Recommendations for Broadening Eligibility Criteria in Inflammatory Bowel Disease Clinical Trials.

BACKGROUND: Clinical trial recruitment for patients with inflammatory bowel disease (IBD) has become more challenging over time. We aimed to develop recommendations for broadening IBD clinical trial eligibility to improve the inclusion of a more representative patient population in a more efficient timeline. METHODS: We applied the RAND/UCLA Appropriateness Method focused on broadening IBD clinical trial eligibility. A literature review was performed for 7 domains, each representing a different area related to trial recruitment. Based on these domains, 32 statements were developed. A questionnaire was sent to IBD specialists to anonymously vote on each statement with regards to its appropriateness and feasibility. After the first round of voting, participants met for a moderated discussion to review all statements. At the end of the discussion a second round of anonymous voting led to the final recommendations. RESULTS: The final round of voting resulted in 26 statements. All were rated as feasible and 25 of 26 rated as appropriate. Recommendations generally are to be more inclusive of complicated disease phenotypes, more liberal around safety criteria, to recognize the importance of non-invasive imaging and biomarkers, to minimize the washout period and to not enforce a minimum or maximum number of prior medications, to allow a recently recorded colonoscopy to count as a baseline study, and to be less restrictive of age. CONCLUSION: Recommendations to broaden clinical trial eligibility were found to be both appropriate and feasible with a high degree of agreement amongst an international group of IBD specialists.

IL-21 conditions antigen-presenting human γδ T-cells to promote IL-10 expression in naïve and memory CD4+ T-cells.

Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly enriched in 'unconventional' lymphocytes such as γδ T-cells. We previously reported that microbial activation of human Vγ9/Vδ2+ γδ T-cells in the presence of the mucosal damage-associated cytokine IL-15 confers the ability to promote epithelial barrier defence, specifically via induction of IL-22 expression in conventional CD4+ T-cells. In the current report, we assessed whether other cytokines enriched in the gut milieu also functionally influence microbe-responsive Vγ9/Vδ2 T-cells. When cultured in the presence of IL-21, Vγ9/Vδ2 T-cells acquired the ability to induce expression of the immunoregulatory cytokine IL-10 in both naïve and memory CD4+ T-cells, at levels surpassing those induced by monocytes or monocyte-derived DCs. These findings identify an unexpected influence of IL-21 on Vγ9/Vδ2 T-cell modulation of CD4+ T-cell responses. Further analyses suggested a possible role for CD30L and/or CD40L reverse signalling in mediating IL-10 induction by IL-21 conditioned Vγ9/Vδ2 T-cells. Our findings indicate that the local microenvironment exerts a profound influence on Vγ9/Vδ2 T-cell responses to microbial challenge, leading to induction of distinct functional profiles among CD4+ T-cells that may influence inflammatory events at mucosal surfaces. Targeting these novel pathways may offer therapeutic benefit in disorders such as inflammatory bowel disease.

Tumor-immune signatures of treatment resistance to brentuximab vedotin with ipilimumab and/or nivolumab in Hodgkin lymphoma.

PURPOSE: To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin Lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA-4 and PD1. PATIENTS AND METHODS: Phase 1/2, multicenter, open-label, trial NCT01896999 enrolled patients with refractory or relapsed HL (R/R HL) after one or more lines of therapy, with adequate performance status and organ function. Using peripheral blood, we assessed soluble proteins, cell composition, T cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. RESULTS: NCT01896999 reported high (>75%) overall objective response rates with brentuximab-vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed durable increase in soluble PD-1 and plasmacytoid dendritic cells as well as decreases in plasma CCL17, ANGPT2, MMP12, IL13, and CXCL13 in N-containing regimens (BV+N and BV+I+N) compared with BV+I (p<0.05). Non-responders and patients with short progression free-survival showed elevated CXCL9, CXCL13, CD5, CCL17, adenosine-deaminase, and MUC16 at baseline or after one treatment cycle and a higher prevalence of NY-ESO-1-specific autoantibodies (p<0.05). CONCLUSIONS: The results suggest a circulating tumor-immune-derived signature of BV±I+N treatment resistance that may be useful for patient stratification in combination checkpoint therapy.

The role of circulating T cells with a tissue resident phenotype (ex-TRM) in health and disease.

