Academic literature on the topic 'Kevin weeks'

Abstract Introduction: Recombinant human interleukin 15 (rhIL-15) has been shown to stimulate the activation and expansion in the number of effector T lymphocytes and natural killer cells in patients. The addition of the immune checkpoint inhibitors (ICI) CTLA-4 and PD-1 has shown increased antitumor efficacy in preclinical models, and the triplet is hypothesized to enhance anti-tumor immune response by augmenting effector cell expansion, differentiation, cytotoxic activity, and immune checkpoint inhibition. Results of the lead-in safety arms of rhIL-15/ipilimumab (Ipi) or rhIL-15/nivolumab (N) doublets were previously reported (O’Sullivan et al. AACR. 2019) and we now report results for the dose escalation phase of the triplet combination (NCT03388632). Methods: This phase 1, open-label, 3+3 dose escalation trial enrolled adult patients (pts) with measurable metastatic or refractory solid tumors and ECOG performance status ≤2. Prior therapy with 2 of the 3 study agents was permitted. Pts were treated on three dose levels (DL 1-3) of rhIL-15 (0.5, 1, or 2 mcg/kg/day) administered subcutaneously on days (D)1-8 and D22-29 of a 6-week cycle for the first 4 cycles only. Nivolumab (240mg IV) was administered on D8, 22, 36 and ipilimumab (1mg/kg IV) on D8 of every cycle. Response was assessed by RECIST 1.1. Upon progression, pts could continue for response assessment utilizing iRECIST if clinically stable and without toxicity. Treatment-induced changes in circulating and tumor T cell activation, signaling, and the PD-L1 checkpoint will be assessed with validated pharmacodynamic biomarker assays. Results: A total of 17 pts were enrolled on the triplet dose escalation phase; 15 pts were evaluable for response and 6 pts had received prior treatment with a PD-1/PD-L1 inhibitor. Median time on treatment (MTT) was 12 weeks (range 3-101). A confirmed partial response (PR) was observed in a pt with intrahepatic cholangiocarcinoma (MSI-H) after 3 cycles (total time on treatment 101 weeks). Across all dose levels, 7 pts (46.7%) had stable disease (SD) that prolonged their time on treatment with MTT of 20.4 weeks; 7 pts (46.7%) experienced progressive disease (PD) with MTT of 6.4 weeks. To better profile toxicity, 5 pts were replaced due to incomplete dosing of C1. Dose limiting toxicities at DL 3 (rhIL-15 at 2 mcg/kg/day) were photosensitivity and rash. Main drug-related adverse events included grade 4 lymphopenia (n=1) and grade 3 colitis, hyperthyroidism, hyponatremia, myocarditis, neutropenia, and photosensitivity (n=1, each). No pts discontinued therapy due to toxicity events. No deaths occurred on study. Conclusions: The recommended phase 2 dose (RP2D) of rhIL-15 is 1 mcg/kg/day when administered in combination with N+Ipi. The triplet dose expansion phase with the RP2D is currently accruing and includes biomarker studies in blood and tumor biopsies to assess the tumor microenvironment. This study was funded in part by NCI Contract HHSN261200800001E. *In memorium: Dr. Thomas Waldmann7. Citation Format: Sarah J. Shin, Geraldine O'Sullivan Coyne, Howard Streicher, Naoko Takebe, Ashley Bruns, Elad Sharon, Richard Piekarz, Lamin Juwara, Larry Rubinstein, Ralph Parchment, Kristin Fino, King L. Fung, Katherine Ferry-Galow, Arjun Mittra, Abdul Rafeh Naqash, Kevin Conlon, James H. Doroshow, Alice P. Chen. Phase 1 study of recombinant interleukin 15 (rhIL-15) in combination with checkpoint inhibitors nivolumab and ipilimumab in subjects with refractory cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT147.

