Clinical Responders Research Articles

Abstract 914: Preinfusion polyfunctional profiles and cytokine secretion activity of transgenic TCR-T cells, and serum cytokine profiles, are associated with clinical outcomes in sarcoma and melanoma

Abstract Background: Transgenic TCR-T cells targeting MART-1 and NY-ESO-1 for the treatment of melanoma and sarcoma, respectively, are associated with robust initial clinical responses. However, these responses are often not durable, and a significant proportion of patients do not respond to therapy at all. Therefore, there is a significant need to understand the factors driving success or failure of these therapeutics. Methods: We analyzed the functional single-cell and bulk cytokinetic secretome profiles of TCR-T products infused into 26 patients (MART-1 n = 13, NY-ESO-1 n = 13) under associated TCR-T cell clinical trials at UCLA (NCT00910650, NCT02070406, NCT01697527, NCT03240861) using the IsoPlexis proteomic barcode chip platform. TCR-T cells were separated into CD4 and CD8 compartments and stimulated with their cognate antigen presented by transgenic HLA-A:02:01 K562 cells in vitro at an effector:target ratio of 1:1. Stimulated cells were loaded into IsoCode chips for single-cell polyfunctionality analysis while culture media supernatants from the antigen-specific stimulation were loaded into CodePlex chips for bulk analysis. All chips were automatically processed using an IsoSpark machine and analyzed using IsoSpeak software. Patients’ baseline preinfusion serum cytokine levels were analyzed via Luminex Immunoassay. Results: Single-cell secretome analysis showed that polyfunctional CD4 TCR-T cells producing TNF-a and IL-17A were significantly associated with improved progression-free survival and overall survival, respectively (p = 0.036; p = 0.014). Polyfunctional CD8 TCR-T cells producing TNF-a and MIP-1a were significantly lower in patients with progressive disease at end-of-study compared to patients without progressive disease (p = 0.0498; p = 0.0468). Bulk secretome analysis demonstrated that aggregate CD4 production levels of IL-4 and IL-5 were both significantly lower in clinical responders compared to non-responders (286.9 vs 1088.5 pg/mL, p = 0.0073; 811.8 vs 1957.9 pg/mL, p = 0.034). Preinfusion patient serum IL-15 levels examined by Luminex were significantly greater in clinical responders compared to non-responders (19.65 vs 4.74 pg/mL p = 0.0122). Conclusions: In clinical samples of preinfusion TCR-T cells targeting MART-1 and NY-ESO-1, polyfunctional CD4 TCR-T cells producing TNF-a and IL-17A, CD8 TCR-T cells producing TNF-a and MIP-1a, as well as preinfusion serum IL-15 levels, are significantly correlated with improved clinical outcomes in TCR-T cell therapy targeting MART-1 and NY-ESO-1. Furthermore, aggregate TCR-T cell production of the Th2-associated cytokines IL-4 and IL-5 were significantly associated with non-response to therapy. These results have important implications for the design of future generations of transgenic cellular therapies. Citation Format: Cole W. Peters, Crystal Quiros, Edward X. Han, Moe Kawakami, Conner Kidd, Alexandra Klomhaus, Antoni Ribas, Theodore S. Nowicki. Preinfusion polyfunctional profiles and cytokine secretion activity of transgenic TCR-T cells, and serum cytokine profiles, are associated with clinical outcomes in sarcoma and melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 914.

Rapamycin Restores Different Patterns of Cytokine Expression to Dexamethasone Treatment on CD14++CD16+ Monocytes from Steroid-Resistant Asthma Patients.

We aimed to investigate the differences in interleukin (IL)-10, IL-1β, IL-6, and tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated CD14++CD16+ monocytes obtained from asthmatics after dexamethasone or dexamethasone plus rapamycin treatments between clinical steroid responders (R) and non-responders (NR). Cytokine expressions in LPS-stimulated CD14++CD16+ p-mammalian target of rapamycin (mTOR) monocytes from R and NR were determined using flow cytometry. IL-10high CD14++CD16+ p-mTOR population following LPS stimulation increased in the R group although decreased in the NR group with dexamethasone treatment. IL-1βhigh population decreased in the R group although increased in the NR group. Rapamycin treatment after LPS and dexamethasone resulted in a significant increase in the IL-10high population and a significant decrease in the IL-1βhigh population in the NR group. Dexamethasone treatment resulted in different patterns of change in cytokine expressions in LPS-stimulated CD14++CD16+ p-mTOR monocytes between the R and NR. mTOR inhibition can restore steroid responsiveness involving IL-10 and IL-1β in CD14++CD16+ p-mTOR monocytes.

Systems-based digital twins to help characterize clinical dose-response and propose predictive biomarkers in a Phase I study of bispecific antibody, mosunetuzumab, in NHL.

