk of bias assessment conducted independently by two reviewers; application of NMA for comparing three or more interventions simultaneously in a single analysis via the common comparator; and use of GRADE approach for assessing the quality of evidence. Sensitivity analysis focusing only on RCTs with low risk of bias was also conducted, yielding results similar to the primary meta-analysis. This supports the robustness of our findings.Four component peri-discharge complex interventions might be the core effective interventions in reducing 30-day COPD-related readmissions, more RCTs may be conducted to investigate the comparative effectiveness between the Four component peri-discharge complex interventions and well-specified usual care. Lastly, content of usual care as well as individual intervention components may vary according to local practices in different health system contexts. Unclear reporting of intervention content may limit interpretation of our findings. Researchers conducting future RCTs should fully describe usual care and intervention components following the TIDieR guideline [Our findings also have several limitations. Firstly, quality of evidence varied from moderate to low across comparisons in NMA of reducing 30-day all-cause readmissions. Imprecision was the main reason for downgrading the NMA effect estimate. Secondly, with a small number of included RCTs, there was a lack of direct comparisons between many peri-discharge complex interventions, thereby weakening the comprehensiveness of comparisons. As the uideline .Four component peri-discharge complex interventions, which comprise patient education, self-management, patient-centred discharge instructions, and telephone follow up, seems to be key components in reducing 30-day COPD-related readmissions. This beneficial effect may help to reduce a substantial proportion of readmission. Prior to implementing the Four component peri-discharge complex interventions, policymakers from different health system contexts should consider carefully the aspects of problem priority, benefits, harms, equity, acceptability, and feasibility.Peri-discharge complex interventions may not differ from usual care for reducing 30-day all-cause readmissions among COPD patients. Yet, the major cause of 30-day readmissions among these patients is COPD-related. The The additional file for this article can be found as follows:10.5334/ijic.6018.s1Appendices.Appendix 1 to 16.


Vascular adhesion protein-1 (VAP-1) is a semicarbazide-sensitive amine oxidase (SSAO), whose enzymatic activity regulates the adhesion/exudation of leukocytes in/from blood vessels. Due to its abundant expressions in vascular systems and prominent roles in inflammations, increasing attentions have been paid to the roles of VAP-1/SSAO in atherosclerosis, a chronic vascular inflammation that eventually drives clinical cardiovascular events. Clinical studies have demonstrated a potential value of soluble VAP-1 (sVAP-1) for the diagnosis and prognosis of cardiovascular diseases. Recent findings revealed that VAP-1 is expressed in atherosclerotic plaques and treatment with VAP-1 inhibitors alleviates the progression of atherosclerosis. This review will focus on the roles of VAP-1/SSAO in the progression of atherosclerotic lesions and therapeutic potentials of VAP-1 inhibitors for cardiovascular diseases. AOC3 (amine oxidase copper-containing 3) gene, is an endothelial adhesion molecule with amine oxidase activity (Cardiovascular diseases (CVD) are the leading cause of death worldwide. Most CVD patients die of ischemic heart disease and ischemic stroke . The patactivity . The enzactivity . This arin-vitro binding experiments have shown that bindings of lymphocytes, monocytes, and granulocytes to high endothelial venules (HEVs) and/or blood vessels in different tissues are partially dependent on the expression levels of VAP-1  and adipocytes does not mediate lymphocyte binding . In SMCsSoluble VAP-1 (sVAP-1) in circulation is produced by proteolytic cleavage of its membrane-bound form , and plaElevated circulating sVAP-1 levels are evident in patients with all kinds of CVD including CAD, arterial stiffness, aortic stenosis, hypertension with echocardiographic alterations, chronic/congestive heart failure, and ischemic/hemorrhagic stroke  Chen et. ConsistClinical studies have demonstrated that serum sVAP-1 is a biomarker for atherosclerotic cardiovascular diseases . Notablyin-vivo VAP-1 antibody labeling experiments showed the absence of VAP-1 in the aortas of healthy C57BL/6N mice. However, the expression of VAP-1 is induced in endothelial cells lining the atherosclerotic plaques of LDLr−/−ApoB100/100 mice on 4-month Western-type diet (WTD), indicating the involvement of endothelial VAP-1 in leukocyte recruitment to atherosclerotic lesions  obesity associated with low-grade adipose inflammation . Consequin vivo (As outlined above, VAP-1/SSAO inhibitors may prevent adverse clinical events in CVD by reducing the lesion size/inflammation and/or increasing plaque stability. Moreover, VAP-1/SSAO inhibitors have shown beneficial effects on the treatment of CVD, such as stroke and myocardial infarction after onset, as well. In a rat embolic stroke model treated with tPA, SCZ prevented adverse effects caused by delayed tPA administration, leading to a smaller infarct volume . The admin vivo .So far, clinical trials investigating hVAP-1-targeting therapeutics on CVD have not yet been initiated. Most inhibitors tested in preclinical studies could not proceed into clinical trials because of potential off-target toxicity or the appearance of better substitutions . NonetheSSAO/VAP-1 is involved in the development of atherosclerosis. The enzymatic activity of VAP-1/SSAO facilitates the transendothelial migration of leukocytes, while the toxic products generated may inhibit the phenotypic switch of vascular SMCs. Extensive clinical studies have demonstrated the potential value of sVAP-1 in diagnosis and prognosis of CVD. Moreover, prevention of atherosclerosis and obesity, as well as the improvement of infarcts and injury after onset of CVD are evident in rodents treated with VAP-1 inhibitors. However, cell/stage-specific effects of VAP-1 and impacts of its inhibitors on atherosclerosis, as well as underlying mechanisms, warrant further investigations in rodents and non-rodent animals.


