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Abstract The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME’s contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME’s implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

Abstract Background Cognitive impairment is an increasingly recognized comorbidity of diabetes, yet the mechanisms underlying this association remain poorly understood. This knowledge gap has contributed to conflicting findings regarding the impact of diabetes on long-term cognitive outcomes in older adults. The presence of cerebrovascular disease (CeVD) may potentially modify this relationship. However, interactive effect between diabetes and subclinical MRI markers of CeVD on cognitive trajectories and incident dementia remains unexplored. Methods A total of 654 participants underwent brain MRI at baseline, from whom 614 with at least one follow-up were selected for longitudinal analysis. Cognitive tests were performed annually up to 5 years. CeVD markers of interest were lacunes, white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), cortical microinfarcts (CMIs), intracranial stenosis (ICS), and cortical infarcts. Blood-based Alzheimer biomarkers, including p-tau181 and p-tau181/Aβ42 ratio, were used as indicators of Alzheimer pathology. Results At baseline, diabetes was associated with lower cognitive performance and higher burden of CeVD, but not p-tau181 or p-tau181/Aβ42 ratio. Longitudinally, we found an interactive effect of diabetes and WMHs, rather than an independent effect of diabetes, on cognitive decline and dementia risk. Subgroup analyses showed association of diabetes with cognitive outcomes was stronger in participants with high WMHs load but non-significant in those with low WMHs load. Moreover, these associations remained unchanged after adjusting for blood-based Alzheimer biomarkers. Conclusions The effect of diabetes on cognitive decline is contingent upon the presence of WMHs and independent of Alzheimer’s pathology. This finding raises the possibility of utilizing WMHs as an imaging biomarker to identify diabetic subgroup at greater risk of developing cognitive impairment. Furthermore, therapeutic interventions targeting WMHs may prevent cognitive deterioration in older adults with diabetes.

Background CV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death protein-1 (PD-1) therapy-naïve or anti-PD-1 therapy-refractory cutaneous melanoma (cMEL) and in patients with advanced cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma and adenoid cystic carcinoma.Methods This open-label, cohort-based, phase I dose escalation study aimed to establish the maximum tolerated dose (MTD), recommended dose (RD), safety and preliminary efficacy of CV8102 as monotherapy or in combination with a PD-1 inhibitor. The preliminary efficacy of the RD was assessed in patients with cMEL in the expansion cohorts.Results Between September 2017 and October 2022, 98 patients were enrolled in monotherapy and combination therapy dose escalation and dose expansion cohorts. Two patients in the CV8102 monotherapy dose escalation cohort experienced relevant toxicities at the 900 µg dose level. One patient had Grade 3 aspartate transaminase/alanine aminotransferase elevation which met dose-limiting toxicity (DLT) criteria. Another patient experienced Grade 3 immune-mediated pneumonitis. No DLTs occurred in the combination therapy dose escalation cohort. The MTD was not formally reached and the RD for expansion was 600 µg. Common treatment-emergent adverse events were fever (57%), chills (37%) and fatigue (25%). In the dose escalation part, objective responses occurred in 3/33 patients treated with CV8102 as monotherapy and in 2/25 patients treated with CV8102 plus a PD-1 inhibitor. In the expansion cohorts in patients with anti-PD-1 therapy-refractory melanoma, 0/10 patients treated with CV8102 as monotherapy and 5/30 patients (17%) treated in combination with a PD-1 inhibitor experienced objective responses.Conclusions IT CV8102 was generally well tolerated with preliminary signs of efficacy as monotherapy and in combination with a PD-1 inhibitor.Trial registration number NCT03291002.