Phase I oncology clinical trials often comprise a limited number of patients representing different disease subtypes who are divided into cohorts receiving treatment(s) at different dosing levels and schedules. Here, we leverage a previously developed quantitative systems pharmacology model of the anti-CD20/CD3 T-cell engaging bispecific antibody, mosunetuzumab, to account for different dosing regimens and patient heterogeneity in the phase I study to inform clinical dose/exposure-response relationships and to identify biological determinants of clinical response. We developed a novel workflow to generate digital twins for each patient, which together form a virtual population (VPOP) that represented variability in biological, pharmacological, and tumor-related parameters from the phase I trial. Simulations based on the VPOP predict that an increase in mosunetuzumab exposure increases the proportion of digital twins with at least a 50% reduction in tumor size by day 42. Simulations also predict a left-shift of the exposure-response in patients diagnosed with indolent compared to aggressive non-Hodgkin's lymphoma (NHL) subtype; this increased sensitivity in indolent NHL was attributed to the lower inferred values of tumor proliferation rate and baseline T-cell infiltration in the corresponding digital twins. Notably, the inferred digital twin parameters from clinical responders and nonresponders show that the potential biological difference that can influence response include tumor parameters (tumor size, proliferation rate, and baseline T-cell infiltration) and parameters defining the effect of mosunetuzumab on T-cell activation and B-cell killing. Finally, the model simulations suggest intratumor expansion of pre-existing T-cells, rather than an influx of systemically expanded T-cells, underlies the antitumor activity of mosunetuzumab.

The analysis of gut microbiota in patients with bile acid diarrhoea treated with colesevelam.

Bile acid diarrhoea (BAD) is a common disorder that results from an increased loss of primary bile acids and can result in a change in microbiome. The aims of this study were to characterise the microbiome in different cohorts of patients with BAD and to determine if treatment with a bile acid sequestrant, colesevelam, can alter the microbiome and improve microbial diversity. Patients with symptoms of diarrhoea underwent 75-selenium homocholic acid (75SeHCAT) testing and were categorised into four cohorts: idiopathic BAD, post-cholecystectomy BAD, post-operative Crohn's disease BAD and 75SeHCAT negative control group. Patients with a positive 75SeHCAT (<15%) were given a trial of treatment with colesevelam. Stool samples were collected pre-treatment, 4-weeks, 8-weeks and 6-12 months post-treatment. Faecal 16S ribosomal RNA gene analysis was undertaken. A total of 257 samples were analysed from 134 patients. α-diversity was significantly reduced in patients with BAD and more specifically, in the idiopathic BAD cohort and in patients with severe disease (SeHCAT <5%); p < 0.05. Colesevelam did not alter bacterial α/β-diversity but patients who clinically responded to treatment had a significantly greater abundance of Fusobacteria and Ruminococcus, both of which aid in the conversion of primary to secondary bile acids. This is the first study to examine treatment effects on the microbiome in BAD, which demonstrated a possible association with colesevelam on the microbiome through bile acid modulation in clinical responders. Larger studies are now needed to establish a causal relationship with colesevelam and the inter-crosstalk between bile acids and the microbiome.

A180 PLACEBO RATES IN MICROSCOPIC COLITIS RANDOMIZED TRIALS: APPLICATIONS FOR FUTURE DRUG DEVELOPMENT USING A HISTORICAL CONTROL ARM

Abstract Background There remains a need to develop effective medical therapies for patients with microscopic colitis (MC) who do not respond, are intolerant, or relapse on budesonide. Conducting randomized trials in MC is logistically and ethically challenging: budesonide is highly effective, and therefore, some institutional review boards have not allowed trials that randomize MC patients to placebo. However, comparing an investigational drug to budesonide is statistically infeasible: powering a non-inferiority study against a budesonide comparator arm with 90% power for a 10% non-inferiority margin would require over 700 subjects, yet fewer than 400 patients have been randomized in all historical MC trials. Therefore, alternative trial designs should be explored in MC, including the use of a historical control arm. Purpose To conduct a systematic review and meta-analysis to determine the proportion of placebo responders in MC trials that will inform future trials using a historical placebo comparator, and evaluate factors associated with placebo response. Method EMBASE, MEDLINE, and CENTRAL were searched from inception to January 7, 2022, and supplemented with conference abstracts to identify randomized controlled trials (RCTs) using a placebo comparator in adult patients with confirmed MC (either lymphocytic, collagenous, or mixed populations but excluding incomplete MC). The proportion of clinical and histologic responders in the placebo arms were pooled using random-effect models, statistical heterogeneity was evaluated using the I2 method, and the Freeman-Tukey double arcsine transformation was used to compute 95% confidence intervals (CI) using the score statistic and exact binomial method. All analyses were conducted in Stata 17.0. Result(s) Twelve placebo controlled RCTs were included, evaluating a total of 391 patients (163 randomized to placebo). The pooled placebo clinical response rate was 24.4% [95% CI 12.4%, 38.4%] (Figure 1), with substantial heterogeneity (I2=60.8%, p&amp;lt;0.01). The pooled histologic response rate was 19.9% [95% CI: 5.3%, 39.0%], with substantial heterogeneity (I2=66.4%, p&amp;lt;0.01). Subgroup analysis demonstrated higher placebo responses in lymphocytic colitis (39.9% [95% CI: 23.9%, 56.7%]) compared to collagenous colitis (19.8% [95% CI: 5.9%, 37.8%]), but not by allowance of baseline anti-diarrheals. Leave-one-out meta-analysis showed a reduction in heterogeneity after removal of Miehlke et al. 2014 (placebo response 21.0% [95% CI: 11.5%, 32.1%], I2=28.6%, p=0.17). Image Conclusion(s) Approximately 1 in 4 patients in MC trials will respond clinically to placebo and 1 in 5 will demonstrate a histologic response, although with substantial heterogeneity. T his highlights the need for standardized outcome definitions in MC trials and can serve to inform a Bayesian prior estimate for future trials that may consider using a historical placebo comparator. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest P. Hamilton: None Declared, K. Buhler: None Declared, G. Kaplan Grant / Research support from: Ferring, Janssen, AbbVie, GlaxoSmith Kline, Merck, and Shire, Consultant of: AbbVie, Janssen, Pfizer, Amgen, Takeda, and Gilead, C. Lu Consultant of: Abbvie, Janssen, Ferring, and Takeda, Speakers bureau of: Janssen and Abbvie, C. Seow Consultant of: Advisory Boards: Janssen, Abbvie, Takeda, Ferring, Shire, Pfizer, Sandoz, Pharmascience, Fresenius Kabi, Amgen, Speakers bureau of: Janssen, Abbvie, Takeda, Ferring, Shire, Pfizer, Pharmascience, K. Novak Grant / Research support from: AbbVie and Janssen, Consultant of: Advisory board fees from AbbVie, Janssen, Pfizer, Ferring, and Takeda, speaker’s fees from AbbVie, Janssen, and Pfizer, R. Panaccione Consultant of: Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, UCB. Advisory Boards for: AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda Pharmaceuticals, Speakers bureau of: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals, C. Ma Grant / Research support from: Ferring, Pfizer, Consultant of: AbbVie, Alimentiv, American College of Gastroenterology, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Sanofi/Regeneron, Takeda, Pendopharm, Pfizer, Roche, Speakers bureau of: : AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer

A201 EFFECT OF MIRIKIZUMAB ON BOWEL URGENCY CLINICALLY MEANINGFUL IMPROVEMENT AND REMISSION: RESULTS FROM THE PHASE 3 LUCENT INDUCTION AND MAINTENANCE STUDIES

Abstract Background Bowel urgency (BU) was assessed in mirikizumab (miri) Phase 3 LUCENT studies in moderately-to-severely active UC using the validated Urgency Numeric Rating Scale (UNRS). UNRS measures BU severity in the past 24 hours from 0 (no urgency) to 10 (worst possible urgency). Psychometric evaluation of the UNRS showed Clinically Meaningful Improvement (CMI) is &amp;gt;3 point change; Remission is a score of 0 or 1. Purpose This analysis evaluated the proportions of patients in LUCENT studies achieving BU CMI and BU remission. Method The modified intent-to-treat (mITT) population (patients receiving ≥1 dose of miri or placebo (PBO); N= 1281) was randomized at induction study baseline in a 3:1 ratio to IV doses of 300mg miri or PBO every 4 weeks (Q4W) during induction (W0, 4, and 8). Patients achieving Clinical Response, measured by Modified Mayo Score (MMS), to miri during induction were re-randomized at W0 of the maintenance study in a 2:1 ratio to subcutaneous (SC) 200mg miri or PBO Q4W through W40 (52 weeks of treatment). Patients recorded their UNRS score daily in an e-diary. Mean weekly UNRS scores were calculated from diary data if ≥4 days of data were available. Rates of BU CMI and BU remission in the miri v PBO groups were compared at W12 (induction) in the mITT population with a baseline UNRS score ≥3, and W52 (maintenance) among miri clinical responders at W12 with a baseline UNRS score ≥3. Cochran-Mantel-Haenszel tests with non-responder imputation for missing values were used for all treatment comparisons. Result(s) Patient population: mean age 43 years, 60% male, disease duration 7 years; 63.0% left-sided colitis; 36.3% pancolitis; 46.7% moderate disease (MMS 4-6); 53.2% severe disease (MMS 7-9). Significantly higher proportions of miri versus PBO patients achieved BU CMI (48.7% v 32.2%) and BU remission (22.1% v 12.3%) at W12 (both p&amp;lt;0.001; Table) in the induction study. Similarly, at W40 of maintenance, significantly greater proportion of miri patients achieved BU CMI (65.2% v 41.9%) and BU remission (42.9% v 25.0%) compared to PBO among miri induction responders (both p&amp;lt;0.001; Table). Image Conclusion(s) Miri had a highly significant and clinically meaningful benefit on reducing bowel urgency, one of the most disruptive UC symptoms. The Urgency Numeric Rating Scale usefully quantified the baseline level and change in bowel urgency after treatment across a spectrum of severity. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest None Declared

A186 ASSOCIATION OF ULCERATIVE COLITIS BOWEL URGENCY IMPROVEMENT WITH CLINICAL RESPONSE AND REMISSION

A186 ASSOCIATION OF ULCERATIVE COLITIS BOWEL URGENCY IMPROVEMENT WITH CLINICAL RESPONSE AND REMISSION

Immunologic Predictors for Clinical Responses during Immune Checkpoint Blockade in Patients with Myelodysplastic Syndromes.

