Clinical and video-polysomnographic characterization of restless sleep disorder in adult patients.

Adults with restless sleep disorder (RSD) have never been studied clinically and polysomnographically. This study aimed to describe the clinical manifestation, duration, and distribution of sleep-related movements in adult patients with restless sleep disorder. Patients who had performed VPSG from Jan 2021 to Jan 2022 and met the diagnosis criteria of RSD were enrolled in the study. Patients' bed partners were also interviewed or telephoned in identifying this disorder. Scoring of movements during sleep was according to the diagnosis criteria of RSD and scoring of large muscle group movements during sleep proposed by the International RLS Study Group in 2020 and 2021, respectively. The clinical manifestation, the distribution of sleep stage as well as the types and duration of the movements were carefully recorded and analyzed. We included ten patients in the study with a mean age of 27.6 years (range 22-38). There was a male prevalence in adults with RSD. The study highlighted the findings from video-polysomnography, which indicated frequent sleep-related movements occurring throughout the Night. These movements were most prominent during N1 and N2 sleep stage, followed by REM sleep, while fewer movements were observed during N3 sleep. Adults with RSD experienced significant daytime functioning impairments, including non-refreshing sleep, daytime fatigue/sleepiness, and mood disturbance. Two of the patients in the study were diagnosed with anxiety and depression, further underscoring the impact of RSD on mental health. Adult patients also suffer from severe RSD, and the RSD that originates in childhood tends to persist into adulthood. In these cases, longer duration of the disease and poor sleep quality may be associated with an increased risk of developing psychiatric comorbidities. Our cases represent an objectively documented type of RSD in younger adult patients. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-024-00524-1.

Trends in management of patients with new-onset refractory status epilepticus (NORSE) from 2016 to 2023: An interim analysis.

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

Preferences of physicians for treatment-related toxicity vs. recurrence in melanoma (GERMELATOX-A): the doctors' perspective.

INTRODUCTION: Adjuvant treatment with immune checkpoint inhibitors, such as PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT), has shown a significant improvement in disease-free survival (DFS) for high-risk melanoma patients. However, due to specific side effects, the choice of treatment is often influenced by the risk of toxicity. Therefore, the role of physicians in treatment decisions of patients is crucial. This study investigated for the first time in a multicenter setting the attitudes and preferences of dermatooncologists in Germany and Switzerland regarding adjuvant treatment with (c)ICI and TT. METHODS: In the GERMELATOX-A study, 108 physicians (median age: 32 yrs, 67.6% female) from 11 skin cancer centers were surveyed to rate typical side effect scenarios of (c)ICI and TT treatments and then compared to patients' ratings evaluated in a previous analysis from the same centers. The scenarios described mild-to-moderate or severe toxicity and included melanoma relapse leading to death. The physicians were asked about the level of side effects they would tolerate in exchange for a reduction in melanoma relapse and an increase in survival at 5 years. RESULTS: The preferences of physicians and patients revealed significant differences regarding adjuvant melanoma treatment with (c)ICI and TT (p < 0.05). Compared to patients, physicians tend to value a melanoma relapse less severe, according to a visual analog scale. They were also less threatened by all scenarios of side effects during adjuvant treatment with (c)ICI or TT, compared to patients. Physicians required lower risk reductions for disease-free survival (DFS) and overall survival (OS) for both ICI and TT and their drug-related side effects to accept these treatments. In case of severe side effects, physicians required similar 5-year DFS rates for ICI and TT (60-65%), while patients needed a 15% improvement of 5-year DFS for ICI compared to TT (80%/65%). For survival, physicians expected an OS improvement of + 10% for all three treatment modalities, whereas patients required a higher increase: + 18-22% for ICI and + 15% for TT. CONCLUSION: Our study highlights the importance of understanding the patient's perspective and a potential difference to the doctor's view when making decisions about adjuvant melanoma treatment with (c)ICI and TT, especially as these treatments are increasingly being implemented in earlier stages.

Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Correlation between Dermatology Life Quality Index and Psoriasis Area and Severity Index in Patients with Psoriasis: A Cross-sectional Global Healthcare Study on Psoriasis.