Background Left ventricular (LV) geometric patterns are associated with cognitive impairment and cerebral small vessel disease. As a novel magnetic resonance imaging marker of cerebral small vessel disease and a risk factor for cognitive dysfunction, cortical cerebral microinfarcts (CMIs) have been associated with heart disease through mechanisms including cardioembolism and cerebral hypoperfusion. Further investigation is required to determine whether cortical CMIs could arise from hemodynamic changes related to LV geometry, thus elucidating the connection between LV geometry and cognitive function. This study aims to investigate the cross‐sectional relationship between LV geometric patterns, cortical CMIs, and cognition. Methods and Results A total of 261 patients, aged 75.3±6.8 years, were enrolled from a memory clinic study. LV dimensions were obtained using 2‐dimensional echocardiography. LV mass index and relative wall thickness were determined to categorize LV geometric patterns. Cortical CMIs were graded on 3T magnetic resonance imaging. Cognition was assessed using neuropsychological tests and clinical diagnosis. Linear, zero‐inflated Poisson, and logistic regression were employed for continuous, count, and binary outcomes, respectively. Mediation analysis was conducted to examine the mediation effect of cortical CMIs. A significant association was observed between concentric LV hypertrophy and cortical CMI counts (rate ratio, 3.85 [95% CI, 1.85–8.01]), as well as the odds of having dementia (odds ratio, 2.86 [95% CI, 1.07–7.89]), in the fully adjusted model. Cortical CMIs may partly explain the relationship between concentric LV hypertrophy and cognitive function. Conclusions Concentric LV hypertrophy was associated with cortical CMIs and dementia. Further verification is warranted to determine the role of cortical CMIs in the association between LV geometry and cognition.

Background: The Hedgehog inhibitor sonidegib had durable efficacy and a manageable safety profile in patients with locally advanced basal cell carcinoma (laBCC) through 42 months of the BOLT trial. In this analysis, we characterize the effects of 200-mg and 800-mg sonidegib on tumors in patients in the BOLT trial. Methods: Tumors were assessed using color photography and magnetic resonance imaging (MRI) by central and investigator review at baseline; Weeks 5, 9, and 17 after the start of treatment; then every 8 weeks during the first year; and every 12 weeks thereafter. Results: In patients with laBCC receiving sonidegib, the decrease in best percentage change from baseline in target lesions was 92.3 % per central review and 96.7 % per investigator review in the 200-mg treatment arm, and 90.1 % per central review and 95.2 % per investigator in the 800-mg treatment arm. The kinetics of response to treatment appeared to influence tumor reduction, with patients responding within the first 3 months of treatment experiencing a greater decrease in tumor size over time than later responders. Additionally, patients whose best overall response to treatment was complete response or partial response had a generally longer duration of response compared with patients who had stable disease as best overall response. Tumor reduction and duration of response were greater when assessed by investigator review compared with central review. Conclusion: Treatment with sonidegib for up to 42 months substantially reduced tumors in patients with laBCC.

ObjectiveImmunotherapeutic inhibition of PD-1 by systemically administered monoclonal antibodies is widely used in cancer treatment, but it may cause severe immune-related adverse events (irSAEs). Neoadjuvant PD-1 inhibition before surgery has shown promise in reducing recurrence by stimulating durable antitumor immunity. Local intratumoral (IT) immunotherapy is a potential strategy to minimize irSAEs, but antibodies have limited tumor penetration, making them less suitable for this approach. Therapeutic self-delivering RNAi (INTASYL) is an emerging modality well-suited for neoadjuvant immunotherapy. This study presents preclinical proof-of-concept for PH-762, an INTASYL designed to silence PD-1, currently in clinical development for advanced cutaneous malignancies (ClinicalTrials.gov#NCT06014086).Methods and analysisPH-762 pharmacology was characterized in vitro, and in vivo antitumor efficacy was evaluated using a murine analogue (mPH-762) in syngeneic tumor models with varying PD-1 responsiveness. Bilateral Hepa1-6 models assessed abscopal effects of local treatment. Ex vivo analyses explored mechanisms of direct and abscopal efficacy.ResultsPH-762 was rapidly internalized by human T cells, silencing PD-1 mRNA and decreasing PD-1 surface protein, enhancing TCR-stimulated IFN-γ and CXCL10 secretion. In vivo, IT mPH-762 provided robust antitumor efficacy, local and lymphatic biodistribution, and was well tolerated. Ex vivo analyses revealed that IT mPH-762 depleted PD-1 protein, promoted leukocyte and T cell infiltration, and correlated with tumor control. IT mPH-762 also demonstrated efficacy against untreated distal tumors (abscopal effect) by priming systemic antitumor immunity.ConclusionThese data support PH-762 as a promising candidate for neoadjuvant immunotherapy in clinical studies.