How do outcomes associated with first-line abiraterone therapy differ by race in a real-world cohort of patients with metastatic castration-resistant prostate cancer (mCRPC)?In this propensity score–adjusted cohort study of 3808 patients with mCRPC, among men receiving first-line abiraterone, African American men had significantly longer median overall survival compared with non-Hispanic White men (23 vs 17 months). Among non-Hispanic White men, first-line abiraterone was associated with significantly lower median overall survival than enzalutamide (17 vs 20 months).Abiraterone in mCRPC was associated with differential outcomes by race, possibly driven by decreased benefit among non-Hispanic White men. This cohort study of African American and non-Hispanic White men uses the Flatiron Health database to examine survival outcomes associated with first-line abiraterone therapy for metastatic castration-resistant prostate cancer. Prospective evidence suggests abiraterone is associated with superior progression-free survival for African American men compared with non-Hispanic White men with metastatic castration-resistant prostate cancer (mCRPC).To investigate differences in outcomes with first-line abiraterone therapy between African American and non-Hispanic White men with mCRPC in a national real-world cohort.This retrospective cohort study used a nationwide electronic health record–derived database of 3808 men receiving first-line therapy for mCRPC between January 1, 2012, and December 31, 2018. Data analysis was performed between January 1, 2020, and June 1, 2021. Median follow-up was 13 months . Propensity score–based inverse probability of treatment weighting was applied to reduce imbalance in measured confounders between patients receiving first-line abiraterone vs other first-line therapies. Deidentified patient data originated from a geographically diverse set of approximately 280 cancer clinics (approximately 800 sites of care) throughout the United States. Participants had newly diagnosed mCRPC and were receiving first-line systemic therapy during the study period.Receipt of abiraterone for first-line therapy.Overall survival from start of first-line treatment. Stratified analyses investigated overall survival within each race group, with first-line enzalutamide as the comparator.P = .02). There was no overall survival difference between first-line abiraterone and first-line enzalutamide among African American patients . First-line abiraterone was associated with decreased median overall survival relative to first-line enzalutamide among non-Hispanic White patients .Among 3808 patients with mCRPC, there were 2615 non-Hispanic White men  and 404 African American men , and 1729 patients (45.4%) in the cohort received first-line abiraterone. Among patients receiving first-line abiraterone, African American men had higher median overall survival than non-Hispanic White men . A race-by-treatment interaction existed for first-line abiraterone vs first-line enzalutamide (hazard ratio for abiraterone vs enzalutamide: non-Hispanic White men, 1.21 ; African American men, 1.05 ; interaction In this cohort study of patients who received first-line systemic therapy for mCRPC, African American men who received abiraterone had improved overall survival compared with non-Hispanic White men. Future prospective studies should assess drivers of differential abiraterone outcomes in mCRPC between African American and non-Hispanic White men, including differences in genetic factors and socioeconomic status, to inform treatment strategies. Moreover, through comparing abiraterone with enzalutamide, our study is the first to our knowledge to evaluate for an association between race and androgen receptor signaling inhibition therapy and thereby examine both the prognostic value of race among abiraterone-treated patients and the predictive value of race on abiraterone vs enzalutamide outcomes.8 Briefly, CRPC status is identified through an algorithm incorporating physician documentation of hormone-resistant status and resistance to androgen deprivation therapy through certain prostate-specific antigen elevation parameters. Lines of therapy are documented in the database relative to the index date of mCRPC diagnosis, in which the first line of treatment was defined as the first therapeutic agent initiated after mCRPC diagnosis plus any other agents initiated within 28 days of the first agent. The University of Pennsylvania institutional review board approved the protocol with a waiver of informed consent, given use of deidentified data. This report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.This retrospective cohort study used the nationwide Flatiron Health electronic health record–derived deidentified database, a longitudinal data set consisting of deidentified patient-level structured and unstructured data curated via technology-enabled abstraction. During the study period, data originated from approximately 280 cancer clinics (approximately 800 sites of care). The framework and methodology used by the Flatiron Health database to generate its mCRPC cohort is detailed extensively elsewhere.9 for mCRPC , geographic region, and abiraterone prescribing rate. Abiraterone prescribing rate was defined as the proportion of first-line treatment initiations containing abiraterone per practice and was used to account for any variation in baseline practice patterns14 that might influence patient receipt of abiraterone as part of first-line therapy. A secondary analysis assessed exposure to first-line enzalutamide treatment, using the same propensity score–based methodology and covariates.Data analysis was performed between January 1, 2020, and June 1, 2021. The primary exposure was receipt of abiraterone for first-line therapy, either with androgen deprivation therapy alone or in combination with other systemic therapies. Propensity score–based inverse probability of treatment weighting (IPTW) was applied to reduce imbalance in measured confounders between patients receiving first-line abiraterone vs other first-line therapies  was used for data analysis.The primary outcome was overall survival from start of first-line treatment. IPTW-adjusted Kaplan-Meier curves compared treatment-specific overall survival between African American and non-Hispanic White patients to estimate the marginal association between race and overall survival after balance was achieved in measured confounders. Cox proportional hazards regressions estimated IPTW-adjusted hazard ratios (HRs) and 95% CIs. Stratified analyses investigated overall survival within each race group, with first-line single-agent enzalutamide as the comparator. A 2-sided Of 3808 patients with mCRPC, 1729 (45.4%) received abiraterone-based first-line therapy, and 2079 (54.6%) received nonabiraterone-based first-line regimens . The cohP = .03) and for first-line abiraterone vs first-line single-agent enzalutamide   A. Among 5 but no significant race-based differences in abiraterone effectiveness were found in prospective data.7 It is unclear, however, whether the lack of significant differences in these prospective studies was due to insufficient power. Our study suggests that abiraterone is associated with better outcomes for African American vs non-Hispanic White men in real-world practice and extends prior analyses by investigating race-specific overall survival in a large real-world cohort. Our