The aim of this study is to determine immune-related biomarkers to predict effective antitumor immunity in myelodysplastic syndrome (MDS) during immunotherapy (IMT, αCTLA-4, and/or αPD-1 antibodies) and/or hypomethylating agent (HMA). Peripheral blood samples from 55 patients with MDS were assessed for immune subsets, T-cell receptor (TCR) repertoire, mutations in 295 acute myeloid leukemia (AML)/MDS-related genes, and immune-related gene expression profiling before and after the first treatment. Clinical responders treated with IMT ± HMA but not HMA alone showed a significant expansion of central memory (CM) CD8+ T cells, diverse TCRβ repertoire pretreatment with increased clonality and emergence of novel clones after the initial treatment, and a higher mutation burden pretreatment with subsequent reduction posttreatment. Autophagy, TGFβ, and Th1 differentiation pathways were the most downregulated in nonresponders after treatment, while upregulated in responders. Finally, CTLA-4 but not PD-1 blockade attributed to favorable changes in immune landscape. Analysis of tumor-immune landscape in MDS during immunotherapy provides clinical response biomarkers.

Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy

BackgroundCirculating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown...

Proportion of clinical holistic responders in patients with persistent spinal pain syndrome type II treated by subthreshold spinal cord stimulation compared to best medical treatment: a study protocol for a multicentric randomised controlled trial (TRADITION)

BackgroundIntegrating information on bodily functions, pain intensity and quality of life into one composite measure of a holistic responder has recently been proposed as a useful method to evaluate treatment efficacy of spinal cord stimulation (SCS) in patients with therapy-refractory persistent spinal pain syndrome type II (PSPS-T2). Previous studies already demonstrated the efficacy of standard SCS over best medical treatment (BMT) and the superiority of new subthreshold (i.e. paresthesia free) SCS paradigms compared to standard SCS. Nevertheless, the efficacy of subthreshold SCS compared to BMT has not yet been investigated in patients with PSPS-T2, neither with unidimensional outcomes nor with a composite measure. The current objective is to examine whether subthreshold SCS, compared to BMT, provided to patients with PSPS-T2 results in a different proportion of clinical holistic responders (as composite measure) at 6 months.MethodsA two-arm multicentre randomised controlled trial will be conducted whereby 114 patients will be randomised (1:1) to (a) BMT or (b) paresthesia-free SCS. After a follow-up period of 6 months (primary time endpoint), patients receive the opportunity to cross over towards the other treatment group. The primary outcome is the proportion of clinical holistic responders at 6 months (i.e. a composite measure of pain intensity, medication, disability, health-related quality of life and patient satisfaction). The secondary outcomes are work status, self-management, anxiety, depression and healthcare expenditure.DiscussionWithin the TRADITION project, we propose to shift the focus from a unidimensional outcome measure towards a composite measure as primary outcome measure to evaluate the efficacy of currently used subthreshold SCS paradigms. The lack of methodologically rigorous trials exploring the clinical efficacy and socio-economic consequences of subthreshold SCS paradigms is pressing, especially in light of the growing burden of PSPS-T2 on the society.Trial registrationClinicalTrials.gov NCT05169047. Registered on December 23, 2021

Investigation of the low glutamate diet as an adjunct treatment for pediatric epilepsy: A pilot randomized controlled trial

IntroductionCurrent dietary therapies for epilepsy have side effects and are low in nutrients, which would make an alternative dietary treatment, which addresses these issues, advantageous. One potential option is the low glutamate diet (LGD). Glutamate is implicated in seizure activity. Blood brain barrier permeability in epilepsy could enable dietary glutamate to reach the brain and contribute to ictogenesis. Objective: to assess the LGD as an adjunct treatment for pediatric epilepsy. MethodsThis study was a nonblinded, parallel, randomized clinical trial. The study was conducted virtually due to COVID-19 and registered on clinicaltrials.gov (NCT04545346). Participants were eligible if they were between the ages of 2 and 21 with ≥4 seizures per month. Baseline seizures were assessed for 1-month, then participants were allocated via block randomization to the intervention month (N=18), or a wait-listed control month followed by the intervention month (N=15). Outcome measures included seizure frequency, caregiver global impression of change (CGIC), non-seizure improvements, nutrient intake, and adverse events. ResultsNutrient intake significantly increased during the intervention. No significant differences in seizure frequency were observed between intervention and control groups. However, efficacy was assessed at 1-month compared to the standard 3-months in diet research. Additionally, 21% of participants were observed to be clinical responders to the diet. Overall health (CGIC) significantly improved in 31%, 63% experienced ≥1 non-seizure improvements, and 53% experienced adverse events. Clinical response likelihood decreased with increasing age (0.71 [0.50-0.99], p=0.04), as did the likelihood of overall health improvement (0.71 [0.54-0.92], p=0.01). DiscussionThis study provides preliminary support for the LGD as an adjunct treatment before epilepsy becomes drug resistant, which is in contrast to the role of current dietary therapies in drug resistant epilepsy.

Responsive Neurostimulation of the Anterior Thalamic Nuclei in Refractory Genetic Generalized Epilepsy: A Case Series

Genetic generalized epilepsies (GGEs) are thought to represent disorders of thalamocortical networks. There are currently no well-established non-pharmacologic treatment options for patients with drug-resistant GGE. NeuroPace's Responsive Neurostimulation (RNS) System was approved by the United States Food and Drug Administration to treat focal seizures with up to two ictal foci. We report on three adults with drug-resistant GGE who were treated with thalamic RNS. Given the severity of their epilepsies and the potential ictogenic role of the thalamus in the pathophysiology of GGE, the RNS System was palliatively implanted with leads in the bilateral anterior thalamic nuclei (ANT) of these patients. The ANT was selected because it was demonstrated to be a safe target. We retrospectively evaluated metrics including seizure frequency over 18-32 months. One patient required explantation due to infection. The other two patients were clinical responders. By the end of the observation period reported here, one patient was seizure-free for over 9 months. All three self-reported an improved quality of life. The clinical response observed in these patients provides 'proof-of-principle' that GGE may be treatable with responsive thalamic stimulation. Our results support proceeding to a larger study investigating the efficacy and safety of thalamic RNS in drug-resistant GGE.