Background The association between platelet endothelial cell adhesion molecule‐1 (PECAM‐1) with cerebral small‐vessel disease and cognition in dementia‐free subjects remains uninvestigated. Methods and Results A prospective cohort of dementia‐free subjects was recruited from memory clinics and followed up for 5 years. Annual neurocognitive assessments and twice‐yearly brain magnetic resonance imaging scans were performed. Associations of baseline plasma PECAM‐1 levels with cerebral small‐vessel disease, cognitive decline (Montreal Cognitive Assessment scores and executive function Z scores), and incident dementia were evaluated. Of 213 subjects (aged 70.2±7.7 years, 51.2% men), median PECAM‐1 levels were 0.790 (interquartile range, 0.645–0.955 ng/mL). Compared with the highest tertile, subjects within the lowest PECAM‐1 tertile had greater cross‐sectional white matter hyperintensity volume (β=4.84 [95% CI, 0.67–9.01]; P=0.023), age‐related white matter change scores (β=1.39 [95% CI, 0.12–2.67]; P=0.033), and cerebral microbleeds (Adjusted risk ratio, 2.59 [95% CI, 1.19–5.62]; P=0.016). Of the 204 participants with follow‐up data (median, 60.0 [interquartile range, 60.0–60.0] months), 24 (11.8%) developed incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM‐1 had a higher risk of incident dementia (first tertile: adjusted hazard ratio [AHR], 4.52 [95% CI, 1.35–15.13]; P=0.024; second tertile: AHR, 3.28 [95% CI, 1.02–10.60]; P=0.047). The lowest PECAM‐1 tertile was associated with greater progression of white matter hyperintensity volume (β=4.15 [95% CI, 0.06–8.24]; P=0.047), cerebral microbleeds (incident relative risk [IRR], 2.21 [95% CI, 1.05–4.65]; P=0.036), and decline in executive function (β=−0.45 [95% CI, −0.76 to −0.14]; P=0.004), and Montreal Cognitive Assessment (β=−1.32 [95% CI, −2.30 to −0.35]; P=0.008) scores. Conclusions In dementia‐free subjects, lower circulating PECAM‐1 levels are associated with greater cerebral small‐vessel disease progression and cognitive decline, thus warranting future study as a potential therapeutic target.

Abstract Background In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials. Methods We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets. Results Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8+ T-cells (~ 40%), CD4+ FoxP3- T-cells (~ 40%) and CD4+ FoxP3+ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4+FoxP3+ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3+ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8+ T-cells and of CD4+ FoxP3- T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4+ FoxP3+ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels. Conclusions Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type.

Background Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics.Methods Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate

Introduction: The relative contributions of aortic and carotid artery stiffness on cognitive impairment and dementia remain unknown. We examined the associations of aortic and carotid artery stiffness with cerebrovascular disease markers, cognition, and dementia subtypes in a memory clinic cohort. Methods: 272 participants underwent applanation tonometry, carotid ultrasonography, 3T brain MRI, and neuropsychological assessment. Aortic stiffness parameters (carotid-femoral pulse wave velocity, aortic augmentation index, and aortic pulse pressure) were obtained with applanation tonometry whilst carotid artery stiffness parameters (β-index, pressure-strain elastic modulus, and pulse- wave velocity-β) were assessed by carotid ultrasonography, from which composite scores for aortic and carotid artery stiffness were calculated. Brain magnetic resonance images were graded for cerebrovascular disease markers, including white matter hyperintensities (WMH), lacunes, cerebral microbleeds, cortical infarcts, and stenosis. Cognition was assessed by the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the National Institute of Neurological Disorders and Stroke–Canadian Stroke Network harmonization battery in order to classify participants as having no cognitive impairment, cognitive impairment no dementia, or dementia subtyped as Alzheimer disease and vascular dementia. Results: After considering both aortic and carotid artery stiffness in the same regression models, carotid artery stiffness remained independently and significantly associated with WMH (β=0.78, p