study demonstrated a significant race-treatment interaction association, which to our knowledge has not been reported by prior randomized studies investigating abiraterone and enzalutamide. Although there may not be a comparative advantage for abiraterone over other first-line mCRPC agents among African American men, other agents may be favored above abiraterone among non-Hispanic White men. Beyond the context of androgen receptor signaling inhibitors, there is emerging evidence for race-treatment interaction associations in the mCRPC setting with respect to sipuleucel-T therapy, for example,15 which likewise underscores the need to further explore the interplay between race and treatment as it relates to variation in mCRPC outcomes.In this real-world analysis of nearly 4000 patients with mCRPC who were receiving first-line treatment, abiraterone was associated with superior overall survival for African American men compared with non-Hispanic White men. Race-stratified analyses using enzalutamide as a comparator suggested that this overall survival disparity may have been due to decreased benefit associated with abiraterone among non-Hispanic White men. In contrast, among patients receiving first-line enzalutamide, there was no racial difference in overall survival. Favorable outcomes for African American men receiving abiraterone were previously observed in retrospective studies,17 To that end, genetic variants are being explored as factors in mCRPC treatment response. The HSD3B1(1245A>C) gene variation has higher single-nucleotide variation allelic frequency among male individuals of European (32%) vs African American (15%) ancestry19 and has been shown to increase 3βHSD1 enzyme quantity within androgen receptor signaling pathways.20 Increased 3βHSD1 enzyme quantity in turn yields greater androgen production and androgen receptor activation, thereby creating a potential treatment resistance mechanism to abiraterone.22 If future randomized trials confirm this treatment-related association, precision oncology treatment strategies may have important applications in mCRPC and contribute to decreasing disparities in outcomes, but only in concert with systematic efforts to increase representation of non-White populations in cohort studies and clinical trials.Future investigation into drivers of differential outcomes between mCRPC agents should move beyond studying race itself because race may not account for all underlying factors, including socioeconomic differences, that contribute to disparate outcomes.17 Likewise, certain covariates may have been incompletely coded owing to inconsistent electronic health record documentation , and other variables affecting prognosis and outcomes were not collected or easily analyzable in this database . However, this missingness is common with observational data sets, and we have no evidence that it was unbalanced between African American and non-Hispanic White men. In addition, our analysis included a relatively short median follow-up of 13 months. Finally, non-Hispanic White men disproportionately outnumbered African American men in the study sample. However, the sample proportion of African American men exceeded typical representation of African American men in CRPC trials by more than 3-fold.1 Despite these limitations, to our knowledge this is the largest real-world study to date investigating differential outcomes with abiraterone use by race in the mCRPC setting.Because this cohort study was a real-world analysis, a key limitation was the inability to fully account for socioeconomic factors and biases that, in conjunction with race, contribute to receipt of a given therapy and outcomes disparities.Prior research suggests that abiraterone is associated with greater clinical benefit for African American patients than for White patients with mCRPC. This real-world cohort study affirms these findings and is, to our knowledge, the first one to find that first-line abiraterone was associated with improved overall survival among African American patients compared with White patients. This observation may be due to decreased effectiveness of first-line abiraterone relative to other first-line therapies among White patients. Future prospective research in mCRPC should include greater proportions of African American men and investigate mechanisms behind potential decreased abiraterone effectiveness among White men to ultimately inform solutions to ameliorate disparities in outcomes.


This involves triggering of inflammatory signalling, innate immune activation including recruitment and stimulation of dendritic cells (DCs), and ultimately priming of tumour-specific T cells. The ability of tumour localised therapies to trigger these pathways and act as in situ tumour vaccines is being increasingly explored, with the aspiration of developing combination strategies with ICPI that could generate long-lasting responses. In this effort, it is crucial to consider how therapy-induced changes in the tumour microenvironment (TME) act both as immune stimulants but also, in some cases, exacerbate immune resistance mechanisms. Increasingly refined immune monitoring in pre-clinical studies and analysis of on-treatment biopsies from clinical trials have provided insight into therapy-induced biomarkers of response, as well as actionable targets for optimal synergy between localised therapies and ICB. Here, we review studies on the immunomodulatory effects of novel and experimental localised therapies, as well as the re-evaluation of established therapies, such as radiotherapy, as immune adjuvants with a focus on ICPI combinations.Cancer patients with low or absent pre-existing anti-tumour immunity (“cold” tumours) respond poorly to treatment with immune checkpoint inhibitors (ICPI). In order to render these patients susceptible to ICPI, initiation of  Immune checkpoint inhibitors have revolutionised cancer therapy, however they remain largely ineffective in the treatment of poorly immunogenic “cold” tumours.Localised therapies can be used to enhance tumour immunogenicity and overcome resistance to checkpoint blockade, with minimal additive or overlapping side effects.Clinical studies to date have yielded mixed results, from negative studies to results that have already changed clinical practice.Future directions include novel combinations featuring alternative checkpoints, co-stimulatory agonists and agents that target pathways that may enhance antigenicity. Further considerations include the optimal scheduling of immune-modulatory agents.The last decade has seen a revolution in the field of immuno-oncology (IO), driven most notably by the approval and clinical implementation of immune checkpoint inhibitor (ICPI) therapy. In work later recognised in the 2018 Nobel Prize in Physiology or Medicine, James Allison and Tasuku Honjo separately identified two pivotal surface receptors that act as negative regulators of the effector T cell (Teff) response, Cytotoxic T Lymphocyte Associated Protein-4 (CTLA-4) , therebyThese pathways are frequently exploited by tumour cells as a mechanism of immune evasion. Upregulation of PD-L1 on tumour cells, or production of factors that upregulate checkpoint expression on immune cells, leads to exhausted and dysfunctional effector Teff and promotion of regulatory T cells (Treg) within the tumour microenvironment (TME). Monoclonal antibody (mAb) therapy targeting immune checkpoint pathways