Quality of life impairment in dermatology patients and severity of psoriasis are quantified by the Dermatology Life Quality Index (DLQI) and the Psoriasis Area and Severity Index (PASI), respectively. The aim of this study is to compare the correlation between PASI and DLQI in patients from different geographical areas and to identify predictors of high DLQI across geographical regions. Correlations between PASI and DLQI were evaluated using Spearman's rank correlation tests and quantile regression. The study included 1,158 patients with psoriasis, with a median (interquartile range) PASI and DLQI of 6.0 (3.0-12.0) and 8.0 (4.0-15.0), respectively. Correlations were demonstrated between PASI and DLQI, both overall and stratified by geographical region. Quantile (median) regression yielded coefficients of 0.75 (95% confidence interval (95% CI) 0.62, 0.88) for Switzerland, 0.50 (95% CI 0.42, 0.58) for Latin America, 0.34 (95% CI 0.16, 0.51) for Asia, and 0.31 (95% CI 0.08, 0.53) for the USA. Current age, age at diagnosis, sex, body mass index, and psoriasis arthritis affected DLQI in Latin America, while education had an impact among patients treated in Switzerland. Few countries were included within each continent; hence, more data from different countries are necessary for generalizability. The study showed correlations between PASI and DLQI among patients in all included geographical regions. The patients' characteristics affecting DLQI vary worldwide.

Performance of an automated total body mapping algorithm to detect melanocytic lesions of clinical relevance.

IMPORTANCE: Total body photography for skin cancer screening is a well-established tool allowing documentation and follow-up of the entire skin surface. Artificial intelligence-based systems are increasingly applied for automated lesion detection and diagnosis. DESIGN AND PATIENTS: In this prospective observational international multicentre study experienced dermatologists performed skin cancer screenings and identified clinically relevant melanocytic lesions (CRML, requiring biopsy or observation). Additionally, patients received 2D automated total body mapping (ATBM) with automated lesion detection (ATBM master, Fotofinder Systems GmbH). Primary endpoint was the percentage of CRML detected by the bodyscan software. Secondary endpoints included the percentage of correctly identified "new" and "changed" lesions during follow-up examinations. RESULTS: At baseline, dermatologists identified 1075 CRML in 236 patients and 999 CRML (92.9%) were also detected by the automated software. During follow-up examinations dermatologists identified 334 CRMLs in 55 patients, with 323 (96.7%) also being detected by ATBM with automated lesions detection. Moreover, all new (n = 13) or changed CRML (n = 24) during follow-up were detected by the software. Average time requirements per baseline examination was 14.1 min (95% CI [12.8-15.5]). Subgroup analysis of undetected lesions revealed either technical (e.g. covering by clothing, hair) or lesion-specific reasons (e.g. hypopigmentation, palmoplantar sites). CONCLUSIONS: ATBM with lesion detection software correctly detected the vast majority of CRML and new or changed CRML during follow-up examinations in a favourable amount of time. Our prospective international study underlines that automated lesion detection in TBP images is feasible, which is of relevance for developing AI-based skin cancer screenings.

Health Economic Consequences Associated With COVID-19-Related Delay in Melanoma Diagnosis in Europe.