Introduction: Left ventricular hypertrophy (LVH) is associated with increased risk of cardiovascular events, cognitive impairment, and mortality. However, the associations between LVH and cortical cerebral microinfarcts (CMI) and the underlying mechanisms involved are less known. This study examined the associations of LVH geometric patterns with CMI and cognition. In addition, we assessed if the association between LVH and cognition was mediated by CMI. Methods: Participants were recruited from a memory clinic cohort in Singapore. All participants underwent comprehensive physical and medical examination, echocardiography assessment, 3T brain MRI scans, and neuropsychological assessments. Echocardiography was conducted to assess left ventricular mass index (LVMI) and relative wall thickness (RWT) parameters to identify patients with left ventricular hypertrophy (LVH). Participants were further categorized into left ventricular geometric patterns which included normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Brain MRI scans were graded for the presence of CMI. Cognition was assessed by the Mini-Mental State Examination, Montreal Cognitive Assessment, and the National Institute of Neurological Disorders and Stroke–Canadian Stroke Network harmonization battery to classify participants as having no cognitive impairment (NCI), cognitive impairment no dementia (CIND), or dementia. Results: 261 participants were included in the study after assessing for eligibility. The mean age was 75 (6.7) years, majority were female (58%), and of Chinese ethnicity (87%). Participants with concentric hypertrophy were independently associated with presence of CMI (OR=3.38, 95% CI 1.06,10.55), and global cognition (ß=-0.95, p=0.03). The effects of concentric hypertrophy on global cognition were fully mediated by the presence of CMI (Figure 1). Discussion: Elevated LVMI and RWT in concentric hypertrophy is independently associated with presence of CMI and global cognition. The association between concentric hypertrophy and global cognition was mediated by the presence of CMI. Left ventricular geometric patterns could be used as a risk stratification tool to identify patients at risk of developing CMI and cognitive impairment.

Abstract Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyze 38 skin cancer genomes from five XP groups. We find that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors and experiments with POLH knockout cell line reveal the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3’ nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.

As a central node of protein synthesis, the cap-binding complex, eukaryotic translation initiation factor 4 F (eIF4F), is involved in cell homeostasis, development and tumorigenesis. A large body of literature exists on the regulation and function of eIF4F in cancer cells, however the intracellular localization patterns of this complex are largely unknown. Since different subsets of mRNAs are translated in distinct subcellular compartments, understanding the distribution of translation initiation factors in the cell is of major interest. Here, we developed an in situ detection method for eIF4F at the single cell level. By using an image-based spot feature analysis pipeline as well as supervised machine learning, we identify five distinct spatial patterns of the eIF4F translation initiation complex in human melanoma cells. The quantity of eIF4F complex per cell correlated with the global mRNA translation activity, and its variation is dynamically regulated by cell state or extracellular stimuli. In contrast, the spatial patterns of eIF4F complexes at the single cell level could distinguish melanoma cells harboring different oncogenic driver mutations. This suggests that different tumorigenic contexts differentially regulate the subcellular localization of mRNA translation, with specific localization of eIF4F potentially associated with melanoma cell chemoresistance.

Background Our aim was to explore the prognostic value of anthropometric parameters in a large population of patients treated with immunotherapy.Methods We retrospectively included 623 patients with advanced non-small cell lung cancer (NSCLC) (n=318) or melanoma (n=305) treated by an immune-checkpoint-inhibitor having a pretreatment (thorax-)abdomen-pelvis CT scan. An external validation cohort of 55 patients with NSCLC was used. Anthropometric parameters were measured three-dimensionally (3D) by a deep learning software (Anthropometer3DNet) allowing an automatic multislice measurement of lean body mass, fat body mass (FBM), muscle body mass (MBM), visceral fat mass (VFM) and sub-cutaneous fat mass (SFM). Body mass index (BMI) and weight loss (WL) were also retrieved. Receiver operator characteristic (ROC) curve analysis was performed and overall survival was calculated using Kaplan-Meier (KM) curve and Cox regression analysis.Results In the overall cohort, 1-year mortality rate was 0.496 (95% CI: 0.457 to 0.537) for 309 events and 5-year mortality rate was 0.196 (95% CI: 0.165 to 0.233) for 477 events. In the univariate Kaplan-Meier analysis, prognosis was worse (p

Abstract The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2–4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate.