Background:In the INBUILD trial in patients with progressive fibrosing ILDs, nintedanib reduced the rate of decline in forced vital capacity (FVC) versus placebo over 52 weeks both in the overall population and in the subgroup with autoimmune disease-related ILDs. Patients continued blinded randomised treatment until the end of the trial.Objectives:Assess the effects of nintedanib on the risks of death, acute exacerbation of ILD or death, and disease progression or death over the whole INBUILD trial in patients with autoimmune disease-related ILDs and a progressive phenotype.Methods:Patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF) were randomised to receive nintedanib 150 mg bid or placebo. Time to i) death, ii) first acute exacerbation of ILD or death, and iii) disease progression (absolute decline in FVC ≥10% predicted) or death, over the whole trial were analysed in patients with autoimmune disease-related ILDs. Incidence rates of adverse events per 100 patient–years were calculated based on events with onset between the first trial drug intake and the last intake plus 28 days. Analyses were descriptive.Results:Of 663 patients, 170 (82 nintedanib, 88 placebo) had autoimmune disease-related ILDs (89 RA-ILD, 39 SSc-ILD, 19 MCTD-ILD, 23 other autoimmune ILDs including Sjogren’s disease-related ILD [n=7], interstitial pneumonia with autoimmune features [n=5] and undifferentiated CTD-ILD [n=3]). Over the whole trial, in the nintedanib and placebo groups, respectively, mean (SD) exposure to drug was 15.4 (7.4) and 16.9 (6.1) months and maximum exposure was 26.0 and 25.2 months; 62 (75.6%) and 68 (77.3%) patients in these groups, respectively, completed the planned observation time. Over the whole trial, in the nintedanib and placebo groups, respectively, 9.8% and 12.5% of patients died, 12.2% and 20.5% of patients had ≥1 acute exacerbation of ILD or died, and 40.2% and 53.4% of patients had disease progression or died (Table). Diarrhoea was the most common adverse event, with incidence rates of 139.2 and 26.3 events per 100 patient–years in the nintedanib and placebo groups, respectively. Adverse events led to treatment discontinuation in 20.7% of patients in the nintedanib group and 13.6% of patients in the placebo group.Conclusion:Data from the INBUILD trial suggest that nintedanib has a clinically meaningful effect on slowing the progression of ILD in patients with progressive fibrosing autoimmune disease-related ILDs, with adverse events that can be tolerated by most patients.Table.Nintedanib (n=82)Placebo (n=88)HR (95% CI)*Death8 (9.8)11 (12.5)0.80 (0.32, 1.98)≥1 acute exacerbation of ILD or death10 (12.2)18 (20.5)0.58 (0.27, 1.27)Disease progression (absolute decline in FVC ≥10% predicted) or death33 (40.2)47 (53.4)0.72 (0.46, 1.13)n (%) with event over the whole trial (mean [SD] exposure: 15.4 [7.4] and 16.9 [6.1] months in nintedanib and placebo groups, respectively). *Based on time to first event.Disclosure of Interests:Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Clive Kelly Consultant of: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, James Seibold Shareholder of: BriaCell, Pacific Therapeutics, Consultant of: Atlantic, Blade Therapeutics, Eicos Sciences, Eiger Biopharmaceuticals, Indalo Therapeutics, Mitsubishi Tanabe Pharma, Bayer, Xenikos, Boehringer Ingelheim, Camurus, Corbus Pharmaceuticals, EMD Serono, Speakers bureau: Boehringer Ingelheim, Shikha Mittoo Grant/research support from: Pfizer, Consultant of: Novartis, Abbvie, Pfizer, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Paul F. Dellaripa Grant/research support from: Paul Dellaripa has received institutional grants from Genentech, Consultant of: Paul Dellaripa participated in advisory boards for Boehringer Ingelheim, Alexandra James Employee of: Employee of Boehringer Ingelheim, Rozsa Schlenker-Herceg Employee of: Employee of Boehringer Ingelheim, Susanne Stowasser Employee of: Employee of Boehringer Ingelheim, Manuel Quaresma Employee of: Employee of Boehringer Ingelheim, Kevin R. Flaherty Grant/research support from: Kevin Flaherty has received grants from Boehringer Ingelheim, Consultant of: Kevin Flaherty has acted as a consultant for Boehringer Ingelheim, Bellerophon, Blade Therapeutics, Roche/Genentech, and VeracyteHe was a member of the INBUILD trial Steering Committee