was shown to be a potent method of anti-cancer T cell re-invigoration, effectively releasing the brakes that are imposed on effector function by checkpoint-mediated immunosuppression. In 2011, the first anti-CTLA-4 mAb Ipilimumab was approved for clinical use, shortly followed by agents targeting the PD-1/PD-L1 axis .Checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 now form part of first or second-line standard-of-care in melanoma, non-small cell lung cancer (NSCLC), advanced head and neck squamous cell cancer (HNSCC), renal cancer and urothelial cancer, among others , lymphocyte activation gene-3 (LAG-3) and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is emerging .Although ICPI have revolutionised the treatment landscape, low response rates and resistance still plague effective therapy for the majority. On average, only around 12% of patients gain benefit across all tumour types , with paThe enduring problem of primary and secondary resistance, combined with a lack of reliable predictive biomarkers of response, leaves a large proportion of patients at risk of ICPI-related toxicity without clinical benefit. A significant focus has therefore been placed on broadening mechanistic understanding of ICPI resistance, and developing strategies to augment response. One strategy is the use of locally-delivered, immune-modulatory therapies in combination with ICPI. These therapies, which include radiotherapy and treatments delivered by intratumoural injection such as oncolytic viruses (OV), can lead to remodelling of the TME to a more favourable phenotype for effective ICPI therapy.Although accessibility of treatable lesions remains a limitation for some localised therapies, they have several advantages over systemic combinations. They enable targeted manipulation of the TME, minimising off-target effects and systemic or overlapping toxicity. In addition, local treatments have been shown to exert a systemic influence on TME composition and anti-cancer immunity, even in non-treated tumours. Examples of such effects include stimulation of immune cell influx, enhanced immune cell priming and increased expression of checkpoint targets (such as PD-1 or PD-L1). These characteristics form part of the metaphorical notion of the immunological “heat” of a tumour, and are commonly associated with response to ICPI. Accordingly, they are characteristically absent in “cold”, ICPI-refractory tumours. Remodelling of the TME using localised therapies therefore provides potential for global synergy, and enhanced ICPI-responsiveness . This reImmune checkpoints form only part of the complex picture of effective anti-cancer immunity. Huge diversity in mutational burden, antigen release and presentation, inflammatory signalling and TME composition all play a critical role in ICPI efficacy . This diThe unifying concept of tumour Immunological “heat” is a global representation of this multifactorial diversity and represents the ability of a tumour to elicit effective anti-cancer immunity.+ Teff cells with a high CD8:Treg ratio, antigen-presenting cell (APC) and inflammatory M1-polarised macrophage infiltration, and immune-stimulatory cytokine production (such as Type I IFN). High tumour antigen (TAA) availability due to a high tumour mutational burden (TMB) or microsatellite instability (MSI) has also been associated with ICPI responsiveness, and checkpoint expression on activated, antigen-exposed immune cells, along with PD-L1 on tumour cells, provide targets for ICPI therapy  expressed on innate immune cells have evolved to detect microbial pathogenic molecules collectively known as pathogen-associated molecular patterns (PAMPs). The cytosolic nucleic acid sensors cyclic GMP-AMP synthase (cGAS) and retinoic acid inducible gene I (RIG-I) are not only important for detection of infected cells but also for immune recognition of cancer cells . Changesvia P2Y2 and P2X7 receptors respectively  are naturally-occurring or genetically-modified (GM) viruses that selectively infect and destroy tumour cells through direct cell lysis and stimulation of an anti-cancer immune response . Many tuThe immune stimulatory effects of OV are multi-modal. Viral replication triggers cell lysis and ICD. This releases viral progeny to continue the lytic cascade in surrounding tumour cells, as well as TAA for cross-priming of APCs and DAMPs, subsequently leading to stimulation of a Type 1 IFN-mediated anti-tumour immune response . The celThe result is a switch to an immune-stimulatory TME, with influx of activated T cells and APCs, upregulation of MHC and co-stimulatory markers such as CD40, CD80 and CD86 , as wellIn 2015, the oncolytic Herpes Simplex Virus (oHSV), talimogene laherparepvec, became the first OV to gain regulatory approval for cancer therapy , leadingWhat has become apparent is the potential of OV therapy as an immune adjuvant in combination with other immune-modulatory therapies, such as ICPI. In combination, OV present an appealing prospect. They exhibit anti-cancer activity and tumour selectivity, are generally well-tolerated with non-overlapping side-effects, and have the ability to increase the immunological heat of OV-injected and non-injected tumours – a phenomenon demonstrated in both pre-clinical animal models and patients .A further advantage of OV therapy is the application of OV as viral vectors. The large backbone of some OV, such as oncolytic Herpes Simplex Virus (oHSV), Adenovirus (oADV) or Vaccinia Virus (oVV) can be manipulated by insertion of therapeutic transgenes, thus exploiting selective viral replication for concentrated delivery of immune-modulatory agents within the TME. This provides a unique opportunity, not only to manipulate the TME to enhance ICPI therapy, but to deliver the ICPI themselves. This is a particular advantage when considering the delivery of molecules where systemic administration may be limited by toxicity or pharmacokinetic considerations. Examples include the anti-CTLA-4 mAb, or potent immune-stimulators such as agonists of the 4-1BB co-stimulatory receptor or stimulatory cytokine IL-12.Several clinical trials of OV/ICPI combinations are currently ongoing or have recently been completed, backed by pre-clinical evidence of synergistic effects. This section will focus on the rationale and evidence behind locally-delivered OV and ICPI therapy combinations; strategies featuring systemic OV delivery are reviewed in detail elsewhere .Extensive pre-clinical research has evaluated the mechanisms behind OV remodelling of the TME in “cold” tumours, and the implications for subsequent checkpoint blockade. Among the most clinically advanced OV to date are variants of the oHSV and oADV viral platforms, double-stranded DNA viruses that are not only highly immune-stimulatory, but have large viral backbones that provide opportunity for transgene insertion.Zhang et al. showed that oHSV therapy led to an increase in tumour-infiltrating CD4 and CD8 T cells and a decrease in Treg and suppressive TAM in a mouse model of pancreatic ductal adenocarcinoma (PDAC). PDAC is a notoriously immune-excluded, “cold” tumour, with a TME comprising immunosuppressive Treg, tumour associated macrophages (TAM), immunosuppressive cytokines and physical barriers to T cell infiltration such as CAFs and a desmoplastic stroma . TranscrHF-10  is a further oHSV1 which contains natural mutations that enhance selectivity. HF-10 treatment led to an influx