Background Loss of Ambra1 (autophagy and beclin 1 regulator 1), a multifunctional scaffold protein, promotes the formation of nevi and contributes to several phases of melanoma development. The suppressive functions of Ambra1 in melanoma are mediated by negative regulation of cell proliferation and invasion; however, evidence suggests that loss of Ambra1 may also affect the melanoma microenvironment. Here, we investigate the possible impact of Ambra1 on antitumor immunity and response to immunotherapy.Methods This study was performed using an Ambra1-depleted BrafV600E/Pten−/− genetically engineered mouse (GEM) model of melanoma, as well as GEM-derived allografts of BrafV600E/Pten−/− and BrafV600E/Pten−/−/Cdkn2a−/− tumors with Ambra1 knockdown. The effects of Ambra1 loss on the tumor immune microenvironment (TIME) were analyzed using NanoString technology, multiplex immunohistochemistry, and flow cytometry. Transcriptome and CIBERSORT digital cytometry analyses of murine melanoma samples and human melanoma patients (The Cancer Genome Atlas) were applied to determine the immune cell populations in null or low-expressing AMBRA1 melanoma. The contribution of Ambra1 on T-cell migration was evaluated using a cytokine array and flow cytometry. Tumor growth kinetics and overall survival analysis in BrafV600E/Pten−/−/Cdkn2a−/− mice with Ambra1 knockdown were evaluated prior to and after administration of a programmed cell death protein-1 (PD-1) inhibitor.Results Loss of Ambra1 was associated with altered expression of a wide range of cytokines and chemokines as well as decreased infiltration of tumors by regulatory T cells, a subpopulation of T cells with potent immune-suppressive properties. These changes in TIME composition were associated with the autophagic function of Ambra1. In the BrafV600E/Pten−/−/Cdkn2a−/− model inherently resistant to immune checkpoint blockade, knockdown of Ambra1 led to accelerated tumor growth and reduced overall survival, but at the same time conferred sensitivity to anti-PD-1 treatment.Conclusions This study shows that loss of Ambra1 affects the TIME and the antitumor immune response in melanoma, highlighting new functions of Ambra1 in the regulation of melanoma biology.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines. Furthermore, there are no prospective trial data to inform the management of the distinct presentations of irAEs. Recognizing a need for uniform terminology for the natural history, response to treatment, and patterns of irAEs, the Society for Immunotherapy of Cancer (SITC) convened a consensus panel composed of leading international experts from academic medicine, industry, and regulatory agencies. Using a modified Delphi consensus process, the expert panel developed clinical definitions for irAE terminology used in the literature, encompassing terms related to irAE natural history (ie, re-emergent, chronic active, chronic inactive, delayed/late onset), response to treatment (ie, steroid unresponsive, steroid dependent), and patterns (ie, multisystem irAEs). SITC developed these definitions to support the adoption of a standardized vocabulary for irAEs, which will have implications for the uniform application of irAE clinical practice guidelines and to enable future irAE clinical trials.

Background Carotid artery stiffness is associated with cognitive impairment and dementia, but the underlying mechanisms remain unknown. We examined the associations of carotid artery stiffness with cerebral small‐vessel disease markers, cognition, and dementia subtypes in a memory clinic cohort. Methods and Results A total of 272 participants underwent carotid ultrasonography, 3 Tesla brain magnetic resonance imaging, and neuropsychological assessment. Carotid ultrasonography was used to assess β‐index, pressure‐strain elastic modulus, and pulse‐wave velocity‐β. Brain magnetic resonance images were graded for cerebral small‐vessel disease markers, including white matter hyperintensities, lacunes, and cerebral microbleeds. Participants were classified as having no cognitive impairment, cognitive impairment and no dementia, or dementia subtyped as Alzheimer disease and vascular dementia. Cognition was assessed using National Institute of Neurological Disorders and Stroke–Canadian Stroke Network harmonization battery. After adjusting for age, sex, cardiovascular risk factors, and diseases, multivariable models showed that β‐index (β=0.69; P=0.002), elastic modulus (β=0.78; P

Abstract Background The BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily. Methods This phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria. Results Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3–68.3%) and 71.2% (58.7–81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8–72.4%) and 74.2% (62.0–84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE). Conclusions Overall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria. Trial registration BOLT registration: ClinicalTrials.gov ( NCT01327053 ) on March 30, 2011.