Combinatory analysis of immune cell subsets and tumor-specific genetic variants predict clinical response to PD-1 blockade in patients with non-small cell lung cancer.

Immunotherapy by blocking programmed death protein-1 (PD-1) or programmed death protein-ligand1 (PD-L1) with antibodies (PD-1 blockade) has revolutionized treatment options for patients with non-small cell lung cancer (NSCLC). However, the benefit of immunotherapy is limited to a subset of patients. This study aimed to investigate the value of combining immune and genetic variables analyzed within 3-4 weeks after the start of PD-1 blockade therapy to predict long-term clinical response. Blood collected from patients with NSCLC were analyzed for changes in the frequency and concentration of immune cells using a clinical flow cytometry assay. Next-generation sequencing (NGS) was performed on DNA extracted from archival tumor biopsies of the same patients. Patients were categorized as clinical responders or non-responders based on the 9 months' assessment after the start of therapy. We report a significant increase in the post-treatment frequency of activated effector memory CD4+ and CD8+ T-cells compared with pre-treatment levels in the blood. Baseline frequencies of B cells but not NK cells, T cells, or regulatory T cells were associated with the clinical response to PD-1 blockade. NGS of tumor tissues identified pathogenic or likely pathogenic mutations in tumor protein P53, Kirsten rat sarcoma virus, Kelch-like ECH-associated protein 1, neurogenic locus notch homolog protein 1, and serine/threonine kinase 11, primarily in the responder group. Finally, multivariate analysis of combined immune and genetic factors but neither alone, could discriminate between responders and non-responders. Combined analyses of select immune cell subsets and genetic mutations could predict early clinical responses to immunotherapy in patients with NSCLC and after validation, can guide clinical precision medicine efforts.

P464 Effects of ozanimod on histologic remission and mucosal healing over 3 years of continuous treatment in patients with ulcerative colitis

Abstract Background Ozanimod is approved in the European Union, United States, and other countries for the treatment of moderately to severely active ulcerative colitis in adults (UC). The phase 3, randomised True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients with moderately to severely active UC. The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod. This interim analysis of the TN OLE evaluated the efficacy of ozanimod on histologic remission (HR) and mucosal healing (MH) in patients who received approximately 3 years of continuous ozanimod treatment. Methods In TN, patients were randomised to once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo (Cohort 1) or to open-label ozanimod (Cohort 2) for a 10-week induction period. Ozanimod clinical responders were rerandomised at Week 10 to ozanimod or placebo for a 42-week maintenance period (MP). Patients with clinical response to ozanimod at Week 52 in TN were eligible to continue receiving ozanimod in the ongoing OLE. This interim analysis of the OLE (data cutoff: 10 January 2022, the point at which patient disposition was available for patients until OLE Week 94) included all patients on continuous ozanimod in the TN MP who achieved clinical response at Week 52 and enrolled in the OLE (n=131). Endoscopic and histologic endpoints were evaluated at OLE Weeks 46 and 94 (98 and 146 weeks of continuous ozanimod treatment, respectively) and reported using observed case analysis. Mean Mayo endoscopy scores were evaluated from TN baseline to OLE Week 94. Results Of the 131 total patients included in this analysis, 87% completed OLE Week 46 (98 weeks of continuous ozanimod) and 72% completed OLE Week 94 (146 weeks of continuous ozanimod). Patients had a mean age of 44 years and 52% were female. Most patients (68%) had left-sided UC, 69% had prior use of corticosteroids, 99% had prior use of 5-aminosalicylic acid, and 32% had prior use of tumor necrosis factor inhibitors. Most TN Week 52 clinical responders achieved endoscopic improvement (EI), HR, and MH at OLE Weeks 46 and 94 (Figure 1). Ozanimod treatment was associated with a reduction in mean Mayo endoscopy score to 1.0 at TN Week 52; this was sustained through OLE Week 94 (Figure 2). Conclusion In this interim analysis of the TN OLE, a large proportion of clinical responders after 1 year of ozanimod who remained on ozanimod for up to 2 years thereafter, achieved EI, HR, and MH after 2 and 3 years of continuous treatment. Long-term ozanimod use may be associated with sustained endoscopic and histologic benefits in patients with UC.

DOP85 Crohn's Disease Strictures Respond to Drug Treatment and Treat-to-Target Intense Combination Therapy is More Effective than Standard Anti-TNF Therapy. Two year results of the STRIDENT Randomised Controlled Trial.