of CD8 T cells in a poorly immunogenic HNSCC model, with infiltration of PD-L1-expressing macrophages and DCs in both OV-injected and non-injected tumours. Despite a PD-L1-enriched TME, a therapeutic effect was seen with single-agent HF-10 treatment; however, this was significantly enhanced by addition of anti-PD-L1 therapy. Interestingly, synergy was seen with high-dose, but not low-dose, anti-PD-L1 therapy highlighting a dose-dependent factor in the ability of ICPI to overcome either the intrinsic tumour-mediated immunosuppression or OV-induced checkpoint upregulation .Saha et al. showed enhanced CD8 T cell infiltration in an 005-GSC-derived GBM mouse model following treatment with a third-generation triple-mutated oHSV encoding the immunostimulatory cytokine IL-12 (G47ΔV-mIL-12) . GlioblaAdenovirus is a double-stranded DNA virus which has again been extensively investigated in the context of OV therapy, including for GBM. Stereotactic administration of low dose oADV was shown to upregulate PD-1 expression on tumour-infiltrating CD8 T cells, highlighting a mechanism of adaptive resistance. Synergy was seen with anti-PD-1 therapy, with significantly improved survival in GBM tumour-bearing mice .Evidence of efficacy of an oADV encoding co-stimulatory ligand CD40-L was shown by Singh et al. in a mouse melanoma model. Melanoma has been well-established as an immunogenic “hot” tumour site. Despite this, 50% of patients do not respond to dual checkpoint blockade. The B16 mouse melanoma model is highly immunosuppressive, with an immune-excluded TME and production of immunosuppressive cytokines such as TGF-β. Remodelling of the TME was seen following treatment, with an influx of IFNy-producing CD8 T cells, an increase in the CD8:Treg ratio and upregulation of PD-L1 on tumour tissue. Combination treatment with anti-PD-L1 enhanced therapy and led to an increase in CTLA-4-expressing CD8 T cells. Subsequent triple therapy (OV/PD-L1/CTLA-4) significantly improved response, leading to regression of OV-injected and non-injected lesions (including brain metastases). A 45% cure rate was achieved, with protection from tumour re-challenge . Hu et ath century, is also in clinical development as an OV. The modified oVV pexastimogene devacirepvec (JX-594) has yielded disappointing results in clinical trials to date, most notably with the failure of the phase 3 PHOCUS trial in liver cancer  and Tregs. Treatment stimulated a CD8 T cell-mediated anti-tumour response with evidence of immune memory and protection from re-challenge. High levels of anti-TIGIT mAb were seen in tumour tissue, but not in blood from treated mice . A TK-geThe oHSV platform is also amenable to genetic modification. Coffin et al. developed the RP oHSV platform, featuring ICP34.5 and ICP47 deletions to attenuate neurovirulence and enhance antigen presentation and GALV-GP-R and hGM-CSF insertion to enhance OV-induced ICD. Further modification with insertion of ICPI or co-stimulatory ligands  was shown to increase therapeutic efficacy in tumour-bearing mice . EnhanceOther OV in clinical development include polioviruses, Newcastle disease virus (NDV), reovirus and maraba virus. Clinical trials involving both reovirus and NDV in combination with ICPI therapy are ongoing, with pre-clinical evidence of synergy , 71, 72;Oncolytic viruses based on the Herpes Simplex Virus-1 (oHSV-1) have gained the most clinical traction to date following the approval of T-Vec in the treatment of melanoma. In T-Vec, the HSV backbone has been modified by deletion of ICP34.5 and ICP47 and insertion of GM-CSF to enhance selectivity and immune effects. T-vec was shown to induce antigen-specific local and systemic immunity in phase II studies, with an increase in CD8 T cell density in injected and non-injected lesions, increased checkpoint expression , and an T-Vec/ICPI combination therapy has to date yielded mixed results. A phase II trial of IT Tvec and Ipilimumab therapy in advanced melanoma showed a significant improvement in response (38% vs 18%) with regression of non-injected lesions and no additional safety concerns . HoweverThe spontaneous oHSV mutant HF-10 has also been evaluated in clinical trials in combination with ICPI therapy. A phase II study of HF-10 and Ipilimumab in advanced melanoma demonstrated an acceptable safety profile with a best overall response rate (BORR) of 41% and 19-month median PFS . RespondThe RP oHSV platform developed by Coffin et al.  is undergoing clinical evaluation, with ongoing phase I and II trials in combination with anti-PD-1 or anti-PD-L1 agents in advanced solid tumours Table 3.Several oADV are in clinical development and have been tested in combination with ICPI therapy. ONCOS-102 is an oADV with a 24bp deletion in the E1A Rb binding site to attenuate replication in normal tissue, and addition of GM-CSF for immune augmentation. A two-part phase I study of ONCOS-102 in combination with concurrent or sequential anti-PD-1 therapy provided evidence of the ability of OV to overcome ICPI resistance. This trial recruited advanced melanoma patients that were refractory to prior anti-PD-1 therapy, and reported a 35% ORR in an early analysis (NCT03003676). A phase I study of ONCOS-102 in combination with Durvalumab in ovarian and colorectal cancer with peritoneal metastases showed an increase in CD8 T cell infiltration and PD-L1 expression following treatment. Some evidence of clinical activity was seen, but only 1 durable response. Phase II recruitment is ongoing NCT02963831). DNX-2401 is a further oADV with E1A deletion. A phase II dose escalation study of IT DNX-2401 in combination with Pembrolizumab in recurrent GBM noted an 11.9% ORR with 2 ongoing durable responses in the 49 patients recruited, median OS was 12.5 months  and Atezolizumab in PDAC (NCT02705196). Pancreatic cancer is notoriously immune-excluded, however combination treatment was shown to increase antigen-specific T cells and reduce circulating MDSCs, with a partial response in 6/10 subjects in an interim report . FinallySynergy has been demonstrated between oncolytic Coxsackie viral strain CVA21 (Cavatek) and ICPI therapy and, as with other OV, added toxicity in combination was minimal. Changes within the TME were seen following CVA21 treatment, with increased CD8 T cell infiltration and upregulation of PD-L1 and other immune checkpoint receptors. The phase Ib MITCI trial evaluated IT CVA21 therapy in combination with Ipilimumab in patients with advanced melanoma. An ORR of 38% was observed with no dose-limiting toxicity  NCT0230, the stuThe modified vaccinia poxvirus JX-594 (Pexa-Vec) is also under investigation in combination with ICPI therapy. A recent phase Ib study in patients with renal cancer reported evidence of treatment response in combination with Cemiplimab therapy. The first phase of this trial involved IV oVV treatment, however the second phase will evaluate localised IT therapy (NCT03294083). A further study recruiting patients with advanced solid tumours for combined IT JX-594 with Ipilimumab is ongoing (NCT02977156).Intratumoural injection of an oncolytic Vesicular Stomatitis Virus (oVSV) construct VSV-hIFNbetasodium iodide symporter is currently being tested in combination with avelumab in advanced solid tumours (NCT02923466). The oncolytic poliovirus, PVSRIPO, is also being tested in phase I trials in combination with nivolumab in PD-1-refractory melanoma (NCT0412759) and atezolizumab