Importance: The COVID-19 pandemic resulted in delayed access to medical care. Restrictions to health care specialists, staff shortages, and fear of SARS-CoV-2 infection led to interruptions in routine care, such as early melanoma detection; however, premature mortality and economic burden associated with this postponement have not been studied yet. Objective: To determine the premature mortality and economic costs associated with suspended melanoma screenings during COVID-19 pandemic lockdowns by estimating the total burden of delayed melanoma diagnoses for Europe. Design, Setting, and Participants: This multicenter economic evaluation used population-based data from patients aged at least 18 years with invasive primary cutaneous melanomas stages I to IV according to the American Joint Committee on Cancer (AJCC) seventh and eighth editions, including melanomas of unknown primary (T0). Data were collected from January 2017 to December 2021 in Switzerland and from January 2019 to December 2021 in Hungary. Data were used to develop an estimation of melanoma upstaging rates in AJCC stages, which was verified with peripandemic data. Years of life lost (YLL) were calculated and were, together with cost data, used for financial estimations. The total financial burden was assessed through direct and indirect treatment costs. Models were building using data from 50 072 patients aged 18 years and older with invasive primary cutaneous melanomas stages I to IV according to the AJCC seventh and eighth edition, including melanomas of unknown primary (T0) from 2 European tertiary centers. Data from European cancer registries included patient-based direct and indirect cost data, country-level economic indicators, melanoma incidence, and population rates per country. Data were analyzed from July 2021 to September 2022. Exposure: COVID-19 lockdown-related delay of melanoma detection and consecutive public health and economic burden. As lockdown restrictions varied by country, lockdown scenario was defined as elimination of routine medical examinations and severely restricted access to follow-up examinations for at least 4 weeks. Main Outcomes and Measures: Primary outcomes were the total burden of a delay in melanoma diagnosis during COVID-19 lockdown periods, measured using the direct (in US$) and indirect (calculated as YLL plus years lost due to disability [YLD] and disability-adjusted life-years [DALYs]) costs for Europe. Secondary outcomes included estimation of upstaging rate, estimated YLD, YLL, and DALY for each European country, absolute direct and indirect treatment costs per European country, proportion of the relative direct and indirect treatment costs for the countries, and European health expenditure. Results: There were an estimated 111 464 (range, 52 454-295 051) YLL due to pandemic-associated delay in melanoma diagnosis in Europe, and estimated total additional costs were $7.65 (range, $3.60 to $20.25) billion. Indirect treatment costs were the main cost driver, accounting for 94.5% of total costs. Estimates for YLD in Europe resulted in 15 360 years for the 17% upstaging model, ranging from 7228 years (8% upstaging model) to 40 660 years (45% upstaging model). Together, YLL and YLD constitute the overall disease burden, ranging from 59 682 DALYs (8% upstaging model) to 335 711 DALYs (45% upstaging model), with 126 824 DALYs for the real-world 17% scenario. Conclusions and Relevance: This economic analysis emphasizes the importance of continuing secondary skin cancer prevention measures during pandemics. Beyond the personal outcomes of a delayed melanoma diagnosis, the additional economic and public health consequences are underscored, emphasizing the need to include indirect economic costs in future decision-making processes. These estimates on DALYs and the associated financial losses complement previous studies highlighting the cost-effectiveness of screening for melanoma.

Elevated phase amplitude coupling as a depression biomarker in epilepsy.

Depression is prevalent in epilepsy patients and their intracranial brain activity recordings can be used to determine the types of brain activity that are associated with comorbid depression. We performed case-control comparison of spectral power and phase amplitude coupling (PAC) in 34 invasively monitored drug resistant epilepsy patients' brain recordings. The values of spectral power and PAC for one-minute segments out of every hour in a patient's study were correlated with pre-operative assessment of depressive symptoms by Beck Depression Inventory-II (BDI). We identified an elevated PAC signal (theta-alpha-beta phase (5-25 Hz)/gamma frequency (80-100 Hz) band) that is present in high BDI scores but not low BDI scores adult epilepsy patients in brain regions implicated in primary depression, including anterior cingulate cortex, amygdala and orbitofrontal cortex. Our results showed the application of PAC as a network-specific, electrophysiologic biomarker candidate for comorbid depression and its potential as treatment target for neuromodulation.

Responsive Neurostimulation for People With Drug-Resistant Epilepsy and Autism Spectrum Disorder.

PURPOSE: Individuals with autism spectrum disorder (ASD) have comorbid epilepsy at much higher rates than the general population, and about 30% will be refractory to medication. Patients with drug-resistant epilepsy (DRE) should be referred for surgical evaluation, yet many with ASD and DRE are not resective surgical candidates. The aim of this study was to examine the response of this population to the responsive neurostimulator (RNS) System. METHODS: This multicenter study evaluated patients with ASD and DRE who underwent RNS System placement. Patients were included if they had the RNS System placed for 1 year or more. Seizure reduction and behavioral outcomes were reported. Descriptive statistics were used for analysis. RESULTS: Nineteen patients with ASD and DRE had the RNS System placed at 5 centers. Patients were between the ages of 11 and 29 (median 20) years. Fourteen patients were male, whereas five were female. The device was implanted from 1 to 5 years. Sixty-three percent of all patients experienced a >50% seizure reduction, with 21% of those patients being classified as super responders (seizure reduction >90%). For the super responders, two of the four patients had the device implanted for >2 years. The response rate was 70% for those in whom the device was implanted for >2 years. Improvements in behaviors as measured by the Clinical Global Impression Scale-Improvement scale were noted in 79%. No complications from the surgery were reported. CONCLUSIONS: Based on the authors' experience in this small cohort of patients, the RNS System seems to be a promising surgical option in people with ASD-DRE.

Measuring the impact of monoclonal antibody therapies.