Abstract Background: Resistance to PD1/L1 immune checkpoint inhibitors (ICIs) in advanced NSCLC patients is observed in about 80% of individuals with no robust predictive biomarker yet. The PIONeeR trial (NCT03493581) aims to predict such resistances through a comprehensive multiparametric biomarkers analysis. Methodology: Among the >300 advanced NSCLC patients (pts) recruited in PIONeeR, we focused on the first 137 ≥2nd line ECOG PS0-1 pts treated with single-agent nivolumab, pembrolizumab or atezolizumab. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout the 24 weeks post C1D1. Response to PD1/L1 ICIs was assessed by RECIST 1.1 every 6 weeks. Immune contexture was characterized in tumor & blood of each pt through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC/digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma dosage, leading to 331 measured biomarkers in addition to routine clinical parameters. Multivariable (MV) logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histological type & PDL1+ Tumor Cells) with the risk of Early Progression (EP), i.e. within 3.5 months of treatment. Multivariable Cox regression analysis was conducted for association with PFS and OS. Results: Overall, the 137 pts were mainly male (64%), smokers (92%) and <70yrs (68%). Tumors were mainly non-squamous (79%) with >1% PDL1+ TC in 36% of the cases, and 21% of pts were still on treatment at data cut-off. Archived samples were available for 80% of pts at inclusion and re-biopsy was available in 52.9% of these cases. The median follow up was 19.8 months, 22.5% of pts did not progress at data cut-off while 62% presented EP. Tumor Cytotoxic T-cells density, especially PD1+ were lower in EP (MV OR=0.45, p=0.022); conversely, higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in EP (MV OR=3.8, p<0.001). Among other biomarkers, Tregs (MV OR=0.44, p=0.018), NK cell subsets (MV OR≤0.44, p<0.05), albumin (MV OR=0.4, p<0.01) and PDL1 TC % (MV OR=0.27, p<0.01) were decreased whereas alkaline phosphatase was increased (OR=3, p=0.018). >65% inter-pt variability was observed in plasma exposures for all ICIs, with 8-10% of pts displaying trough levels below the target engagement threshold. Data will be presented through unsupervised clustering algorithms & multi-modal supervised learning methods. Changes after 6 weeks of treatment will be analyzed to further investigate drugs mechanisms of action. Conclusion: The PIONeeR trial provides with the 1st comprehensive biomarkers’ analysis to establish predictive models of resistance in advanced NSCLC pts treated with PD1/L1 ICIs and highlights how tumor and circulating biomarkers are complementary. Citation Format: Laurent Greillier, Florence Monville, Vanina Leca, Frédéric Vely, Stephane Garcia, Joseph Ciccolini, Florence Sabatier, Gilbert Ferrani, Nawel Boudai, Lamia Ghezali, Marcellin Landri, Clémence Marin, Mourad Hamimed, Laurent Arnaud, Melanie Karlsen, Kevin Atsou, Sivan Bokobza, Pauline Fleury, Arnaud Boyer, Clarisse Audigier-Valette, Stéphanie Martinez, Hervé Pegliasco, Patrice Ray, Lionel Falchero, Antoine Serre, Nicolas Cloarec, Louisiane Lebas, Stephane Hominal, Patricia Barre, Sarah Zahi, Ahmed Frikha, Pierre Bory, Maryannick Le Ray, Lilian Laborde, Virginie Martin, Richard Malkoun, Marie Roumieux, Julien Mazieres, Maurice Perol, Eric Vivier, Sebastien Benzekry, Jacques Fieschi, Fabrice Barlesi. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB120.

BackgroundRisankizumab (RZB) is a monoclonal antibody that specifically inhibits interleukin 23.ObjectivesTo evaluate the achievement of Minimal Disease Activity (MDA), its components, and achievement of Disease Activity in PsA Low Disease Activity and Remission (DAPSA LDA+REM, [DAPSA score ≤14]) in patients receiving RZB or placebo (PBO) in the KEEPsAKE 1 and 2 clinical trials.MethodsKEEPsAKE-1 and -2, double-blind, phase 3 trials, evaluated the efficacy of RZB versus PBO for the treatment of adult patients with active psoriatic arthritis (PsA). Patients were randomized (1:1) to receive subcutaneous RZB 150 mg or PBO at weeks 0, 4, and 16. The open label extension began at Week 24 with all patients receiving RZB 150 mg every 12 weeks thereafter. Achievement of MDA, its components, and achievement of DAPSA LDA+REM are reported using non-responder imputation.ResultsMDA achievement at Week 52 in KEEPsAKE-1 was 37.9% for patients originally randomized to RZB and 27.4% for patients originally randomized to PBO. In KEEPsAKE-2, MDA achievement was 27.2% and 33.8% for patients originally randomized to RZB and PBO, respectively. Achievement of MDA and its components are presented in Figure 1. In KEEPsAKE-1, at Week 52 59.2% of patients originally randomized to RZB and 51.4% of patients originally randomized to PBO achieved DAPSA LDA+REM. At Week 52 in KEEPsAKE-2, DAPSA LDA+REM was achieved by 44.6% of patients originally randomized to RZB and 46.6% of patients originally randomized to PBO (Figure 1).ConclusionPatients treated with RZB demonstrate achievement of MDA, its components, and DAPSA LDA+REM at Weeks 24 and 52.AcknowledgementsAbbVie