in glioma (NCT03973879). All trials are currently recruiting.Evidence of involvement of the immune system in the anti-tumour effect of radiotherapy has accumulated over many decades. Radiotherapy-induced regression of tumour lesions distant from the radiation field was first described almost 70 years ago and termed the “abscopal” effect . Over thin situ vaccine. This process requires increasing the antigenicity as well as the adjuvanticity of the targeted tumour which is highly dependent on firstly the mode of cell death that the irradiated tumour cells undergo, secondly which molecular signalling pathways are induced and thirdly which DAMPs are released in the TME.Radiotherapy has traditionally been used to treat cancer by utilizing the selective inability of cancer cells to repair DNA damage. When radiotherapy is used as an immune adjuvant, the aim is to transform the tumour into an individualized In vivo focal irradiation of 4T1 tumours was shown to broaden the TCR repertoire with expansion of T cell clones driven by anti-CTLA-4 checkpoint inhibition  in the cytosol, as well as micronuclei formation. This dsDNA is recognized by cyclic GMP-AMP synthase (cGAS)  and subsICD is defined by induction of certain DAMPs, all of which are induced by radiotherapy  resultinAs evidence mounts of the ability of radiotherapy to alter the immune composition of the TME, there are increasing efforts to implement radiotherapy as an adjuvant to ICPI in patients that are unresponsive to immunotherapy alone.ex vivo irradiation of colon- and gastric cancer tumour samples (Radiotherapy (RT) has been shown to promote PD-1/PD-L1-mediated immune resistance, setting the stage for potential synergistic effects. PD-L1 surface expression was shown to be elevated on tumour cells following radiotherapy, which has been attributed to IFNg release from tumour-infiltrating lymphocytes (TILs) . Tumour- samples . Indeed, samples  while si samples .Further, radiotherapy has been shown to potentiate the anti-tumour effect of CTLA-4 blockade in a CD8 T cell-dependent manner in the aggressive and poorly immunogenic breast cancer model 4T1 , 107. Inin vivo when combined with anti-CLTA-4 and anti-PD-1 treatment  and Durvalumab or Tremelimumab treatment. No dose-limiting toxicities were seen with combination therapy, and 2/39 patients had a partial response with an ORR of 5.1% and PFS between 0.9 and 9 months depending on treatment cohort (NCT02311361) .The phase III PACIFIC trial showed that Durvalumab therapy significantly improved survival compared to standard of care concurrent chemo-radiotherapy in patients with locally advanced stage III unresectable NSCLC (NCT02125461). Antonia et al. reported a pronounced benefit in PFS with Durvalumab treatment compared with placebo (16.8 months vs 5.6 months respectively) , highligConversely, in locally-advanced HNSCC, the phase 3 JAVELIN-100 trial evaluating avelumab in combination with standard-of-care chemoradiotherapy failed to meet its primary endpoint of prolonged PFS. Of relevance, subgroup analysis showed the only PFS benefit to be in patients with tumours expressing high levels of PD-L1 (>25%) at baseline, and further research is needed to evaluate the barriers to effective therapy in “cold” tumours .In the metastatic setting, the PEMBRO-RT   and MDACA further treatment setting under evaluation is neo-adjuvant treatment of patients with early-stage disease. A recent phase II study of Durvalumab and SBRT therapy in NSCLC (NCT02904954) showed a significant increase in major pathological response rates with combination therapy when compared to single agent Durvalumab (53.3% and 6.7% respectively), validating the strategy for a larger trial . This seOther strategies aimed at TME manipulation towards a more inflamed phenotype are also in clinical development. These include locally-delivered immune-adjuvants, non-viral oncolytics, and physical thermal therapies such as high intensity focused ultrasound (HIFU). A non-exhaustive selection of ongoing clinical studies are summarised in Rose Bengal disodium is a small-molecule analogue of the commonly-used conjunctival dye fluorescein and is under clinical evaluation in its injectable form PV10 as a cancer immunotherapy. Intralesional PV-10 has been shown selectively to accumulate in lysosomes within tumour cells, leading to immunogenic cell death, PAMP, DAMP and TAA release, and an antigen-specific anti-cancer T cell response. Pre-clinical synergy has been shown with IT PV-10 and anti-PD-L1 therapy, with the initiation of a CD8 T cell-dependent anti-tumour immune response and depletion of Treg . A phaseToll-like receptors (TLRs) are a family of PRRs that are most commonly found on DCs and macrophages, but also on T cells and tumour tissue. They play a key role in the innate and adaptive immune response, recognising potentially harmful PAMPs and DAMPs including microbial nucleic acids and TAA and triggering apoptosis and immune cell maturation and recruitment.Bacillus Calmette Guerin (BCG) is a live attenuated strain of Mycobacterium Bovis, a potent agonist of TLR-2 and 4 that has been routinely used in the treatment of bladder cancer for decades. Schmidt et al. showed intra-tumoural injection of the TLR-9 agonist lefitolimod led to remodelling of the TME to a “hot” phenotype in mouse CRC models – with CD8 T cell influx, an increase in the CD8:Treg ratio and a greater proportion of M1-polarised macrophages . EnhanceSeveral clinical trials are ongoing evaluating TLR agonist/ICPI combinations. The phase I/II ILLUMINATE-204 multi-centre study evaluated intra-tumoural TLR-9 agonist (tilsotolimod) therapy in combination with Ipilimumab in PD-1 refractory metastatic melanoma (NCT02644967). Responses were seen in local and distant lesions, with a 22.4% ORR (2 complete responses) and a 21-month median OS. Tumour biopsies showed evidence of an IFNa inflammatory gene signature and expansion of CD8 T cell clones . The subMilhem et al.  reportedOther ongoing clinical trials include the IT TLR-7 agonist LHC165 in combination with anti-PD-1 in patients with advanced solid tumours (NCT03301896), the TLR-8 agonist motolimod in combination with anti-PD-1 agent nivolumab in HNSCC  and BCG in combination with Durvalumab +/- RT in NMIBC (NCT03317158).The adaptor protein, STING, is a critical component of the previously discussed cGAS/STING pathway and acts as a bridge between innate and adaptive immunity. Cytosolic microbial or tumour-derived DNA is sensed by the PRR, cGAS, which undergoes conformational changes to catalyse ATP and GTP into the cyclic di-nucleodide (CDN) cGAMP. STING is activated on binding with cGAMP or other CDNs, leading to stimulation of a type 1 IFN response, immune cell recruitment, promotion of DC maturation and priming of antigen-specific immunity.via intratumoural injection therefore provides a mechanism to enable therapeutic dosing within the TME, although emerging novel agents such as non-nucleotide small-molecule systemic STING agonists are in development for intravenous or oral administration  reported an encouraging safety profile and early evidence of efficacy . Phase Ivia isolated limb perfusion and systemic anti-CTLA-4 therapy, with remodelling of the TME to an inflamed phenotype. This was translated into a phase II clinical trial, where combination therapy was shown to improve PFS with 62% complete responses and median PFS not reached. However, this did not reach