Objective: Monoclonal antibody (Mab) treatments have significantly improved the quality and quantity of life, but they are some of the most expensive treatments, resulting in a degree of hesitancy to introduce new Mab agents. A system for estimating the effect of Mab drugs, in general, would optimally inform health strategy and fully realize how a single scientific discovery can deliver health benefits. We evaluated such a method with several well-established Mab regimens. Methods: We selected five different Mab regimens in oncology and rheumatology in England. We carried out two systematic literature reviews and meta-analyses to assess health outcomes (Health Assessment Questionnaire-Disability Index for rheumatoid arthritis; overall mortality for melanoma) from real-world data and compared them to the outcomes from randomized control trials (RCTs). We applied economic modeling to estimate the net monetary benefits for health outcomes for the estimated patient population size for each Mab regimen. Results: Meta-analyses of 27 eligible real-world data (RWD) sets and 26 randomized controlled trial (RCT) sets found close agreement between the observed and expected health outcomes. A Markov model showed the net positive monetary benefit in three Mab regimens and the negative benefit in two regimens. However, because of limited access to NHS data, the economic model made several assumptions about the number of treated patients and the cost of treatment to the NHS, the accuracy of which may affect the estimation of the net monetary benefit. Conclusion: RCT results reliably inform the real-world experience of Mab treatments. Calculation of the net monetary benefit by the algorithm described provides a valuable overall measure of the health impact, subject to the accuracy of data inputs. This study provides a compelling case for building a comprehensive, systematized, and accessible database and related analytics, on all Mab treatments within health services.

Stat5a sobers up inTOXicated T cells.

Exhausted T cells are largely hampered by epigenetically enforced mechanisms that limit their effector potential. In this issue of Immunity, Beltra et al. found that Stat5 can alter these epigenetic profiles when T cells transition from the Tpex precursor stage into differentiated cells. At this stage, enforced Stat5 expression increases the number of intermediate exhausted T cells and induces durable effector cells with superior anti-tumor activity.

A multicenter retrospective study of patients treated in the thalamus with responsive neurostimulation.

Introduction: For drug resistant epilepsy patients who are either not candidates for resective surgery or have already failed resective surgery, neuromodulation is a promising option. Neuromodulatory approaches include responsive neurostimulation (RNS), deep brain stimulation (DBS), and vagal nerve stimulation (VNS). Thalamocortical circuits are involved in both generalized and focal onset seizures. This paper explores the use of RNS in the centromedian nucleus of the thalamus (CMN) and in the anterior thalamic nucleus (ANT) of patients with drug resistant epilepsy. Methods: This is a retrospective multicenter study from seven different epilepsy centers in the United States. Patients that had unilateral or bilateral thalamic RNS leads implanted in the CMN or ANT for at least 6 months were included. Primary objectives were to describe the implant location and determine changes in the frequency of disabling seizures at 6 months, 1 year, 2 years, and > 2 years. Secondary objectives included documenting seizure free periods, anti-seizure medication regimen changes, stimulation side effects, and serious adverse events. In addition, the global clinical impression scale was completed. Results: Twelve patients had at least one lead placed in the CMN, and 13 had at least one lead placed in the ANT. The median baseline seizure frequency was 15 per month. Overall, the median seizure reduction was 33% at 6 months, 55% at 1 year, 65% at 2 years, and 74% at >2 years. Seizure free intervals of at least 3 months occurred in nine patients. Most patients (60%, 15/25) did not have a change in anti-seizure medications post RNS placement. Two serious adverse events were recorded, one related to RNS implantation. Lastly, overall functioning seemed to improve with 88% showing improvement on the global clinical impression scale. Discussion: Meaningful seizure reduction was observed in patients who suffer from drug resistant epilepsy with unilateral or bilateral RNS in either the ANT or CMN of the thalamus. Most patients remained on their pre-operative anti-seizure medication regimen. The device was well tolerated with few side effects. There were rare serious adverse events. Most patients showed an improvement in global clinical impression scores.

XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression.

The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL.

Social acceptance of genetic engineering technology.