Inc, participated in the study design; study research; collection, analysis and interpretation of data; and writing, reviewing, and approving of this abstract for submission. AbbVie funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Trisha Rettig, Ph.D. of AbbVieDisclosure of InterestsJoseph F. Merola Consultant of: Amgen, Bristol-Myers Squibb, Abbvie, Dermavant, Eli Lilly, Novartis, Janssen, UCB, Sanofi, Regeneron, Sun Pharma, Biogen, Pfizer and Leo Pharma, Iain McInnes Consultant of: AbbVie, Amgen, Astra Zeneca, Compugen, Cabaletta, Evelo, Janssen, Lilly, Novartis, Pfizer, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Astra Zeneca, Janssen, Lilly, Novartis, Pfizer, UCB, Arthur Kavanaugh Consultant of: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Grant/research support from: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Peter Nash Speakers bureau: Abbvie, Amgen, Janssen, Lilly, Novartis, Pfizer, UCB, BMS, Rocje, Sanofi, Gilead/Galapagos, MSD, Samsung, Celgene, Amgen, Boehringer, Consultant of: Abbvie, Amgen, Janssen, Lilly, Novartis, Pfizer, UCB, BMS, Rocje, Sanofi, Gilead/Galapagos, MSD, Samsung, Celgene, Amgen, Boehringer, Grant/research support from: Abbvie, Amgen, Janssen, Lilly, Novartis, Pfizer, UCB, BMS, Rocje, Sanofi, Gilead/Galapagos, MSD, Samsung, Celgene, Amgen, Boehringer, Zhenyi Xue Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Vassilis Stakias Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Ann Eldred Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Sandra Ciecinski Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Kevin Douglas Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Laura Coates Speakers bureau: AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Novartis, Pfizer and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis and Pfizer

Over the course of our careers we will see many thousands of patients, but there are one or two who we remember vividly; it is often these patients who shape and change our practice most. The problem-based review written by Kevin Jones’ team in Bolton in this edition reminded me of one of the first patients I clerked as a medical Senior House Off icer, while working in a District General Hospital back in the early 1990s. I was revising for the written part of the MRCP Part 2 examination at the time, so when the general practitioner described the young man’s fatigue, low grade fever and rash as ‘probable viraema’, my thoughts immediately turned to far more esoteric diagnoses. For once my suspicions were confirmed. The ‘fatigue’ was clearly proximal myopathy with marked tenderness suggesting a myositis; his rash had the typical ‘heliotrope’ distribution accompanied by nail-fold oedema; the diagnosis of dermatomyositis was sealed long before the consultant ward round when the laboratory phoned through his Creatinine Kinase result of over 15,000. I remember the feeling of elation at having made the diagnosis, the metaphorical pat on the back from my consultant and the look of relief in the eyes of the patient and his mother when I told them that we had the answer. I had no doubt in my mind that the hydrocortisone I had prescribed would rapidly improve his symptoms allowing him to resume his usual activity within a few weeks – I had read all about it in Kumar and Clark or some other erudite medical text book. For a few hours medicine was wonderful – until my cardiac arrest bleep went off. CPR was already in progress when I arrived on the ward; I had attended resuscitation calls before, but never for an 18 year old. A nurse reported that he had complained of dyspnoea and became drowsy shortly before he stopped breathing. There was a cardiac output, but no respiratory effort – he was intubated, ventilated, transferred to intensive care and then to a regional specialist unit, but sadly never regained consciousness before he died 2 weeks later. This was a tragic story which affected many people, but which taught me a really important lesson: making a diagnosis is where our job starts – not where it ends. We will never know whether we could have made any difference to this poor young man by anticipating a different outcome, closer monitoring of his respiratory function or earlier involvement of our critical care team. The speed of his deterioration was such that even today’s focus on early warning scoring and prompt recognition of changes in physiology, which has developed over the past 2 decades, would probably not have changed his outcome. However the key is to expect the unexpected; there are formes frustes of many conditions which behave differently to those which appear in the text books. Making a diagnosis should never be a cause for celebration.