significance over either treatment alone in the study of 26 patients  are short polypeptides with a net positive charge and a large proportion of hydrophobic amino acid residues . This alLTX-315 is currently being explored in a phase I trial including patients with transdermally-accessible tumours in combination with pembrolizumab (NCT04796194).High-intensity focused ultrasound (HIFU) is a non-invasive thermal modality, primarily used to treat solid tumours in cancer patients who are poor candidates for surgery and radiotherapy. HIFU was shown to induce ICD of human cancer cells promoting generation of DAMPs as well as cytokines that could polarize macrophages from a suppressive M2- to an anti-tumour M1-phenotype , 145. InRadiofrequency ablation (RFA) and microwave ablation (MWA) uses needle-like electrode probes to deliver radiofrequency and electromagnetic waves respectively, generating oscillation and subsequent heating of the tumour tissue. In two mouse models of breast (4T1) and colon (CT26) cancer, MWA of primary tumours followed by combined anti-PD-1 and anti-CTLA-4 treatment resulted in prolonged survival compared with MWA or ICPIs alone. MWA + ICPI treatment was also associated with increased frequencies of CD8 T cells in treated tumours and peripheral blood as well as increased plasma levels of IFNγ . Neo-adjPhotothermal therapy (PTT) works by administering optically-absorbent nanoparticles which, when activated by near-infrared light, generates heat and localised thermal damage . PTT, inDespite huge advances in recent years, ICPI therapy remains largely ineffective in the treatment of immunologically cold tumours. Although synergistic effects have been widely demonstrated between localised immune-modulatory therapies and ICPI, clinical response rates remain suboptimal. The mechanisms of response and resistance are highly complex, and it is likely that no single therapy will overcome tumour-mediated immunosuppression across multiple tumour histotypes. Multi-targeted combinations are likely to represent the future of immunotherapeutic strategies, and an overwhelming number of combinations are currently in clinical development.in situ immune modulation using sequentially delivered local therapies – RT, DC recruitment agent Fms-like tyrosine kinase 3 ligand (Flt3L) and TLR-3/CD40 stimulation - in overcoming checkpoint resistance in an immune-excluded mouse melanoma model  pathways. An effective anti-cancer immune response is dependent on the formation of tumour neoantigens regardless of TME immunogenicity, a process that may be a key limiting factor in ICPI efficacy in cold tumours, due to a low mutational load. PARP inhibitors (PARPi) lead to un-repaired DNA damage which triggers a cascade of immunogenic events including enhanced PD-L1 expression on tumour cells, immune cell infiltration and TAA formation , providiCombinations involving co-stimulatory agonists such as 4-1BB or CD40-L are also in clinical development. A recent study in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDA) revealed that an agonist targeting the co-stimulatory receptor CD40 synergized with radiotherapy to promote systemic tumour-targeted immune responses in combination with dual ICB . In mousNovel checkpoints such as TIGIT, TIM-3, LAG3  or otherFor example, the PD-1 pathway also regulates NK cells, B cells and macrophages, and evidence for the impact of the diverse cellular constituents of the TME on response to ICPI continues to accumulate. Indeed, a study of ICPI therapy in melanoma showed enrichment of B cell signatures in responding patients , and conSelective deletion of PD-1 in myeloid cells has also recently been shown to induce a more effective anti-cancer immune response than ablation on T cells , and othvs sequential treatment (NCT03799744).As more complex combinations move into the spotlight, the question of optimal dose delivery and scheduling becomes of paramount importance both with regards to efficacy and toxicty. There is a rationale for checkpoint blockade as a priming agent before radiotherapy, and equally for OV administered prior to ICPI to prime for an effective anti-cancer immune response. Conversely, concurrent administration may enable maxiumum synergy, and sequential ICPI delivered after localised therapy may be the most effective way of sustaining immunity and overcoming T cell exhaustion. This is currently under investigation, and ongoing trials will begin to shed light on optimal scheduling. For example, a study evaluating priming vs concurrent atezolizumab in combination with conventional chemoradiotherapy in cervical cancer has recently finished recruiting (NCT03738228). A study combining an oADV with anti-PD-L1 agent Durvalumab is also currently recruiting and will evaluate concomitant In the context of radiotherapy, the differential effects of dose-fractionation on immunogenicity are also largely unknown. Demaria et al. reported that RT doses above 12-18 Gy induced the Trex1 exonuclease and attenuated any immunogenic effects, while repeated lower doses led to IFN production, DC recruitment and immune-cell priming , and fraFor OV treatment, a key limitation to optimal delivery is that many typically “cold” tumour sites such as brain, pancreatic and ovarian, do not have easily accessible lesions for repesated injection. Viral infectivity is highly heterogenous, and the barrier of anti-viral immunity, either from prior infection, vaccination or neutralizing antibodies (nAb) secondary to OV treatment, also hinders viral replication and therefore efficacy following systemic delivery. Novel methods of viral encapsulation to overcome the barrier of anti-viral immunity may provide a potential method of enhancing anti-tumour effects, for example, Francini et al. published evidence of ablation of nAb binding without viral inactivation using a new class of coating polymers .There is much still to learn in order to overcome the lack of ICPI efficacy in cold tumours and to maximise the synergistic benefit of localised therapy combinations. However, continued research intended specifically to understand the biological changes occurring in tumours following administration of localised therapies is laying the groundwork for the design of more effective strategies. Checkpoint inhibitors have been proven to provide a widely-applicable method of immune rejuvenation, and are likely to form an integral part of future strategies. With the ability of localised therapies to manipulate the TME and enhance tumour immunogenicity without excessive additive side effects, they remain an attractive addition to the therapeutic armoury, with the potential of rendering more patients responsive to immune checkpoint blockade.EA and EW devised and conceptualized the idea and drafted the manuscript. NS designed the figure. JH, CC, AW, AS, MO, AM, and KH have contributed to the writing of the manuscript. All authors contributed to the article and approved the submitted version.Supported by Cancer Research UK (CRUK), the Institute of Cancer Research/Royal Marsden Hospital Centre for Translational Immunotherapy and RadNet Radiation Research Network.