Genetic engineering of animals has been proposed to address societal problems, but public acceptance of the use of this technology is unclear. Previous work has shown that the source of information proposing the technology (e.g. companies, universities), the term used to describe the technology (e.g. genome editing, genetic modification), and the genetic engineering application (e.g. different food products) affects technology acceptance. We conducted three mixed-method surveys and used a causal trust-acceptability model to understand social acceptance of genetic engineering (GE) by investigating 1) the source of information proposing the technology, 2) the term used to describe the technology, and 3) the GE application for farm animals proposed. Further, participants expressed their understanding of technology using a range of terms interchangeably, all describing technology used to change an organism's DNA. We used structural equation modelling and confirmed model fit for each survey. In each survey, perceptions of benefit had the greatest effect on acceptance. Following our hypothesized model, social trust had an indirect influence on acceptance through similar effects of perceived benefit and perceived risk. Additional quantitative analysis showed that the source of information and technology term had little to no effect on acceptance. Applications involving animals were perceived as less beneficial than a plant application, and an application for increased cattle muscle growth was perceived as more risky than a plant application. When assessing the acceptability of applications participants considered impacts on plants, animals, and people, trust in actors and technologies, and weighed benefits and drawbacks of GE. Future work should consider how to best measure acceptability of GE for animals, consider contextual factors and consider the use of inductive frameworks.

Enhanced Carrier Diffusion Enables Efficient Back-Contact Perovskite Photovoltaics.

Back-contact architectures offer a promising route to improve the record efficiencies of perovskite solar cells (PSCs) by eliminating parasitic light absorption. However, the performance of back-contact PSCs is limited by inadequate carrier diffusion in perovskite. Here, we report that perovskite films with a preferred out-of-plane orientation show improved carrier dynamic properties. With the addition of guanidine thiocyanate, the films exhibit carrier lifetimes and mobilities increased by 3-5 times, leading to diffusion lengths exceeding 7 µm. The enhanced carrier diffusion results from substantial suppression of nonradiative recombination and improves charge collection. Devices using such films achieve reproducible efficiencies reaching 11.2 %, among the best performances for back-contact PSCs. Our findings demonstrate the impact of carrier dynamics on back-contact PSCs and provide the basis for a new route to high-performance back-contact perovskite optoelectronic devices at low cost.

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.

Orbital Extenteration Defects: Ablative and Reconstructive Flowchart Proposal.

ABSTRACT: Orbital exenteration is a radical and disfiguring operation. It is still under debate the absence of correlation between the term describing the resulting orbital defect and the type of reconstruction. Authors' goal was to propose a consistent and uniform terminology for Orbital Exenteration surgery in anticipation of patients' tailored management. Twenty-five patients who underwent orbital exenteration between 2014 and 2020 were reviewed. A parallel comprehensive literature review was carried on. Five different types of orbital exenteration where outlined. Multiple reconstructive procedures were enclosed. An algorithm for orbital reconstruction was proposed based on anatomic boundaries restoration. Eyelid removal was first considered as an independent reconstructive factor, and both orbital roof and floor were indicated as independent reconstructive goals, which deserve different defect classification. In our opinion, this algorithm could be a useful tool for patient counseling and treatment selection, which might allow a more tailored patient care protocol. LEVEL OF EVIDENCE: Level III.

Targeting KIR as a novel approach to improve CAR-NK cell function.

Chimeric antigen receptor (CAR) NK cells are demonstrating promising activity in clinical trials and possess a favorable safety profile compared to CAR-T cells. The Killer cell Immunoglobulin-like Receptors (KIR) have a critical role in the control of NK cell function, and recently, this family of activating and inhibitory receptors have been targeted to improve CAR-NK function. These strategies include the utilisation of inhibitory KIR to reduce trogocytosis-associated NK cell fratricide, the downregulation of inhibitory KIR on CAR-NK cells to alleviate HLA mediated suppression, the selection of CAR-NK cell donors enriched for activating KIR, and the use of activating KIR intracellular domains within novel CAR constructs. These pre-clinical studies demonstrate the potential utility of targeting the KIR to improve CAR-NK cell efficacy and patient outcomes.

Disruption of the NKG2A:HLA-E Immune Checkpoint Axis to Enhance NK Cell Activation against Cancer.

Ligation of the inhibitory receptor NKG2A by its ligand HLA-E negatively regulates the activation of natural killer (NK) cells, as well as subsets of CD8+ T cells and innate T cell populations. NKG2A has recently become a novel immune checkpoint target for the treatment of cancer and direct antibody mediated blockade of NKG2A function is currently under assessment in two phase 3 clinical trials. In addition to direct targeting, the NKG2A:HLA-E axis can also be disrupted indirectly via multiple different targeted cancer agents that were not previously recognised to possess immunomodulatory properties. Increased understanding of immune cell modulation by targeted cancer therapies will allow for the design of rational and more efficacious drug combination strategies to improve cancer patient outcomes. In this review, we summarise and discuss the various strategies currently in development which either directly or indirectly disrupt the NKG2A:HLA-E interaction to enhance NK cell activation against cancer.