BackgroundUpadacitinib (UPA) 15 mg once daily (QD) has demonstrated efficacy and safety in patients with psoriatic arthritis (PsA) for up to 56 weeks in the Phase 3 SELECT-PsA 1 and 2 trials.1,2ObjectivesThis post hoc analysis of these studies explored the association of baseline characteristics and short-term responses with achievement of minimal disease activity (MDA) and Disease Activity Index for Psoriatic Arthritis (DAPSA) low disease activity (LDA).MethodsData were pooled from patients with prior inadequate response or intolerance to ≥1 non-biologic (b) DMARDs (SELECT-PsA 1) or ≥1 bDMARDs (SELECT-PsA 2) originally randomized to UPA 15 mg QD. Logistic regression models were used to assess the association between baseline characteristics and short-term (Week 12) responses with achieving MDA or DAPSA LDA at 56 weeks, sustained MDA (MDA at Weeks 36 and 56), or sustained DAPSA LDA (DAPSA LDA at Weeks 36, 44, and 56). Each predictor was evaluated separately in an initial model that included effects for study and concurrent non-bDMARD use. Odds ratios and concordance (c-)statistics were used to determine the predictive accuracy. Statistically significant predictors were then evaluated simultaneously using stepwise logistic regression with the Akaike Information Criterion for model-building.ResultsOf 640 patients included in the analysis, 40% and 47% achieved MDA and DAPSA LDA, respectively, at 56 weeks. Evaluated separately, younger age, sex (male), geographic region, lower weight, lower body mass index, the presence of dactylitis or enthesitis, and lower scores of Patient’s Assessment of Pain (Pt-Pain), Patient’s Global Assessment (PtGA), tender joint count in 68 joints, and Health Assessment Questionnaire-Disability Index (HAQ-DI) were significant baseline predictors for achieving MDA and DAPSA LDA at Week 56. Lower Pt-Pain (Weeks 12–24) and PtGA (Weeks 16–24) scores were strongly predictive (c-statistics >0.8) of achieving MDA at Week 56, and both measures (from Week 8) were moderately predictive (c-statistics >0.7) of achieving DAPSA LDA. Evaluated simultaneously with several baseline characteristics, lower Pt-Pain and HAQ-DI scores at Week 12 were included in models strongly predictive of achieving MDA (c-statistic=0.850; Figure 1) and DAPSA LDA (c-statistic=0.840; Figure 2) at Week 56. For each 1-point increase in Pt-Pain or HAQ-DI scores at Week 12 (after adjusting for other effects in the model), patients were less likely to achieve MDA (by 32% or 56%, respectively) or DAPSA LDA (by 23% or 31%, respectively) at Week 56. Predictors for achieving sustained MDA and sustained DAPSA LDA were generally similar to those identified for achieving MDA and DAPSA LDA, respectively.ConclusionIn patients with PsA receiving UPA 15 mg, baseline characteristics and early responses strongly predicted achievement of MDA or DAPSA LDA at Week 56. This may guide considerations of treatment targets in clinical trials and encourage physicians to further optimize treatment of their patients in clinical practice.References[1]McInnes IB, et al. Ann Rheum Dis 2020;79:16–7.[2]Mease PJ, et al. Rheumatol Ther 2021 [Epub ahead of print].AcknowledgementsAbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Hilary Wong, PhD, of 2 the Nth (Cheshire, UK), which was funded by AbbVie.Disclosure of InterestsDaniel Aletaha Consultant of: AbbVie, Grünenthal, Janssen, Medac, Merck, Mitsubishi/Tanabe, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Grünenthal, Janssen, Medac, Merck, Mitsubishi/Tanabe, Pfizer, Roche, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, and Janssen, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, and Janssen, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, and Janssen, Ralph Lippe Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Frank Behrens Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: Chugai, GlaxoSmithKline, Janssen, Pfizer, and Roche, Derek Haaland Speakers bureau: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, and UCB, Consultant of: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, and UCB, Grant/research support from: AbbVie, Adiga Life Sciences, Amgen, Bristol-Myers Squibb, Can-Fite BioPharma, Celgene, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, Regeneron, Sanofi, and UCB, Penelope Palominos Speakers bureau: AbbVie, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Janssen, Novartis, Pfizer, and UCB, Apinya Lertratanakul Shareholder of: formerly of AbbVie, Employee of: former employee of AbbVie, Michael Lane Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Kevin Douglas Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Peter Nash Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Arthur Kavanaugh Speakers bureau: AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB

Abstract Background Guidelines for immunization following solid organ transplantation discourage live virus vaccination (LVV) in most recipients. Single-center studies support LVV as safe and effective in orthotopic liver transplant (OLT) recipients on steroid-free immunosuppression (IS). We retrospectively evaluated LVV after OLT at 2 pediatric hospitals. Methods Records from OLT recipients between Jan 2007 and Dec 2017 at Lurie Children’s (Chicago) and Children’s Hospital of Philadelphia were reviewed. Patients who underwent OLT at either institution, had ≥ 2 years of follow up, and had documentation of vaccination prior to OLT were included. Adverse events (AEs) within two weeks of receipt of LVV were captured. Factors that might influence the selection of patients for LVV were reviewed, including choice, dose, frequency, and levels of IS medications. IS in non-vaccinated patients was compared to vaccinated patients at two year post-transplant follow-up in both groups using Chi-Square and T-test. Results Data from 249 patients met inclusion criteria. Varicella zoster (VZV) vaccine was given at least once to 92 patients post-transplant, and MMR to 91 (Table 1). Compared to patients who were re-vaccinated after transplant, those who received their first LVV after OLT were transplanted at a younger age (0.8 v 2.2 years) and received LVV sooner post-OLT (649 v 907 days). AEs were rare for either LVV: 2 experienced injection site reaction, 2 localized rash, and 1 had fever. One recipient experienced worsening rejection one month after MMR and received IV steroids and increased IS, but had no clinical findings concerning for viral infection from vaccination. Most LVV recipients were on a single IS agent both at time of LVV and 2 year post-OLT (Table 2), with tacrolimus the most frequent agent. Compared to those that did not received LVV post-OLT, those that did were on one IS agent more often. Tacrolimus levels were similar among patients receiving LVV post-OLT compared with those who did not. Table 1 Table 2 Conclusion In a series of pediatric OLT recipients, post-OLT LVV was generally safe and well tolerated. Patients who received LVV post-OLT were more often on one IS agent at 2 year follow up compared to those who did not. Our study supports prospective efforts to define guidelines for patients who may safely receive LVV after OLT. Disclosures Kevin J. Downes, MD, Merck, Inc. (Grant/Research Support)

Abstract Background: Optical-based imaging modalities play an important role in assessing breast tissue composition by measuring optical property contrast from endogenous chromophores. The advantages of optical techniques are the use of non-ionizing radiation, ease of use, and relatively low cost. The primary objective of this study is to examine changes in optically derived parameters (i.e., deoxy-hemoglobin concentration, ctHHb) from different breast cancer subtypes under neoadjuvant chemotherapy (NAC), and correlate with tumor pathologic complete response (pCR). Methods: This retrospective study evaluated 89 tumors in total divided into three distinct subtypes: HR+/HER2- (n=34), HER2+ (n=27), and TNBC (n=28). All patients were imaged at baseline, before starting NAC (TP0), and two weeks after receiving one cycle of taxane-based chemotherapy (TP1). HER2+ breast cancer patients also received HER2-target therapy. pCR was defined as complete absence of invasive carcinoma in the breast and lymph node(s) (ypT0/is ypN0 Mx) at the time of surgery. Whole breast volume was imaged by a diffuse optical tomography breast imaging system (DOTBIS) using low-intensity near-infrared light. ctHHb tumor volume concentration was normalized by the non-affected health tissue ctHHb mean value (ctHHbN). For each molecular subgroup, we conducted an independent-samples t-test to determine if there was a difference in ctHHbN levels at TP1 compared to TP0 between patients with a pCR and non-pCR. Significance was assumed at a confidence interval of 95% (α = 0.05). Results: In total, 69 patients were imaged with DOTIBS at both time points, TP0 and TP1. HR+/HER2-, TNBC and HER2+ accounted for 32% (n=23), 37% (n=22) and 30% (n=22), respectively. The ratio between ctHHbN levels measured at TP1 and TP0 was statistically significantly lower in the pCR group than non-pCR for the HER2+ and HR+/HER2- molecular subgroups, Table 1. Conclusion: Aligned to the current practices in breast cancer management based on the characterization of breast cancer subtypes, our work evaluated changes in DOTBIS optically derived features and pCR status for different subtypes. We observed that ctHHbN levels change after two weeks of NAC and these changes are modifiable according to pCR status and are dependent on immunophenotype. Table 1.Ratio between ctHHbN levels measured at TP1 and TP0 between pCR and non-pCR according to different molecular subtypes.Molecular SubtypepCR (mean ± SD )non-pCR (mean ± SD )p-valueHR+/HER2- (n=23)0.77 ± 0.22 (n=6)1.14 ± 0.24 (n=17).01HER2+ (n=24)0.74 ± 0.30 (n=15)1.54 ± 0.98 (n=9).04TNBC (n=22)0.96 ± 0.38 (n=4)1.29 ± 0.37 (n=18).18Bold values indicate statistical significance at p<.05 level. Citation Format: Mirella L Altoe, Kevin M Kalinsky, Hua Guo, Hanina Hibshoosh, Mariella Tejada, Katherine D Crew, Melissa K Accordino, Meghna S Trivedi, Alessandro Marone, Hyun K Kim, Andreas H Hielscher, Dawn L Hershman. Prediction of breast cancer response to neoadjuvant chemotherapy in different biological breast cancer subtypes using diffuse optical tomography [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-04.