Tissue-resident memory T cells (TRM) are long-lived memory lymphocytes that persist in non-lymphoid tissues and provide the first line of defence against invading pathogens. They adapt to their environment in a tissue-specific manner, exerting effective pathogen control through a diverse T cell receptor (TCR) repertoire and the expression of proinflammatory cytokines and cytolytic proteins. More recently, several studies have indicated that TRM can egress from the tissue into the blood as so-called "ex-TRM", or "circulating cells with a TRM phenotype". The numerically small ex-TRM population can re-differentiate in the circulation, giving rise to new memory and effector T cells. Following their egress, ex-TRM in the blood and secondary lymphoid organs can be identified based on their continued expression of the residency marker CD103, alongside other TRM-like features. Currently, it is unclear whether exit is a stochastic process, or is actively triggered in response to unknown factors. Also, it is not known whether a subset or all TRM are able to egress. Ex-TRM may be beneficial in health, as mobilisation of specialised TRM and their recruitment to both their site of origin as well as distant tissues results in an efficient distribution of the immune response. However, there is emerging evidence of a pathogenic role for ex-TRM, with a suggestion that they may perpetuate both local and distant tissue inflammation. Here, we review the evidence for the existence of ex-TRM and examine their potential involvement in disease pathogenesis.

Single cell sequencing data identify distinct B cell and fibroblast populations in stricturing Crohn's disease.

Single cell RNA sequencing of human full thickness Crohn's disease (CD) small bowel resection specimens was used to identify potential therapeutic targets for stricturing (S) CD. Using an unbiased approach, 16 cell lineages were assigned within 14,539 sequenced cells from patient-matched SCD and non-stricturing (NSCD) preparations. SCD and NSCD contained identical cell types. Amongst immune cells, B cells and plasma cells were selectively increased in SCD samples. B cell subsets suggested formation of tertiary lymphoid tissue in SCD and compared with NSCD there was an increase in IgG, and a decrease in IgA plasma cells, consistent with their potential role in CD fibrosis. Two Lumican-positive fibroblast subtypes were identified and subclassified based on expression of selectively enriched genes as fibroblast clusters (C) 12 and C9. Cells within these clusters expressed the profibrotic genes Decorin (C12) and JUN (C9). C9 cells expressed ACTA2; ECM genes COL4A1, COL4A2, COL15A1, COL6A3, COL18A1 and ADAMDEC1; LAMB1 and GREM1. GO and KEGG Biological terms showed extracellular matrix and stricture organization associated with C12 and C9, and regulation of WNT pathway genes with C9. Trajectory and differential gene analysis of C12 and C9 identified four sub-clusters. Intra sub-cluster gene analysis detected 13 co-regulated gene modules that aligned along predicted pseudotime trajectories. CXCL14 and ADAMDEC1 were key markers in module 1. Our findings support further investigation of fibroblast heterogeneity and interactions with local and circulating immune cells at earlier time points in fibrosis progression. Breaking these interactions by targeting one or other population may improve therapeutic management for SCD.

Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

Identifying Oncology Clinical Trial Candidates Using Artificial Intelligence Predictions of Treatment Change: A Pilot Implementation Study.

PURPOSE: Precision oncology clinical trials often struggle to accrue, partly because it is difficult to find potentially eligible patients at moments when they need new treatment. We piloted deployment of artificial intelligence tools to identify such patients at a large academic cancer center. PATIENTS AND METHODS: Neural networks that process radiology reports to identify patients likely to start new systemic therapy were applied prospectively for patients with solid tumors that had undergone next-generation sequencing at our center. Model output was linked to the MatchMiner tool, which matches patients to trials using tumor genomics. Reports listing genomically matched patients, sorted by probability of treatment change, were provided weekly to an oncology nurse navigator (ONN) coordinating recruitment to nine early-phase trials. The ONN contacted treating oncologists when patients likely to change treatment appeared potentially trial-eligible. RESULTS: Within weekly reports to the ONN, 60,199 patient-trial matches were generated for 2,150 patients on the basis of genomics alone. Of these, 3,168 patient-trial matches (5%) corresponding to 525 patients were flagged for ONN review by our model, representing a 95% reduction in review compared with manual review of all patient-trial matches weekly. After ONN review for potential eligibility, treating oncologists for 74 patients were contacted. Common reasons for not contacting treating oncologists included cases where patients had already decided to continue current treatment (21%); the trial had no slots (14%); or the patient was ineligible on ONN review (12%). Of 74 patients whose oncologists were contacted, 10 (14%) had a consult regarding a trial and five (7%) enrolled. CONCLUSION: This approach facilitated identification of potential patients for clinical trials in real time, but further work to improve accrual must address the many other barriers to trial enrollment in precision oncology research.

Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn's Disease Regardless of Prior Biologic Exposure.

BACKGROUND & AIMS: Upadacitinib, an oral Janus kinase inhibitor, achieved significantly higher rates of clinical remission and endoscopic response vs placebo during induction (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]) and maintenance (U-ENDURE [NCT03345823]) treatment in patients with moderate-to-severe Crohn's disease. Prior biologic failure is often associated with reduced responses to subsequent therapies. This post hoc analysis assessed upadacitinib efficacy by prior biologic failure status. METHODS: Patients were randomized to placebo or upadacitinib 45 mg (UPA45) for 12 weeks (induction). UPA45 clinical responders were enrolled in U-ENDURE and rerandomized to placebo, upadacitinib 15 mg, or upadacitinib 30 mg (UPA30) for 52 weeks. Assessments were by prior biologic failure. RESULTS: Of 1021 patients, 733 (71.8%) had prior biologic failure. Across outcomes and subgroups, upadacitinib-treated patients achieved higher rates vs placebo. During induction, upadacitinib had higher rates vs placebo for clinical remission based on stool frequency/abdominal pain score (without failure: 54.0% vs 28.3%; with failure: 42.2% vs 14.1%) and endoscopic response (without failure: 52.0% vs 16.2%; with failure: 35.7% vs 5.3%). In maintenance, the greatest treatment effect (upadacitinib vs placebo) was among patients with prior biologic failure treated with UPA30 (clinical remission without failure: 58.5% vs 32.7%; with failure: 42.5% vs 8.7%; endoscopic response without failure: 43.9% vs 17.9%; with failure: 38.9% vs 4.0%). Patients without vs with prior biologic failure had fewer adverse events. CONCLUSIONS: Upadacitinib led to higher absolutes rates of clinical and endoscopic outcomes in patients without vs with prior biologic failure. Patients treated with upadacitinib achieved greater rates of clinical and endoscopic improvements vs placebo, regardless of prior biologic exposure. CLINICALTRIALS: gov: NCT03345849, NCT03345836, NCT03345823.

Ultra-processed foods and food additives in gut health and disease.

Ultra-processed foods (UPFs) and food additives have become ubiquitous components of the modern human diet. There is increasing evidence of an association between diets rich in UPFs and gut disease, including inflammatory bowel disease, colorectal cancer and irritable bowel syndrome. Food additives are added to many UPFs and have themselves been shown to affect gut health. For example, evidence shows that some emulsifiers, sweeteners, colours, and microparticles and nanoparticles have effects on a range of outcomes, including the gut microbiome, intestinal permeability and intestinal inflammation. Broadly speaking, evidence for the effect of UPFs on gut disease comes from observational epidemiological studies, whereas, by contrast, evidence for the effect of food additives comes largely from preclinical studies conducted in vitro or in animal models. Fewer studies have investigated the effect of UPFs or food additives on gut health and disease in human intervention studies. Hence, the aim of this article is to critically review the evidence for the effects of UPF and food additives on gut health and disease and to discuss the clinical application of these findings.

Innovative cellular therapies for autoimmune diseases: expert-based position statement and clinical practice recommendations from the EBMT practice harmonization and guidelines committee.

Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert-based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated.

Association of Bowel Urgency With Quality-of-Life Measures in Patients With Moderately-to-Severely Active Ulcerative Colitis: Results From Phase 3 LUCENT-1 (Induction) and LUCENT-2 (Maintenance) Studies.