Abstract Background The randomised STRIDENT (Stricture Definition and Treatment) trial showed that Crohn’s disease symptomatic strictures are responsive to anti-TNF therapy with most patients clinically improved after 12 months treatment with adalimumab +/- thiopurine. Treat to target intensification resulted in greater stricture morphology improvement. We present here 2 year (from study entry) follow up to assess response durability and risk of surgery. Methods Patients with symptomatic Crohn’s disease strictures and associated inflammation (elevated faecal calprotectin and CRP) were assessed with imaging (intestinal ultrasound and MRI) and ileo-colonoscopy. The Obstructive Symptom Score (OSS) was used for clinical assessment. Patients were randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) followed by 40mg fortnightly plus thiopurine, with adalimumab dose increase at 4 and/or 8 months if evidence of ongoing inflammation, versus standard dose adalimumab monotherapy. The primary endpoint was improved OSS at 12 months. Patient interview was conducted at 24 months, assessing drug treatment, symptoms, need for endoscopic therapy, hospitalisation and surgery. Results In the initial 12 months study 52 patients were randomised to the intensive and 25 to the standard treatment arm. 64/77 (83%) patients recorded an outcome at 12 months (13/77 (17%) withdrawn: 8 surgery, 5 other) 74/77 (96.1%) patients were followed up at a mean of 25.3 (IQR 24.4-26.3) months. Of these, 59 (79.7%) remained on adalimumab, 10 (13.5%) had switched to another biologic and 5 (6.7%) had ceased biologic therapy. For patients who were on adalimumab at 12 months the risk of surgery by 24 months was 15%. Of patients on adalimumab 40mg fortnightly at 12 months, 12/48 (25%) had been dose escalated by 24 months. Endoscopic balloon dilatation, hospitalisation or surgery was required in 6 (8.1%), 14 (18.9%) and 13 (17.5%) respectively; rates were not different between the standard and intensive treatment groups (P = 0.982). Median time to intestinal resection was 12.2 (IQR 6.9-18.6) months. Clinical responders at 12 months, compared to non-responders, had a reduced likelihood of surgery at 24 months (9% vs 42%, P=0.003). Conclusion Clinical response to adalimumab for structuring Crohn’s disease is durable in a majority of patients, with most patients remaining on adalimumab and avoiding surgery at two years. Rates of surgery were not different between the standard and intensive therapy arms. Clinical response to adalimumab at 12 months is an important predictor of future surgical risk.

P179 Comparative benefit-risk profile of induction and maintenance therapy with upadacitinib versus placebo in patients with moderately to severely active ulcerative colitis

Abstract Background Upadacitinib (UPA) demonstrated efficacy and safety as induction and maintenance therapy for ulcerative colitis (UC) in Phase 3 trials U-ACHIEVE (NCT02819635) and U-ACCOMPLISH (NCT03653026). This post-hoc analysis aims to characterise the benefit-risk profile of UPA induction and maintenance therapy vs placebo (PBO) in patients (pts) with moderately to severely active UC based on a number needed to treat/harm (NNT/NNH) analysis. Methods Efficacy and safety data from the pooled intention-to-treat population of U-ACHIEVE and U-ACCOMPLISH trials were included. Pts received UPA 45 mg (UPA45) once daily (QD) or PBO for 8 weeks (induction trials). Clinical responders (per Adapted Mayo score) at Week 8 of induction were re-randomised to receive UPA 15 mg (UPA15) or 30 mg (UPA30) QD, or PBO in the 52-week maintenance study. The primary efficacy endpoint was clinical remission per Adapted Mayo score. Secondary outcomes are listed in Table 1 and safety outcomes are listed in Table 2. N, percentages, and outcome differences compared by Z test were reported. NNT/NNH was calculated as the inverse of the difference in proportions achieving efficacy/safety outcomes for UPA vs PBO. Positive NNT values indicate greater efficacy and negative NNH values imply lower safety risk for UPA vs PBO. Results A significantly greater proportion of pts achieved clinical remission at induction (UPA45 29.9% vs PBO 4.4%) and maintenance (UPA15 40.4%, UPA30 53.6% vs PBO 10.8%) with UPA vs PBO, as well as all secondary endpoints (all p&amp;lt;0.001; Table 1). The NNT for clinical remission at Week 8 was 4.0, ranging from 2.1 to 9.6 for secondary endpoints. At Week 52, the NNT for clinical remission was 2.4; NNTs for secondary endpoints ranged from 1.8 to 5.9 (Table 1). At Week 8, adverse events (AEs) were lower for worsening of UC for UPA45 vs PBO-treated pts and greater for creatine phosphokinase (CPK) elevation, acne, neutropenia, and lymphopenia (p≤0.01). At Week 52, AEs were lower for UPA15 and UPA30 vs PBO for worsening of UC, AEs leading to discontinuation (UPA15 only), and arthralgia (UPA30 only), and greater for CPK elevation, herpes zoster, hepatic disorder (UPA15 only), and neutropenia (UPA30 only) (p≤0.05; Table 2). All other AEs were similar between UPA and PBO. Among the safety outcomes significantly different between UPA and PBO, the NNH for UPA vs PBO ranged from –16.1 to 25.6 (Table 2). Conclusion This post-hoc Phase 3 analysis demonstrates greater efficacy and generally comparable safety of UPA vs PBO, indicating a favourable benefit-risk profile for UPA in pts with moderately to severely active UC.