Purpose While there is still a significant need to identify potential biomarkers that can predict which patients are most likely to respond to immunotherapy treatments, radiomic approaches have shown promising results. The objectives of this study were to evaluate whether a previously validated radiomics signature of CD8 T-cells could predict progressions at a lesion level and whether the spatial heterogeneity of this radiomics score could be used at a patient level to assess the clinical response and survival of melanoma patients.Methods Clinical data from patients with advanced melanoma treated in our center with immunotherapy were retrieved. Radiomic features were extracted and the CD8 radiomics signature was applied. A progressive lesion was defined by an increase in lesion size of 20% or more. Dispersion metrics of the radiomics signature were estimated to evaluate the impact of interlesion heterogeneity on patient’s response. Fine-tuned cut-offs for predicting overall survival were evaluated after splitting data into training and test sets.Results A total of 136 patients were included in this study, with 1120 segmented lesions at baseline, and 1052 lesions at first evaluation. A low CD8 radiomics score at baseline was associated with a significantly higher risk of lesion progression (AUC=0.55, p=0.0091), especially for lesions larger than >1 mL (AUC=0.59 overall, p=0.0035, with AUC=0.75, p=0.002 for subcutaneous lesions, AUC=0.68, p=0.01, for liver lesions and AUC=0.62, p=0.03 for nodes). The least infiltrated lesion according to the radiomics score of CD8 T-cells was positively associated with overall survival (training set HR=0.31, p=0.00062, test set HR=0.28, p=0.016), which remained significant in a multivariate analysis including clinical and biological variables.Conclusions These results confirm the predictive value at a lesion level of the biologically inspired CD8 radiomics score in melanoma patients treated with anti-PD1-based immunotherapy and may be interesting to assess the disease spatial heterogeneity to evaluate the patient prognosis with potential clinical implication such as tumor selection for focal ablative therapies.

The absence of scaffold protein Ambra1 leads to hyperproliferation and growth in mouse models. Here the authors show that Ambra1 deficiency accelerates melanoma growth and increases metastasis in mouse models of melanoma through FAK1 hyperactivation.

Background Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.Methods Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).Results In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.Conclusion While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

Summary: Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.

BackgroundAn increasing aging population has become a pressing problem in many countries. Smart systems and intelligent technologies support aging in place, thereby alleviating the strain on health care systems. ObjectiveThis study aims to identify decision-making factors involved in the adoption of smart home sensors (SHS) by older adults in Singapore. MethodsThe study involved 3 phases: as an intervention, SHS were installed in older adults’ homes (N=42) for 4 to 5 weeks; in-depth semistructured interviews were conducted with 18 older adults, 2 center managers, 1 family caregiver, and 1 volunteer to understand the factors involved in the decision-making process toward adoption of SHS; and follow-up feedback was collected from 42 older adult participants to understand the reasons for adopting or not adopting SHS. ResultsOf the 42 participants, 31 (74%) adopted SHS after the intervention, whereas 11 (26%) did not adopt SHS. The reasons for not adopting SHS ranged from privacy concerns to a lack of family support. Some participants did not fully understand SHS functionality and did not perceive the benefits of using SHS. From the interviews, we found that the decision-making process toward the adoption of SHS technology involved intrinsic factors, such as understanding the technology and perceiving its usefulness and benefits, and more extrinsic factors, such as considering affordability and care support from the community. ConclusionsWe found that training and a strong support ecosystem could empower older adults in their decision to adopt technology. We advise the consideration of human values and involvement of older adults in the design process to build user-centric assistive technology.

Immune checkpoints inhibitors or MAPK inhibitors are currently used as standard of care therapies for patients with advanced melanoma. Here the authors report a phase 1 clinical trial testing the anti-PD-L1 antibody durvalumab in combination with the BRAF inhibitor dafrafenib and the MEK inhibitor trametinib in patients with BRAFV600-mutant melanoma.

The gut microbiota has been reported to regulate the efficacy of cancer therapy. Here, the authors show that short-chain fatty acids, which are generated through bacterial fermentation, increases immune tolerance leading to resistance to anti-CTLA-4 immunotherapy in mice and patients with metastatic melanoma.