Background: Improvement in bowel urgency (BU) was associated with better clinical outcomes in phase 3 LUCENT-1 (induction) and LUCENT-2 (maintenance) studies in moderately-to-severely active ulcerative colitis (UC). We assessed association of BU with quality-of-life (QoL) outcomes. Methods: LUCENT-1: 1162 patients randomized 3:1 to intravenous mirikizumab 300 mg or placebo every 4 weeks (Q4W) for 12 weeks. LUCENT-2: 544 mirikizumab induction responders re-randomized 2:1 to subcutaneous mirikizumab 200 mg or placebo Q4W through Week (W) 40 (W52 of continuous treatment). Patients reported BU severity in the past 24 hours using a validated Urgency Numeric Rating Scale (NRS). In patients with baseline Urgency NRS ≥3, the association between BU Clinically Meaningful Improvement (CMI; ≥3-point decrease) and remission (score 0 or 1) with patient-reported outcomes was assessed at W12 and W52. Results: A significantly greater proportion of patients with versus without BU Remission achieved IBDQ remission (W12: 87.3% vs 42.7%, P < .0001; W52: 91.4% vs 45.5%, p < .0001). Similarly, BU Remission was associated with more patients achieving CMI in SF-36 Physical Component Summary (W12: 69.0% vs 44.4%, P < .0001; W52: 77.5% vs 42.1%, P < .0001) and Mental Component Summary (W12: 53.5% vs 41.0%, P = .0019; W52: 62.0% vs 38.3%, P < .0001) scores. At W12 and W52, patients with BU CMI or Remission showed significant improvements in EQ-5D-5L and Work Productivity and Activity Impairment:UC scores. Significant improvements were also seen in fatigue, abdominal pain, and nocturnal stool. Conclusions: In patients with moderately-to-severely active UC, improvement in BU was associated with improved QoL in phase 3 LUCENT-1 and LUCENT-2 studies. Clinical Studies: LUCENT-1: NCT03518086; LUCENT-2: NCT03524092.

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.

BACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 µg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 µg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial.

BACKGROUND: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. METHODS: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 µg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. INTERPRETATION: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial.

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. CONCLUSIONS: The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC.

Matching-Adjusted Indirect Comparisons of Filgotinib vs Vedolizumab, Tofacitinib, and Ustekinumab for Moderately to Severely Active Ulcerative Colitis.

BACKGROUND: Where head-to-head trials are lacking, indirect comparative effectiveness can aid treatment decisions. We conducted matching-adjusted indirect comparisons of clinical outcomes with filgotinib vs recently approved comparators (vedolizumab, tofacitinib, ustekinumab) in patients with moderately to severely active ulcerative colitis (UC). METHODS: Individual patient data from the SELECTION trial (NCT02914522) for filgotinib 200 mg were weighted to match average baseline characteristics of active treatment and placebo arms in comparator trials. Efficacy outcomes were compared for biologic-naive and biologic-experienced subgroups in induction and maintenance populations, if data were available. Safety and health-related quality of life outcomes were compared in the overall maintenance population. RESULTS: Filgotinib had a similar effect on efficacy outcomes compared with tofacitinib, ustekinumab, and subcutaneous vedolizumab in both the induction and maintenance populations. Filgotinib showed improved clinical response vs intravenous (IV) vedolizumab (odds ratio, 2.4; 95% confidence interval [CI], 1.0 to 5.5; P < .05) among the biologic-experienced induction population, and improved corticosteroid-free clinical remission (odds ratio, 15.2; 95% CI, 1.6 to 139.9; P < .05) among the biologic-naive maintenance population. Improved efficacy outcomes were reported with filgotinib compared with ustekinumab among the maintenance population. Higher estimates of serious adverse events were reported for filgotinib compared with vedolizumab IV 300 mg and tofacitinib 5 mg; however, imbalances were noted in their placebo groups. Health-related quality of life outcomes were similar between filgotinib and comparators. CONCLUSIONS: Matching-adjusted indirect comparison results suggest superiority of filgotinib 200 mg over vedolizumab IV in terms of clinical response and corticosteroid-free clinical remission in certain patient populations, noting small sample sizes and wide CIs, which may aid the selection of advanced therapies for moderately to severely active UC. A potential increased risk of serious adverse events was reported for filgotinib 200 mg vs vedolizumab IV and tofacitinib 5 mg, but findings should be interpreted with caution owing to underlying imbalances observed between the placebo groups of SELECTION and comparator trials.

Matching-adjusted indirect comparisons between filgotinib and subcutaneous vedolizumab, tofacitinib, and ustekinumab demonstrated similar effects on efficacy, safety, and health-related quality of life in patients with ulcerative colitis. Clinical response and corticosteroid-free remission were improved with filgotinib compared with intravenous vedolizumab.