Abstract Introduction: Cryoablation is a non-surgical approach that uses rapid freeze-thaw cycles to kill cancer cells while preserving tumor-derived antigens. Our recent preclinical study in mice bearing bilateral high-risk metastatic breast tumors revealed cryoablation of the primary tumor enriched tumor-infiltrating lymphocytes in the non-treated abscopal tumor compared to resection, and prolonged overall mouse survival. Thus, it is clinically relevant to define the specific mechanisms by which cryoablation promotes antitumor immunity in abscopal tumors compared to resection. Here, we used RNA-sequencing (RNA-Seq) to identify immune gene signatures associated with enhanced abscopal effect following cryoablation versus resection in a murine model of metastatic breast cancer. Methods: BALB/c mice were implanted orthotopically and bilaterally with 4T1-12B (luciferase-expressing) cells. Two weeks after, left tumors were resected or cryoablated (tumor remained in mouse); right tumors were removed one week posttreatment to assess the abscopal immune response by RNA-Seq. Left tumors resected at two weeks were used as baseline controls. FASTQ files were trimmed and aligned to GRCm39; read counts were analyzed with edgeR and resulting differentially expressed genes with Ingenuity Pathway Analysis. Results: Cryoablation and resection uniquely affected the overall gene signatures and global activation of distinct signaling pathways in abscopal tumors compared to baseline and to each other. Since we observed differences in immune-related pathways, we further examined changes in the tumor immune landscape. Genes of various T cell populations and B cells were more upregulated in abscopal tumors following cryoablation compared to resection, suggesting cryoablation uniquely affects lymphocyte status. Within immune pathways in abscopal tumors following primary tumor cytoablation compared to resection, we found similar activation of Th1 signaling and greater activation of nitric oxide and reactive oxygen species production in macrophages, as well as Th2, NK cell, and IL-7 signaling. By contrast, crosstalk between dendritic cells and NK cells, PD-1/PD-L1 signaling, phagosome formation, and TREM1 signaling were less activated. Within these pathways, genes that promote angiogenesis and immunosuppression (Cxcl2) or metastasis (Cx3cr1) were downregulated in abscopal tumors following cryoablation compared to resection, whereas genes involved in T and NK cell-mediated cytolysis (perforin 1, Prf1), and tumor suppression (Stat6 and Nlrp12), were upregulated. Summary: We identified important pathways and genes involved in tumorigenesis and immune function, which may serve as biomarkers of the abscopal effect induced by cryoablation. Our findings suggest cryoablation reduces immunosuppression while enhancing T cell infiltration and cytotoxicity within abscopal tumors compared to resection. Future in silico and in vivo approaches will further define mechanisms by which cryoablation shapes the abscopal tumor immune landscape. Citation Format: Rachel L. Babcock, Dalia Martinez-Marin, Flavia Sardela de Miranda, Sonia Y. Khan, Maribel Castro, Isabel Castro-Piedras, Kevin Pruitt, Michael W. Melkus, Rakhshanda Layeequr Rahman. Identification of immune gene signatures as potential biomarkers of abscopal effect post-cryoablation of breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B09.