Tumor necrosis factor-receptor 1 (TNF-R1)-mediated signaling is critical to the regulation of inflammatory responses. TNF-R1 can be proteolytically released into systemic blood circulation in a soluble form (sTNF-R1), where it binds to circulating TNF and functions to attenuate TNF-mediated inflammation. Increases of peripheral sTNF-R1 have been reported in both Alzheimer’s disease (AD) dementia and vascular dementia (VaD). However, the status of sTNF-R1 in predementia subjects (cognitive impairment, no dementia, CIND) is unknown, and putative associations with cerebral small vessel disease (CSVD), as well as with longitudinal changes in cognitive functions are unclear. We measured baseline serum sTNF-R1 in a longitudinally assessed cohort of 93 controls and 103 CIND, along with neuropsychological evaluations and neuroimaging assessments. Serum sTNF-R1 levels were increased in CIND compared with controls (p < 0.001). Higher baseline sTNF-R1 levels were specifically associated with lacunar infarcts (rate ratio = 6.91, 95% CI 3.19–14.96, p < 0.001), as well as lower rates of cognitive decline in the CIND subgroup. Our data suggest that sTNF-R1 interacts with vascular cognitive impairment in a complex manner at predementia stages, with elevated levels associated with more severe CSVD at baseline, but which may subsequently be protective against cognitive decline.

Summary: The eukaryotic translation initiation complex eIF4F plays an important role in gene expression. The methods that are used to monitor the formation of the eIF4F complex are usually indirect and provide no information on its subcellular localization. This protocol describes a proximity ligation assay-based procedure allowing the direct in situ visualization of the eIF4F complex, as well as its absolute quantification per cell using adapted image analysis software.For complete details on the use and execution of this protocol, please refer to Boussemart et al. (2014).

Immunotherapy using immune-checkpoint modulators revolutionizes the oncology field far beyond their remarkable clinical efficacy in some patients. It creates radical changes in the evaluation of treatment efficacy and toxicity with a more holistic vision of the patient with cancer.

Melanoma persister cells are tolerant to anti-BRAF and anti-MEK inhibition and can trigger cancer relapse. Here the authors show that a subset of N6-methyladenosine modified mRNAs is translationally activated in persister cells. This preferential translation can be abrogated via eIF4A inhibition.

Background Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer.Methods We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality.Findings Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off.Interpretation COVID-19–related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.

Background A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma.Patients and methods A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics.Results 19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5–2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2–1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS.Conclusion When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation.Trial registration number NCT01557114.

Background We have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.Methods This randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.Results At a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutant BRAF tumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.Conclusions This 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.Trial registration number NCT01515189.

Background: Singapore faces challenges in providing efficient health-care services for the ageing population. Objectives: We evaluated the effectiveness of a novel holistic nutrition programme among the elderly who were staying in several senior activity centres in Singapore. Methods: A total of 83 elderly participants (>55 years old) took part in a mixed-methods experimental study. Participants were assigned to the control group (CG), the intervention group without health talks (IGH–) or the intervention group with health talks (IGH+). Demographics, perceived satisfaction score of the administered programme and pre–post measurement on nutritional knowledge and perceived competence were measured. Subsequently, in-depth interviews were also carried out with some participants. Results: One-way analysis of variance revealed significantly higher scores for the IGH– and IGH+ groups compared to the CG in terms of perceived satisfaction of the programme ( p= 0.009 and p= 0.005, respectively). There was also a significant difference in terms of the change in nutritional knowledge before and after the programme between the IGH– and IGH+ groups ( p= 0.002) but not for perceived competence ( p= 0.26). Several determinants of dietary behaviours in the elderly such as living arrangements, attitudes and finances were identified from thematic analyses of the interviews. Conclusions: The findings from the study demonstrate the effectiveness of an holistic programme in effecting changes in nutritional knowledge but not perceived competence.

Abstract Background Recently, the intervention calculus when the DAG is absent (IDA) method was developed to estimate lower bounds of causal effects from observational high-dimensional data. Originally it was introduced to assess the effect of baseline biomarkers which do not vary over time. However, in many clinical settings, measurements of biomarkers are repeated at fixed time points during treatment and, therefore, this method needs to be extended. The purpose of this paper is to extend the first step of the IDA, the Peter Clarks (PC)-algorithm, to a time-dependent exposure in the context of a binary outcome. Methods We generalised the so-called “PC-algorithm” to take into account the chronological order of repeated measurements of the exposure and proposed to apply the IDA with our new version, the chronologically ordered PC-algorithm (COPC-algorithm). The extension includes Firth’s correction. A simulation study has been performed before applying the method for estimating causal effects of time-dependent immunological biomarkers on toxicity, death and progression in patients with metastatic melanoma. Results The simulation study showed that the completed partially directed acyclic graphs (CPDAGs) obtained using COPC-algorithm were structurally closer to the true CPDAG than CPDAGs obtained using PC-algorithm. Also, causal effects were more accurate when they were estimated based on CPDAGs obtained using COPC-algorithm. Moreover, CPDAGs obtained by COPC-algorithm allowed removing non-chronological arrows with a variable measured at a time t pointing to a variable measured at a time t´ where t´