P749 Crohn’s disease stricture response and resolution with adalimumab therapy demonstrated with intestinal ultrasound. The STRIDENT randomised trial

Abstract Background Transmural healing is a treatment goal in the management of Crohn’s disease, and intestinal ultrasound (IUS) is potentially a sensitive, non-invasive and reproducible means to assess the response to treatment. Methods The STRIDENT (Stricture Definition and Treatment) study was a randomised controlled trial of standard dose monotherapy adalimumab versus intensive high-dose adalimumab combined with a thiopurine. Crohn’s disease patients with symptomatic intestinal strictures were randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) with 40mg fortnightly maintenance plus thiopurine, with possible dose escalation at 4 and 8 months, versus standard dose adalimumab monotherapy. The primary endpoint was clinical response, defined as a reduction in the Obstructive Symptom Score (OSS) of ≥1, at 12 months. IUS was performed at baseline, 4, 8 and 12 months. IUS endpoints included stricture resolution (normalisation of pre-stenotic dilation (&amp;lt;2.5cm); reduced stricture bowel wall thickness (BWT ≥25% reduction); reduced colour doppler blood flow (inflammation, Limberg score ≤1) and normalisation of BWT (≤3mm). Patients with good quality baseline IUS and IUS-visible strictures were included for analysis. Results 77 patients underwent therapy randomisation. Of 63 patients with IUS-visible strictures 43 (68%) were in the intensive arm. Primary outcome was achieved by 32 (74%) patients in the intensive and 14 (70%) in the standard arms. Stricture resolution was seen in 1/5 non-responders and 18/45 responders. Median BWT reduced from 6.4mm (IQR 5.2-7.3mm) at baseline to 4.9mm (IQR 3-6mm) at 12 months (P&amp;lt;0.001). Clinical responders had significant reduction in median BWT from 6.0mm (IQR 4.5-7.1) at baseline to 4.3mm (IQR 3-5.7) at 12 months (P&amp;lt;0.001). There was no significant reduction in BWT at 4, 8 or 12 months in non-responders (P=0.26, P=0.29, P=0.26 respectively). BWT &amp;gt;3mm at 12 months occurred more often in non-responders than responders (P&amp;lt;0.05). Stricture resolution was seen in 13/36 in the intensive arm and 6/14 standard arm (P=0.75). The intensive arm had significant reduction in median BWT from 6.6mm (IQR 5.5-7.4mm) at baseline to 5.1mm (IQR 3-6.4mm) at 12 months (P&amp;lt;0.001). There was no significant reduction in BWT at 4, 8 or 12 months in the standard arm (P=0.75, P=0.42, P=0.09 respectively). There was no significant difference in BWT&amp;gt;3mm between trial arms at 12 months (P=1). Conclusion Stricture resolution and bowel wall thickness normalisation were demonstrated on intestinal ultrasound in stricturing Crohn’s disease patients treated with adalimumab therapy. Adalimumab therapy is associated with clinical improvement, and transmural improvement and healing, in patients with Crohn’s disease strictures.

P582 Efficacy of etrasimod at week 52 among subjects who reached clinical response at week 12: post hoc analysis of the phase 3 ELEVATE UC 52 trial

Abstract Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of ulcerative colitis (UC). The ELEVATE UC 52 trial utilized a treat-through design which evaluated efficacy at week 52 among all subjects randomised from baseline. Here, we report a post hoc analysis of efficacy at week 52 among subjects who did or did not achieve clinical response at the end of the 12-week induction period in ELEVATE UC 52. Methods In ELEVATE UC 52 (NCT03945188), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). This post hoc analysis assessed achievement of clinical remission, 12-week corticosteroid-free remission, endoscopic improvement, endoscopic improvement-histologic remission, and symptomatic remission at week 52 among subjects with baseline MMS 5-9 who did or did not achieve clinical response criteria at week 12 (defined as a ≥2-point and ≥30% decrease from baseline in MMS and a ≥1-point decrease from baseline in rectal bleeding subscore or an absolute rectal bleeding subscore ≤1). Results At week 12 in ELEVATE UC 52, 171 (62.4%) etrasimod-treated subjects vs 46 (34.1%) PBO-treated subjects achieved clinical response (P&amp;lt;0.001) and were included in the week 52 clinical responder analysis. Among clinical responders at week 12, subjects treated with etrasimod were more likely to be in clinical remission at week 52 vs PBO (49.1% [n=84/171] vs 17.4% [n=8/46]; P&amp;lt;0.001) (Figure 1). Similar results were observed for the achievement of all other efficacy endpoints at week 52 among those who met clinical response criteria at week 12 (all P&amp;lt;0.05). At week 12 in ELEVATE UC 52, 103 (37.6%) etrasimod-treated subjects and 89 (65.9%) PBO-treated subjects either did not achieve clinical response at week 12 or had discontinued the study prior to the week 12 assessment. There were no significant treatment differences in achievement of efficacy endpoints at week 52 among subjects who did not achieve clinical response at week 12. Conclusion Among subjects who reached clinical response criteria at week 12, greater proportions of etrasimod-treated subjects vs PBO-treated subjects achieved week 52 efficacy across both objective and subjective measures of disease activity. Among subjects who did not reach clinical response or had discontinued prior to week 12, no significant treatment differences were observed at week 52 between etrasimod-treated subjects vs PBO-treated subjects. These results may help contextualize the 52-week efficacy results of ELEVATE UC 52 when considering other treatments that utilized re-randomisation of responder designs.