Two days a week, Kevin leaves his office 45 minutes early to take charge of his 2-year-old daughter, Sophie, while her mother, a university professor, teaches a late class. One balmy spring afternoon, Kevin retrieved Sophie at her child-care center and drove the 15-minute route home. Invited to look in on Sophie’s play, I met the pair at the front door and nestled into a rocking chair from which to observe unobtrusively. After downing the last bite of her snack, Sophie grabbed Kevin’s hand and led him across the family room to a rug lined on two sides by shelves filled with books, stuffed animals, and other play props. Sophie moved a toy horse and cow inside a small, enclosed fence that she and Kevin had put together the day before. Then she turned the animals on their sides and moved them toward each other. “Why are horse and cow lying down?” Kevin asked. “’Cause they’re tired,” Sophie answered, pushing the two animals closer together. “Oh, yes,” Kevin affirmed. Then, building on Sophie’s theme, he placed a teddy bear on another part of the rug and offered, “I think Ted’s tired, too. I’m going to start a bed over here for some other animals.” Sophie turned toward the teddy bear, lifted his paw, and exclaimed, “She wants a lollipop to hold in her hand!” “A lollipop in her hand? We haven’t got any lollipops, have we?” answered Kevin. “Laura has!” declared Sophie, glancing at me. “Has Laura got a lollipop?” Kevin queried. “Yes! She’s got all of those, and a swing and a table, too!” Sophie remarked, referring to my chair, which rocked back and forth next to an end table. “Maybe this could be a make-believe lollipop,” suggested Kevin, placing a round piece on the end of a long TinkerToy stick and handing the structure to Sophie “That’s a lollipop,” agreed Sophie, placing it in the paw of the teddy bear. “Can she suck that while she’s going off to sleep?” asked Kevin. “Do you think that’s what she wants?” “It’s a pacifier,” explained Sophie, renaming the object.

Eines der einflussreichsten Bücher der westlichen Philosophie ist die Politeia von Platon – meist mit „Der Staat“ übersetzt. Leicht ist erkennbar, dass das Werk viel mehr als politische Philosophie enthält – der Beitrag fasst insgesamt zwölf Argumente dafür zusammen, dass es überhaupt keine überzeugende politische Philosophie enthält. Die erkenntnistheoretischen, metaphysischen und anthropologischen Voraussetzungen und Argumente der Politeia erlauben keine adäquate Beschreibung und Reflexion der Natur eines Staates, noch seines Bezugs zu den Individuen, die ihn konstituieren, noch des Charakters politischer Institutionen oder der politischen Sphäre an sich.Selbst wenn angenommen wird, dass die erste Absicht des Werks gewesen sei, Gerechtigkeit und Moralität auf individualethischer Ebene zu begründen, verhindern die idealistischen und dualistischen Grundelemente ein Verständnis von Tugenden und Handlungsnormen.Erst recht ist es unmöglich, den Staat aufgrund der Prämissen der Politeia selbst zu konstruieren oder theoretisch zu rekonstruieren. Das Scheitern Platons als politischer Berater verdankt sich nicht oder nicht nur kontingenten historischen Faktoren, sondern vor allem den Defiziten seiner politischen Theorie.

The Ultra stable Low-noise Current Amplifier (ULCA) is a user-friendly and superior alternative to existing instruments for small direct currents in the range between about 1 fA and 5 μA. The principle of the portable laboratory table-top device, operated at room temperature, is based on a novel dual-stage transimpedance amplifier concept. The total transimpedance of 1 GO is calibrated with a cryogenic current comparator with an uncertainty < 0.1 μO/O traceable to the quantum Hall resistance. The output voltage is measured with a voltmeter calibrated traced to the Josephson voltage standard. In addition to its electrometer function, in combination with a voltage source the ULCA also can be used as a current generator. Therefore, it represents a new tool for ultra-accurate small-current measurement and generation traceable to quantum electrical standards. It outperforms commercial devices and calibration setups used in metrology institutes by up to two orders of magnitude in accuracy. The unique features of the ULCA are the excellent stability of its transimpedance (drift less than 5 μO/O per year, short-term fluctuations over one week< 0.1 μO/O), its small temperature coefficient (typically about 0.2 μO/O per Kelvin), fast settling(difference to final value < 0.1 μA/A after 3 s), and the low input current noise of 2.4 fA/vHz. This enables measuring a direct current of 100 pA with a total relative uncertainty of 0.1 μA/A in about 10 h. Besides being excellently suited for R&D in small-current metrology (e.g. for research on single-electron pumps) the ULCA is also widely applicable for calibrations, for instance for electrometers, small-current sources, or high-value resistors. Corresponding fields (and specific examples) are electronic industry (ICs), medicine and biotechnology (dosimetry, radiation protection, DNA sequencers) as well as environmental monitoring (concentration measurements of small particles in air or aerosols), and lighting industry (photo current measurement). Framed by two patent applications, the technology was transferred from the Physikalisch-Technische Bundesanstalt (PTB) to a German company (Magnicon GmbH, Hamburg), which manufactures and markets the ULCA since 2016 licensed by PTB.