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Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D , an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes. Although circulating tumour DNA (ctDNA) can predict immune checkpoint blockade (ICB) responses, its association with tumour biomarkers remains unknown. Here, the authors use ctDNA to inform exome and transcriptome profiling of >100 patients with 30 cancer types on a single clinical ICB trial and identify tumour microenvironment features associated with response.

Extracellular vesicles (EVs) are cell-derived nanoparticles that have attracted significant attention in the investigation of human health and disease, including cancer biology and its clinical management. Concerning cancer, EVs have been shown to influence numerous aspects of oncogenesis, including tumor proliferation and metastasis. EVs can augment the immune system and have been implicated in virtually all aspects of innate and adaptive immunity. With immunotherapy changing the landscape of cancer treatment across multiple disease sites, it is paramount to understand their mechanisms of action and to further improve upon their efficacy. Despite a rapidly growing body of evidence supporting of the utility of EVs in cancer diagnostics and therapeutics, their application in clinical trials involving solid tumors and immunotherapy remains limited. To date, relatively few trials are known to incorporate EVs in this context, mainly employing them as biomarkers. To help address this gap, this review summarizes known applications of EVs in clinical trials and provides a brief overview of the roles that EVs play in cancer biology, immunology, and their proposed implications in immunotherapy. The impetus to leverage EVs in future clinical trials and correlative studies is crucial, as they are ideally positioned to synergize with advancements in multi-omics research to further therapeutic discovery and our understanding of cancer biology.

Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation and management. Patients treated with anti-PD-1, PDL-1 or CTLA-4 therapy in Phase I/II clinical trials between August 2012 and December 2018 were included. Clinical records of patients with significant liver enzyme elevations were retrospectively reviewed. Of 470 ICI-treated patients, liver enzyme elevation occurred in 102 (21.6%), attributed to disease progression (56; 54.9%), other drugs/toxins (7; 6.9%), other causes (22; 21.6%) and ICI immunotoxicity (17; 16.7%; 3.6% of total cohort). Immunotoxicity was associated with higher peak ALT than other causes of enzyme elevation (N = 17; M = 217, 95% CI 145-324 for immunotoxicity, N = 103; M = 74, 95% CI 59-92 for other causes; ratio of means 0.34, 95% CI 0.19-0.60, p = <0.001) and higher ALT:AST ratio (M = 1.27, 95% CI 0.78-2.06 for immunotoxicity, M = 0.69, 95% CI 0.59-0.80 for other causes, ratio of means 0.54, 95% CI 0.36-0.82, p = 0.004). Immunotoxicity was more often seen in patients with prior CPI exposure (41.2% of immunotoxicity vs 15.9% of patients without, p = 0.01), anti-CTLA-4 -containing ICI treatments (29.4% of immunotoxicity vs 6.8% of patients without, p = <0.001) and other organ immunotoxicity (76.5% of immunotoxicity vs 19.2% of patients without, p = <0.001). Cause for enzyme elevation was established in most patients after non-invasive investigation. Liver biopsy was reserved for four patients with atypical treatment response. Liver enzyme elevation is common in patients receiving ICI, but often has a cause other than immunotoxicity. A biochemical signature with higher ALT and ALT/AST ratio, a history of prior ICI exposure and other organ immunotoxicities may help to identify patients at a higher likelihood of immunotoxicity. Liver biopsy can be safely deferred in most patients. We propose an approach to diagnostic evaluation in patients with liver enzyme elevations following ICI exposure.

The therapeutic landscape of malignant melanoma has been radically reformed in recent years, with novel treatments emerging in both the field of cancer immunotherapy and signalling pathway inhibition. Large-scale tumour genomic characterization has accurately classified malignant melanoma into four different genomic subtypes so far. Despite this, only somatic mutations in BRAF oncogene, as assessed in tumour biopsies, has so far become a validated predictive biomarker of treatment with small molecule inhibitors. The biology of tumour evolution and heterogeneity has uncovered the current limitations associated with decoding genomic drivers based only on a single-site tumour biopsy. There is an urgent need to develop minimally invasive biomarkers that accurately reflect the real-time evolution of melanoma and that allow for streamlined collection, analysis, and interpretation. These will enable us to face challenges with tumour tissue attainment and process and will fulfil the vision of utilizing “liquid biopsy” to guide clinical decisions, in a manner akin to how it is used in the management of haematological malignancies. In this review, we will summarize the most recent published evidence on the role of minimally invasive biomarkers in melanoma, commenting on their future potential to lead to practice-changing discoveries.

Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While most of the research on T cell exhaustion and PD-1 blockade has been focused on conventional αβ T cells, the contribution of innate-like T cells such as γδ T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive γδ T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy. We find clonally expanded γδ T cells in the blood and tumor after pembrolizumab treatment, and this Vγ2Vδ1 clonotype recognizes Merkel cancer cells in a TCR-dependent manner. Notably, the intra-tumoral γδ T cells in the MCC patient are characterized by higher expression of PD-1 and TIGIT, relative to conventional CD4 and CD8 T cells. Our results demonstrate that innate-like T cells could also contribute to an anti-tumor response after PD-1 blockade. Immune checkpoint blockade cancer therapy has been designed to enable tumor killing by conventional αβ T cells. Here authors show that in a Merkel cell carcinoma patient showing complete response to anti-PD-1 treatment, innate-like γδ T cells that specifically recognize the tumor cells expand, and likely contribute to therapeutic success.