P746 Identification of Altered Microbial Genera at Baseline in Adalimumab Clinical Remitters and an Absence of Change in Total Microbial Composition Post Induction Treatment in the SERENE UC Study

Abstract Background The gut microbiome plays an integral role in the pathogenesis of Inflammatory Bowel Disease (IBD). However, there have been a limited number of studies investigating the composition of the gut microbiome in anti-TNF-treated Ulcerative Colitis (UC) patients. The aims of this study were to 1) identify novel microbial baseline predictors of clinical response and remission to Adalimumab treatment, and 2) assess the impact of Adalimumab induction treatment on the gut microbiome of UC patients. Methods The SERENE UC study (NCT02065622) compared the efficacy of higher adalimumab dosing regimens to the standard regimen in patients with moderately to severely active UC. 16S rRNA gene sequencing was performed on 204 stool samples from 107 UC patients at baseline and Week 8. An ANOVA test followed by Tukey HSD was used to compare microbial content within (baseline) or across (baseline vs Week 8) visits between clinical remitters (n=16), clinical responders (n=38), and patients who failed to respond to Adalimumab treatment (n=53). Clinical response was defined as a full Mayo score decrease of ≥3 points and ≥30% from baseline, plus ≥1-point decrease in rectal bleeding score or absolute bleeding score ≤1 at Week 8. Clinical remission was defined as a full Mayo score ≤2 with no sub-score &amp;gt;1 at Week 8. Results There were no differences in alpha diversity in terms of richness and evenness when comparing samples from patients across response categories, or alpha and beta diversity when comparing paired samples from patients pre- and post-treatment. In addition, principal coordinate analysis of the microbiome did not highlight any clustering of the samples between response groups or visits. When stratifying patients by clinical response status at Week 8, we identified 4 genera that were significantly altered at baseline in the clinical remitters compared to the clinical responders and/or non-responders, including Dorea, Ruminococcus torques group, Subdoligranulum, and Collinsella. Unexpectedly, when comparing paired pre- and post-treatment samples within a response group, we failed to detect any significant changes on the total microbiome composition regardless of response status at Week 8. Conclusion These findings suggest that baseline microbial composition is significantly altered in UC patients who achieve clinical remission, but that Adalimumab treatment does not significantly alter the composition of the gut microbiome after 8 weeks of treatment. Future work is focused on achieving a deeper understanding of the gut landscape in UC patients treated with Adalimumab through 1) investigation of bacterial, viral, and fungal composition by metagenomics, and 2) integration of serum metabolomics data.

OP20 The effects of upadacitinib on ulcerative colitis symptom resolution and fatigue normalization in patients with moderately to severely active ulcerative colitis: Phase 3 U-ACHIEVE and U-ACCOMPLISH results

Abstract Background Abdominal pain (AP), bowel urgency (BU), stool frequency (SF), rectal bleeding (RB) and fatigue are debilitating symptoms that reduce quality of life in patients with ulcerative colitis (UC). Results from two Phase 3 induction trials and one maintenance trial (U-ACHIEVE [NCT02819635] and U-ACCOMPLISH [NCT03653026]) showed significant and clinically meaningful improvements in these symptoms following induction and maintenance treatment with upadacitinib (UPA) in patients with moderately to severely active UC. We evaluated the effects of 8-week UPA induction and 52-week UPA maintenance treatment on UC symptom resolution, defined as no BU, no AP, and symptomatic remission (no RB, SF≤1), and normalization of fatigue, defined as achievement of a Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT–F) score ≥ 40.1. Methods A total of 988 patients were randomized in the U-ACHIEVE and U-ACCOMPLISH induction studies to receive UPA 45 mg once daily (QD; n=660) or placebo (PBO) QD (n=328). Patients who achieved a clinical response after 8 weeks of induction (n=451) were enrolled in the U-ACHIEVE maintenance study and re-randomised 1:1:1 to UPA 15 mg QD (n=148), UPA 30 mg QD (n=154), or PBO QD (n=149). Symptom resolution was assessed at induction Weeks 0, 2, 4, 6, 8 and maintenance Weeks 0, 4, 8, 12, 20, 28, 36, 44, and 52. A more stringent assessment of symptom resolution and normalization of fatigue was conducted at Weeks 0, 2, and 8 of induction and Weeks 0 and 52 of maintenance. Results A higher percentage of patients achieved symptom resolution during induction treatment as early as Week 2 with UPA 45 mg vs PBO (11.1% vs 0.9%, p &amp;lt;0.001; Figure 1), and sustained through Week 8 (31.2% vs 7.9%, p&amp;lt;0.001). This difference was also observed during maintenance treatment among clinical responders starting at Week 8 with UPA (15 mg: 43.2%; 30 mg: 42.2% vs PBO: 30.2%, p&amp;lt;0.01 and p&amp;lt;0.05, respectively; Figure 2) and sustained through Week 52 (15 mg: 37.2%; 30 mg: 46.1% vs PBO: 12.8%, p&amp;lt;0.001 for both). Furthermore, the percentage of patients who achieved symptom resolution and fatigue normalization was greater with UPA vs PBO at Week 8 of induction (45 mg: 23.4% vs PBO: 6.7%, p &amp;lt;0.001; Figure 3) and Week 52 of maintenance (15 mg: 24.3%; 30 mg: 36.4% vs PBO: 12.1%, p&amp;lt;0.01 and p&amp;lt;0.001, respectively). Conclusion Patients with moderately to severely active UC were more likely to achieve symptom resolution and normalization of fatigue during induction treatment with UPA compared to PBO, and these benefits were sustained during maintenance therapy.