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Recently, immune checkpoint inhibitors (ICIs) therapy has become a promising therapeutic strategy with encouraging therapeutic outcomes due to their durable anti-tumor effects. Though, tumor inherent or acquired resistance to ICIs accompanied with treatment-related toxicities hamper their clinical utility. Overall, about 60–70% of patients  who received ICIs show no objective response to intervention. The resistance to ICIs mainly caused by alterations in the tumor microenvironment (TME), which in turn, supports angiogenesis and also blocks immune cell antitumor activities, facilitating tumor cells' evasion from host immunosurveillance. Thereby, it has been supposed and also validated that combination therapy with ICIs and other therapeutic means, ranging from chemoradiotherapy to targeted therapies as well as cancer vaccines, can capably compromise tumor resistance to immune checkpoint blocked therapy. Herein, we have focused on the therapeutic benefits of ICIs as a groundbreaking approach in the context of tumor immunotherapy and also deliver an overview concerning the therapeutic influences of the addition of ICIs to other modalities to circumvent tumor resistance to ICIs. During the last two decades, tumor immunotherapy has evolved the clinical management of a diversity of tumors even with undesired prognoses , 2. As oIn the present review, we deliver an overview about the therapeutic merits of ICIs as a pioneering tactic in tumor immunotherapy and also discuss recent reports evaluating the combined use of ICIs with other conventional approaches to overcome tumor resistance to ICI, with a particular concentration on last decade in vivo reports.Communication between immune checkpoints and their responding ligands abrogates T cell activation and resultant anti-tumor immunity by targeting a myriad of signaling axes, in particular, phosphatidylinositol-3-kinase (PI3K)/Akt pathway . As a reAs known, CD80 B7-1) and CD86 (B7-2) co-stimulation by CD28 delivers vital stimulatory signals, which eases T cell proliferation and differentiation throughout the induction phase of immunological response . The CTL-1 and CDAnti-tumor T cells following acquirement of cytokine-producing and cytolytic effector competencies can undergo additional negative regulation by an interaction between PD-1 on such cells with PD-L1 on tumor cells or tumor-associated antigen-presenting cell (APC) in the TME , 64. IntGiven that ICIs with the goal of targeting CTLA-4, PD-1, or PD-L1 can dampen immune checkpoints-induced inhibitory impacts on T cells biological processes, making further progress to evolve novel ICIs for broader types of malignancies is urgently justified.The monoclonal antibody ipilimumab which targets CTLA-4 has been approved on March 25, 2011, to treat patients with metastatic melanoma . It is aNivolumab, pembrolizumab, and cemiplimab, well-known PD-inhibitors, are fully human IgG4 mAb and have demonstrated capable potential to treat advanced melanoma and NSCLC patients . Apart fRecently, study of the efficacy and safety of nivolumab in 440 patients with wild-type BRAF and mutant BRAF metastatic melanoma showed that nivolumab administration caused improved ORR regardless of the PD-L1 status of the tumor . As wellThree anti-PD-L1 antibodies have gained approval from the FDA: atezolizumab (IgG4 mAb), and also durvalumab and avelumab, which are IgG1 mAb . Since 2Currently, a phase 3 trial indicated that atezolizumab could stimulate objective responses in metastatic UC with or without platinum-based chemotherapy, as shown by improved PFS and also acceptable safety profile . Also, aIt is now generally documented that tumor cells make close interfaces with the ECM, stromal cells, and also immune cells which typically exist in TME. Such cells in TME support evolving chronic inflammation, enhancing immunomodulation, and simultaneously providing a pro-angiogenic intratumoral microenvironment, and thus ease tumor cells escape from recognition and subsequent removal by host immunosurveillance , 121. FoThe FDA approved atezolizumab and durvalumab for use in combination with chemotherapy for first-line treatment of patients with advanced SCLC. These approvals were rendering consequences derived from two randomized controlled trials, IMpower133 (atezolizumab)  and CASPRecent studies have shown that the combined use of cyclophosphamide, ICI, and vinorelbine could stimulate APC recruitment and also activation, and so hurdle local and metastatic TNBC growth mainly by T-cell-mediated influences in vivo . The intBesides, gemcitabine combined with anti- PD-L1 antibody inhibited tumor growth in advanced pancreatic ductal adenocarcinoma (PDAC) murine models . The comRecently, Chen and coworkers suggested that doxorubicin and cisplatin might stimulate a more valued TME and boost the likelihood of response to anti-PD-1 antibody in TNBC . FurtherA summary of conducted studies respecting combination therapy with ICIs and chemotherapy have been listed in Tables  and 4.TaHuman epidermal growth factor receptor (HER) 2 amplification befalls numerous tumor types counting breast, gastric, salivary, vaginal, bladder, CRC endometrial, and cervical. HER2 activation results in the activation of a myriad of oncogenic signaling axes , thereby improving malignant cell survival, proliferation, migration, and also resistance to immunotherapy , a HER2-targeting antibody, could promote antitumor immunity by enhanced expression of DCs markers, boosted expression of MHC class I in tumor cells, and also the rejection of rechallenged murine HER2-expressing breast cancer cells by adaptive immune cells . BesidesAbnormal vasculature is one the most prominent possessions of solid tumors and is complicated in tumor immune escape . This deTherapeutic cancer vaccines simplify abrogation of tumor progress, eradication of minimal residual disease (MRD), and also inaugurating the durable antitumor memory and ducking untoward reactions , 180. StVarious preliminary reports explain that combination therapy with ICIs and cancer vaccines may encourage reinforced immunogenicity and also fence immunosuppressive TME . A recenCurrent clinical trials also have signified that DCs-based mRNA vaccination in combination with ipilimumab could stimulate strong CD8 + T-cell responses in stage III or IV melanoma patients . As wellA summary of conducted studies respecting combination therapy with ICIs and cancer vaccines have been listed in Tables  and 4.TaRadiotherapy (RT) is employed generally as a standard treatment for more than 50% of patients suffering from tumors . The absStudies have reported that RT in combination with targeting CTLA-4 and/or PD-1/PD-L1 could provoke CTLs-mediated anti-tumor immunity . For insIn this regard, a trial conducted, between February 2016 and December 2017, on 124 patients with advanced NSCLC verified the safety and efficacy of combination therapy with nivolumab and RT . ResultsAdoptive cell therapy (ACT) with using TILs or gene-modified T cells expressing novel T cell receptors (TCR) or chimeric antigen receptors (CAR) is another tactic to inspire the immune system to induce and so detect maligned cells and eradicate them , 216. ReIn 2017, Shaw et al. found that in HNSCC murine models, co-administration of HER2-redirected CAR-T cell plus PD-1 inhibitor substantially improved survival compared to monotherapy with each of them . SimilarOverexpression of C-X-C chemokine receptor (CXCR) 4 is allied with undesired prognosis in human several tumors , 227. HeA summary of conducted studies respecting combination therapy with ICIs and CXCR4 blockade therapy have been listed in Tables  and 4.TaAs shown in clinical trials Tables  and 5, a