Aim: To describe treatment patterns among patients with stage III melanoma who underwent surgical excision in years 2011–2016, and assess outcomes among patients who subsequently received systemic adjuvant therapy versus watch-and-wait. Methods: Chart review of 380 patients from 17 melanoma centers in North America, South America and Europe. Results: Of 129 (34%) patients treated with adjuvant therapy, 85% received interferon α-2b and 56% discontinued treatment (mostly due to adverse events). Relapse-free survival was significantly longer for patients treated with adjuvant therapy versus watch-and-wait (hazard ratio = 0.63; p < 0.05). There was considerable heterogeneity in adjuvant treatment schedules and doses. Similar results were found in patients who received interferon-based adjuvant therapy. Conclusion: Adjuvant therapies with better safety/efficacy profiles will improve clinical outcomes in patients with stage III melanoma.

Before the era of immune checkpoint blockade, a meta-analysis encompassing fifteen trials reported that adjuvant IFN-α significantly reduces the risk of relapse and improves survival of ulcerated melanoma (UM) with no benefit for higher doses compared to lower doses. IFNa2b affects many cell intrinsic features of tumor cells and modulates the host innate and cognate immune responses. To better understand the biological traits associated with ulceration that could explain the efficacy of prophylactic type 1 IFN, we performed immunohistochemical analysis of various molecules (major histocompatibility complex class I and class II, MX Dynamin Like GTPase 1 (MX1), inducible Nitric-Oxide Synthase (iNOS) or CD47) in two retrospective cohorts of melanoma patients, one diagnosed with a primary cutaneous melanoma (1995–2013, N = 172, among whom 49% were ulcerated melanoma (UM)) and a second one diagnosed with metastatic melanoma amenable to lymph node resection (EORTC 18952 and 18991 trials, N = 98, among whom 44% were UM). We found that primary and metastatic UM exhibit higher basal expression of MHC class I molecules, independently of Breslow thickness, histology and lymphocytic infiltration compared with NUM and that primary UM harbored higher constitutive levels of the antiviral protein Mx1 at the border of tumor beds than NUM. These findings suggest that UM expand in a tumor microenvironment where chronic exposure to type 1 IFN could favor a response to exogenous IFNs.

Molecular signatures specific to particular tumor types are required to design treatments for resistant tumors. However, it remains unclear whether tumors and corresponding cell lines used for drug development share such signatures. We developed similarity core analysis (SCA), a universal and unsupervised computational framework for extracting core molecular features common to tumors and cell lines. We applied SCA to mRNA/miRNA expression data from various sources, comparing melanoma cell lines and metastases. The signature obtained was associated with phenotypic characteristics in vitro, and the core genes CAPN3 and TRIM63 were implicated in melanoma cell migration/invasion. About 90% of the melanoma signature genes belong to an intrinsic network of transcription factors governing neural development (TFAP2A, DLX2, ALX1, MITF, PAX3, SOX10, LEF1, and GAS7) and miRNAs (211-5p, 221-3p, and 10a-5p). The SCA signature effectively discriminated between two subpopulations of melanoma patients differing in overall survival, and classified MEKi/BRAFi-resistant and -sensitive melanoma cell lines.

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell-dependent tumor rejection. In the first Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex on NK cells. Indeed, Dex promoted an IL-15Ralpha- and NKG2D-dependent NK cell proliferation and activation respectively, resulting in anti-metastatic effects mediated by NK1.1(+) cells. In humans, Dex express functional IL-15Ralpha which allow proliferation and IFNgamma secretion by NK cells. In contrast to immature DC, human Dex harbor NKG2D ligands on their surface leading to a direct engagement of NKG2D and NK cell activation ex vivo. In our phase I clinical trial, we highlight the capacity of Dex based-vaccines to restore the number and NKG2D-dependent function of NK cells in 7/14 patients. Altogether, these data provide a mechanistic explanation on how Dex may stimulate non MHC restricted-anti-tumor effectors and induce tumor regression in vivo.