BackgroundAdverse event (AE) reporting in early-phase clinical trials is essential in determining the tolerability of experimental anticancer therapies. The patient-reported outcome version of the CTCAE (PRO-CTCAE) evaluates AE components such as severity and interference in daily life. The aim of this study was to correlate the grade of clinician-reported AEs with patients’ reported experience of these toxicities using PRO-CTCAE.MethodsPatients with advanced solid tumours enrolled on Phase I clinical trials were surveyed using the PRO-CTCAE. Symptomatic AEs were recorded by physicians using the CTCAE. A logistic regression model was used to assess associations between CTCAE grade and PRO responses.ResultsOf 219 evaluable patients, 81 experienced a high-grade (3/4) clinician-reported symptom, and of these, only 32 (40%) and 26 (32%) patients concordantly reported these as either severe or very severe, and interfering with daily life either ‘quite a bit’ or ‘very much’, respectively. Of the 137 patients who experienced a low-grade (1/2) clinician-reported AE as their worst symptom, 98 (72%) and 118 (86%) patients concordantly reported these as either mild–moderate severity and minimally interfering with daily life, respectively. There was a statistically significant association between clinician-reported AE grade and interference. Interference scores were also associated with dose reductions.ConclusionThis is the first study to explore patient-reported severity and interference from symptomatic toxicities and compare clinician grading of the same toxicities. The study provided further evidence to support the added value of the PRO-CTCAE in Phase I oncology trials, which would make AE reporting patient-centred. Further work is needed to determine how this would affect the assessment of tolerability.

Immune checkpoint inhibitors have revolutionized cancer treatment. They can induce cutaneous immune-related adverse events. One patient with immune-related eczema and two with immune-related bullous pemphigoid were successfully treated with dupilumab. Guidelines recommend the use of systemic steroids to manage moderate-to-severe cutaneous immune-related adverse events. They could potentially interfere with immunotherapy. There is a need to find alternative treatments that are safe in a cancer setting.

HMA mice are models that better represent human gut ecology compared to conventional laboratory mice and are commonly used to test the effects of the gut microbiome on disease or treatment response. We evaluated the fidelity of using HMA mice as avatars of ecological response to a human microbial consortium, Microbial Ecosystem Therapeutic 4. Our results show that HMA mice in our cohort and across other published studies are more similar to each other than the human donors or inoculum they are derived from and harbor a taxonomically restricted gut microbiome. These findings highlight the limitations of HMA mice in evaluating the ecological effects of complex human microbiome-targeting interventions, such as microbial consortia.

BackgroundNIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-β). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors.MethodsPatients received NIS793 (0.3–1 mg/kg every 3 weeks (Q3W)) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 plus spartalizumab (NIS793 0.3–30 mg/kg Q3W and spartalizumab 300 mg Q3W or NIS793 20–30 mg/kg every 2 weeks [Q2W] and spartalizumab 400 mg every 4 weeks (Q4W)). In dose expansion, patients with non-small cell lung cancer (NSCLC) resistant to prior anti-programmed death ligand 1 or patients with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE).ResultsSixty patients were treated in dose escalation, 11 with NIS793 monotherapy and 49 with NIS793 plus spartalizumab, and 60 patients were treated in dose expansion (MSS-CRC: n=40; NSCLC: n=20). No dose-limiting toxicities were observed. The RDE was established as NIS793 30 mg/kg (2100 mg) and spartalizumab 300 mg Q3W. Overall 54 (49.5%) patients experienced ≥1 treatment-related adverse event, most commonly rash (n=16; 13.3%), pruritus (n=10; 8.3%), and fatigue (n=9; 7.5%). Three partial responses were reported: one in renal cell carcinoma (NIS793 30 mg/kg Q2W plus spartalizumab 400 mg Q4W), and two in the MSS-CRC expansion cohort. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression analyses in tumor biopsies demonstrated decreased TGF-β target genes and signatures and increased immune signatures.ConclusionsIn patients with advanced solid tumors, proof of mechanism of NIS793 is supported by evidence of target engagement and TGF-β pathway inhibition.Trial registration numberNCT02947165.

PurposeTo evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab.Experimental designPD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1–14 (cycles 1–3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1–21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated. Patients underwent paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) collection for immune-profiling, transcriptomic and epigenomic analyzes.ResultsA total of 28 patients were enrolled, 19 patients treated on regimen A and 9 on regimen B. The combination of CC-486 and durvalumab was tolerable. Regimen B, with a lower dose of CC-486 extended over a longer treatment course, showed less grade 3/4 adverse effects. Global LINE-1 methylation assessment of serial PBMCs and genome-wide DNA methylation profile in paired tumor biopsies demonstrated minimal changes in global methylation in both regimens. The lack of robust tumor DNA demethylation was accompanied by an absence of the expected ‘viral mimicry’ inflammatory response, and consequently, no clinical responses were observed. The disease control rate was 7.1%. The median progression-free survival was 1.9 months (95% CI 1.5 to 2.3) and median overall survival was 5 months (95% CI 4.5 to 10).ConclusionsThe evaluated treatment schedules of CC-486 in combination with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors. Lessons learned from this biomarker-rich study should inform continued drug development efforts using these agents.Trial registration number NCT02811497.