Human Intestinal Dendritic Cells Can Overcome Retinoic Acid Signaling to Generate Proinflammatory CD4 T Cells with Both Gut and Skin Homing Properties.

Retinoic acid, produced by intestinal dendritic cells (DCs), promotes T cell trafficking to the intestinal mucosa by upregulating α4ß7 integrin and inhibiting the generation of cutaneous leukocyte Ag (CLA) required for skin entry. In the present study, we report that activation of human naive CD4 T cells in an APC-free system generates cells expressing α4ß7 alone; in contrast, activation by intestinal DCs that produce retinoic acid and induce high levels of α4ß7 also results in CLA expression, generating CLA+α4ß7+ "dual tropic" cells, with both gut and skin trafficking potential, that also express high levels of α4ß1 integrin. DC generation of CLA+α4ß7+ T cells is associated with upregulation of FUT7, a fucosyltransferase involved in CLA generation; requires cell contact; and is enhanced by IL-12/IL-23. The blood CD4+ T cell population contains CLA+α4ß7+ cells, which are significantly enriched for cells capable of IFN-γ, IL-17, and TNF-α production compared with conventional CLA-α4ß7+ cells. Dual tropic lymphocytes are increased in intestinal tissue from patients with Crohn's disease, and single-cell RNA-sequencing analysis identifies a transcriptionally distinct cluster of FUT7-expressing cells present only in inflamed tissue; expression of genes associated with cell proliferation suggests that these cells are undergoing local activation. The expression of multiple trafficking molecules by CLA+α4ß7+ T cells can enable their recruitment by alternative pathways to both skin and gut; they may contribute to both intestinal and cutaneous manifestations of inflammatory bowel disease.

Efficacy and safety of upadacitinib for 16-week extended induction and 52-week maintenance therapy in patients with moderately to severely active ulcerative colitis.

BACKGROUND: Upadacitinib is an oral, selective Janus kinase inhibitor. AIM: To assess the efficacy and safety of upadacitinib in patients with moderate-to-severe ulcerative colitis following 16-week extended induction therapy, and 52-week maintenance therapy in patients achieving clinical response after 16-week extended induction therapy METHODS: Patients without clinical response to 8 weeks' upadacitinib 45 mg once daily induction therapy in two induction trials were eligible for an additional 8 weeks of therapy. Patients achieving clinical response at Week 16 were subsequently re-randomised (1:1) to upadacitinib 15 or 30 mg once daily for 52-week maintenance therapy. Efficacy was assessed at induction Week 16 (integrated) and maintenance Week 52; safety was assessed throughout. RESULTS: Overall, 127/663 (19.2%) patients did not achieve clinical response to upadacitinib 45 mg at Week 8 and received an additional 8 weeks of therapy; 75/127 (59.1%) subsequently achieved clinical response at Week 16 and entered the maintenance trial. At Week 52, 26.5% of patients receiving upadacitinib 15 mg, and 43.6% receiving 30 mg, achieved clinical remission; efficacy was observed across all other endpoints with both doses. Herpes zoster rates increased with longer duration (16 weeks) of exposure to upadacitinib 45 mg during induction compared with the same population during the first 8 weeks. No other new safety signals were observed, and results are otherwise consistent with the known safety profile of upadacitinib. CONCLUSIONS: Patients without clinical response after 8 weeks' upadacitinib 45 mg induction therapy, may benefit from an additional 8 weeks of therapy. CLINICAL TRIAL REGISTRATION: NCT02819635; NCT03653026.

Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy.

Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.

Epigenetic and metabolic reprogramming of fibroblasts in Crohn's disease strictures reveals histone deacetylases as therapeutic targets.

BACKGROUND & AIMS: No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterised fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. METHODS: We undertook immunohistochemistry, metabolic, signalling pathway and Epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/ NSCD fibroblasts were cultured with TGFß and valproic acid [VPA]. RESULTS: Stricturing CD was characterised by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFß-stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appear "metabolically primed" and responded more strongly to both TGFß and VPA. Treatment with VPA revealed TGFß-dependent and independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. CONCLUSIONS: Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype, and metabolic priming, characterise SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFß-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis.