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3. The judicial harmonisation of national remedies and procedural rules in a differentiated Europe

Author

Dougan, M.

Subjects
340
Abstract

A traditional 'integration through law' approach to EC legal studies portrays national remedies and procedural rules as a serious problem for the Community legal order: they offer fragmented standards of judicial protection in respect of Treaty norms being implemented at a domestic levels, and thus distort competitive conditions within the Common Market and / or undermine the principle of equal treatment between Union citizens. The purported solution is to manufacture a harmonised system of legal protection within Europe. Yet the recent history of European union suggests that the assumptions of "integration" and "uniformity" upon which this analysis is based are now ripe for reconsideration. The alternative values of "disintegration" and "differentiation" have attained the status of central regulatory principles within the Community legal order, and prompt a process of doctrinal reconsideration, seeking to update certain assumptions about the Treaty system which are too closely wedded to an untenable ideal of integration. Within the particular sphere of Community intervention in the domestic systems of judicial protection, this process of doctrinal reconsideration suggests that we should abandon the predominant "integration through law" in favour of an alternative "sectoral" approach. The Treaty's pursuit of uniformity at a substantive level, and thus its need for uniformity at a remedial level, changes according to the field of Community activity in question. In some sectors (such as state aids and competition law), uniformity remains a valid goal of Treaty policy, and the harmonisation of domestic remedies and procedural rules might well seem justified. In other sectors (such as environmental consumer and employee protection), the Treaty does not harbour ambitions of achieving any genuine degree of normative uniformity, and the principles of subsidiary and proportionality suggest that we should adopt a correspondingly more restrained interpretation of the need for remedial approximation. These two completing academic models provide the framework for a critical analysis of the European Court of Justice's caselaw on national remedies and procedural rules. Such an analysis demonstrates, in particular, that the Court's most recent jurisprudence rejects implicitly the pressure of greater remedial harmonisation exerted by an "integration through law" approach. Instead, the ECJ seems sympathetic to the challenges of doctrinal reconsideration stimulated by the rise of regulatory differentiation within the Community legal order: its caselaw reflects a more limited sympathy with the imperative of uniformity, such as forms the basic conceptual premises of the alternative "sectoral" model.

Published
2002

7. Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation

Author

Heckler, M, Ali, LR, Clancy-Thompson, E, Qiang, L, Ventre, KS, Lenehan, P, Roehle, K, Luoma, A, Boelaars, K, Peters, V, McCreary, J, Boschert, T, Wang, ES, Suo, S, Marangoni, F, Mempel, TR, Long, HW, Wucherpfennig, KW, Dougan, M, Gray, NS, Yuan, G-C, Goel, S, Tolaney, SM, Dougan, SK, Heckler, M, Ali, LR, Clancy-Thompson, E, Qiang, L, Ventre, KS, Lenehan, P, Roehle, K, Luoma, A, Boelaars, K, Peters, V, McCreary, J, Boschert, T, Wang, ES, Suo, S, Marangoni, F, Mempel, TR, Long, HW, Wucherpfennig, KW, Dougan, M, Gray, NS, Yuan, G-C, Goel, S, Tolaney, SM, and Dougan, SK

Abstract

CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity. SIGNIFICANCE: CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade.This article is highlighted in the In This Issue feature, p. 2355.

Published
2021

9. High temperature sintering and its effect on dimensional and geometrical precision and on microstructure of low alloyed steels

Author

Toledo, D., primary, Cristofolini, I., additional, Molinari, A., additional, Arnhold, V., additional, Kruzhanov, V., additional, Vervoort, P., additional, Dougan, M., additional, Wimbert, L., additional, Bonnefoy, V., additional, Hellein, R., additional, Weber, H., additional, Baumgärtner, F., additional, Sicre, J., additional, Larsson, C., additional, and Schneider, M., additional

Published
2020
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11. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19.

Author

Dougan, M., Nirula, A., Azizad, M., Mocherla, B., Gottlieb, R. L., Chen, P., Hebert, C., Perry, R., Boscia, J., Heller, B., Morris, J., Crystal, C., Igbinadolor, A., Huhn, G., Cardona, J., Shawa, I., Kumar, P., Adams, A. C., Van Naarden, J., and Custer, K. L.

Abstract

Background: Patients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications.Methods: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19-related hospitalization or death from any cause by day 29.Results: A total of 1035 patients underwent randomization and received an infusion of bamlanivimab-etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab-etesevimab group had a Covid-19-related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, -4.8 percentage points; 95% confidence interval [CI], -7.4 to -2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab-etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19-related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, -1.20; 95% CI, -1.46 to -0.94; P<0.001).Conclusions: Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19-related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.). [ABSTRACT FROM AUTHOR]

Published
2021
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12. Anti-CTLA-4 therapy requires an Fc domain for efficacy

Author

Ingram, J.R., Blomberg, O.S., Rashidian, M., Ali, L., Garforth, S., Fedorov, E., Fedorov, A.A., Bonanno, J.B., Gall, C.M. le, Crowley, S., Espinosa, C., Biary, T., Keliher, E.J., Weissleder, R., Almo, S.C., Dougan, S.K., Ploegh, H.L., Dougan, M., Ingram, J.R., Blomberg, O.S., Rashidian, M., Ali, L., Garforth, S., Fedorov, E., Fedorov, A.A., Bonanno, J.B., Gall, C.M. le, Crowley, S., Espinosa, C., Biary, T., Keliher, E.J., Weissleder, R., Almo, S.C., Dougan, S.K., Ploegh, H.L., and Dougan, M.

Abstract

Item does not contain fulltext, Ipilimumab, a monoclonal antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved "checkpoint"-blocking anticancer therapy. In mouse tumor models, the response to antibodies against CTLA-4 depends entirely on expression of the Fcgamma receptor (FcgammaR), which may facilitate antibody-dependent cellular phagocytosis, but the contribution of simple CTLA-4 blockade remains unknown. To understand the role of CTLA-4 blockade in the complete absence of Fc-dependent functions, we developed H11, a high-affinity alpaca heavy chain-only antibody fragment (VHH) against CTLA-4. The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically. We used H11 to visualize CTLA-4 expression in vivo using whole-animal immuno-PET, finding that surface-accessible CTLA-4 is largely confined to the tumor microenvironment. Despite this, H11-mediated CTLA-4 blockade has minimal effects on antitumor responses. Installation of the murine IgG2a constant region on H11 dramatically enhances its antitumor response. Coadministration of the monovalent H11 VHH blocks the efficacy of a full-sized therapeutic antibody. We were thus able to demonstrate that CTLA-4-binding antibodies require an Fc domain for antitumor effect.

Published
2018

13. Transnuclear TRP1-Specific CD8 T Cells with High or Low Affinity TCRs Show Equivalent Antitumor Activity

Author

Massachusetts Institute of Technology. Department of Biology, Kim, Jun, Dougan, S. K., Dougan, M., Turner, J. A., Ogata, S., Cho, H.-I., Jaenisch, R., Celis, E., Ploegh, H. L., Massachusetts Institute of Technology. Department of Biology, Kim, Jun, Dougan, S. K., Dougan, M., Turner, J. A., Ogata, S., Cho, H.-I., Jaenisch, R., Celis, E., and Ploegh, H. L.

Abstract

We have generated, via somatic cell nuclear transfer, two independent lines of transnuclear (TN) mice, using as nuclear donors CD8 T cells, sorted by tetramer staining, that recognize the endogenous melanoma antigen TRP1. These two lines of nominally identical specificity differ greatly in their affinity for antigen (TRP1(high) or TRP1(low)) as inferred from tetramer dissociation and peptide responsiveness. Ex vivo-activated CD8 T cells from either TRP1(high) or TRP1(low) mice show cytolytic activity in 3D tissue culture and in vivo, and slow the progression of subcutaneous B16 melanoma. Although naïve TRP1(low) CD8 T cells do not affect tumor growth, upon activation these cells function indistinguishably from TRP1(high) cells in vivo, limiting tumor cell growth and increasing mouse survival. The anti-tumor effect of both TRP1(high) and TRP1(low) CD8 T cells is enhanced in RAG-deficient hosts. However, tumor outgrowth eventually occurs, likely due to T cell exhaustion. The TRP1 TN mice are an excellent model for examining the functional attributes of T cells conferred by TCR affinity, and they may serve as a platform for screening immunomodulatory cancer therapies.

Published
2018

16. Europe in Times of Economic Crisis: Bringing Europe's Citizens Closer to One Another?

Author

Amtenbrink, Fabian, Dougan, M., Shuibhne, N.N., Spaventa, E, and Erasmus School of Law

Abstract

Despite its huge consequences for European integration, European Economic and Monetary Union (EMU) has not, until recently, gained the attention of as many legal academics as other supposedly more mainstream areas of European Union law. Even after the establishment of the European System of Central Banks and the introduction of a single currency, the implications of EMU are primarily discussed in terms of the effectiveness and efficiency of the legal framework and its economic implications. While the shortcomings of the present regulatory system, which have contributed to the Euro zone debt crisis since 2010, certainly justify such analyses, they deflect from the question whether and to what extent EMU actually contributes to European integration, as defined by the Treaty on European Union in terms of a `process of creating an ever closer union among the peoples of Europe. A Union in which decisions are taken as openly as possible and as closely as possible to the citizen¿ and that promotes economic, social and territorial cohesion, and solidarity among its Member States and its citizens. It is at least not self-evident that EMU actually contributes to the identification of the citizens of the Member States with the European project. In fact, one may wonder whether the Euro zone debt crisis actually provides evidence to the contrary. This contribution explores whether and to what extent in times of (economic) crisis the policies exercised at the supranational level have the potential to contribute to or indeed undermine the appreciation of the European Union by its citizens and, in the long term, the emergence of a transnational citizenship beyond the creation and upholding of rights. In addressing these questions, two fairly distinct topics in European integration studies are connected, namely the conduct of macroeconomic and monetary policy in the EU and the discourse on the existing or perceived lack of identification with and ownership by the citizens in relation to European policies and supranational integration as such. In this chapter, therefore, the debate on the existence or emergence of a European demos is first recalled, thereby reflecting on the notion of the `European citizen¿ and exploring the role that common goods and solidarity may have in this context. Thereafter, it is explored whether and to what extent EMU pursues `common goods¿ that bring citizens closer to Europe and each other, thereby creating solidarity among Europeans. Finally, the contribution seeks an answer to the question whether the current Euro zone debt crisis is uniting Member States and their citizens in solidarity in pursuing these common goods in defense of the aims of European integration. The legal analysis will be enriched with relevant references to political science and political economy scholarship, adding a multidisciplinary dimension to the contribution.

Published
2012

25. Molecular Tracer Dynamics in Crystalline Organic Films at the Solid−Liquid Interface

Author

Padowitz, D. F., Sada, D. M., Kemer, E. L., Dougan, M. L., and Xue, W. A.

Abstract

A molecular tracer method for scanning tunneling microscopy allowed the observation of individual molecular events at a crystal surface in solution. Long-chain alkanes or ethers were coadsorbed with similar length thioethers on a graphite surface. Due to the distinctive contrast of the sulfur atoms, it was possible to track individual thioether tracer molecules. The exchange of tracer molecules between the adsorbed monolayer and the overlying solution was measured at equilibrium. Rates depended on chain length, temperature, and neighboring molecules. Tracers at boundaries between crystal domains revealed specific molecular processes driving boundary fluctuations and domain growth. In addition to adsorption−desorption driven rearrangements, collective motion within the monolayer has been seen. Longer chain ethers exhibit two phases having different molecular configurations at grain boundaries and different microstructural habits. Transition between phases was promoted by the scanning probe.

Published
2002

31. Towards a clearer delimitation of internal European Community competences

Author

Konstadinides, T., O'Keeffe, D., Oliver, D., Dougan, M., and Ashiagbor, D.

Subjects
337.1
Abstract

This thesis is a study of the distribution of competences between the main actors in European integration: namely the European Community and the Member States. It aims to evaluate the place of the competence provisions in the current Treaty structure as well as within the Treaty Establishing a Constitution for Europe. This task first involves a legal-technical exercise based on a textual interpretation of different categories of competences within the above-mentioned sources. Second, it involves a review of the relevant Court of Justice case law with regard to those competences. The study of both has led the author to consider how the evolution of Community competence has given rise to the phenomenon of 'competence' creep'. It is argued that Member States contend that the Community assumes more powers than those it possesses. Thus, the thesis provides an insight into concerns about 'creeping competence'. Certain types of situations are identified under the title of 'creeping competence'. These include, the adoption of unjustified or undesired EC legislation under qualified majority voting the expansion of the Community's competence under Article 308 EC and finally the adoption of EC legislation that goes beyond the scope of Article 5 EC (principle of attribution of powers). The thesis will provide certain examples to underline the problem. It will take account of the use of the flexibility provisions of Article 95 EC and 308 EC with regard to the regulation of health and the Community's accession to the European Convention of Human Rights (ECHR), which are treated as case studies in the thesis. In the context of a problematic system of competences, the author will consider the assumptions made in the Nice and Laeken IGCs as well as the European Convention for a clearer distribution of competence and assess the role of the principle of subsidiarity as a tool against the expansion of Community competence into new policy areas. It is argued that the reform of subsidiarity will enhance EU legitimacy and enlarge the role of national legislatures in the Union. The reconstruction of subsidiarity procedures may remedy the tensions in the current system of competence and provide limits to the degree of EU intervention. Besides tidying up competences between the EU and Member States, European Constitutionalisation hides a question of political finality and further integration. How can the EU establish an effective and democratically legitimate governance beyond the Nation State Via a European Constitution or through alternative methods This question is particularly important in the current context following the French and Dutch rejection of the EU Constitutional Treaty. The chances of the EU Constitution being revived in the near future are slim, since it is unlikely that either France or Holland will soon hold another referendum. Thus, either a period of reflection shall be allowed to Member States or alternative routes to integration shall be considered. The thesis concludes with the hypothesis that as the EU Constitutional Treaty does not provide the answers to most of the questions posed by the Nice and the Laeken European Councils, enhanced cooperation may be utilised as a future method of governance and Fischer's 'Core Europe' as a tool capable of a redistribution of competences inside the Union. But then again the European Union needs to avoid a new iron curtain descending between those Member States that represent the 'core' and those that constitute the 'periphery'.

Published
2006

32. The European precariat

Author

Carter, D.W., Tobler, R.C., Jesse, M., Dougan, M., Nic Shuibhne, N., Van den Bogaert, S., Kosta, V., and Leiden University

Subjects
Employment Law, Social Security Law, Social Law, European Union Law, European Union Citizenship, The Free Movement of Workers, Migration Law, Bogus Self-employment, Precarious Employment
Abstract

The traditional concept of employment, which involved fixed, permanent contracts, with full time hours and security in work has gradually been replaced by a ‘neoliberal’ model of employment that prioritises the development of competitive labour markets through increased flexibility in work⁠. This shift has resulted in increasing levels of ‘precarious’ work: forms on non-standard employment that places the individual in a situation where they have little security in work or power over their working situation⁠. Examples of precarious employment include platform work, zero-hour and on-demand contracts, the repeated use of temporary⁠/short-term contracts, and bogus⁠/false self-employment⁠.The European Precariat asks what level of protection is available to EU migrant workers engaged in precarious employment, who must navigate complex national migration and social security rules linked to their employment status⁠. The thesis assesses how economic and political changes affect the constitutional and political limitations of European integration; how the legal framework applicable to precarious workers risks creating gaps in the law and excluding them from certain protections; and finally suggests how EU migrant workers engaged in precarious work can be better protected under EU law while adhering to the economic, political, and constitutional limitations of the legal system⁠.

Published
2023

33. The rules of standing of the European Union: a contextual understanding

Author

Bradford, J, Craig, P, Dougan, M, Goudkamp, J, and Young, A

Subjects
Administrative law--European Union countries, Law, Administrative law
Abstract

This thesis looks at the context surrounding the EU standing rules for the individual applicant. It seeks to build upon the extensive academic literature on this topic, by further exploring how far this context can explain and justify the approach taken towards the rules themselves, which have generally been considered to be restrictive in character. The analysis is conducted by reference to a selection of factors which represent part of the wider constitutional context. The central arguments of this thesis are as follows: first, it is argued that that certain factors of the context (namely the underlying judicial strategy and the role of privileged applicants) go some way towards explaining the narrow approach taken. They also have some capacity (to a limited extent) to qualify one’s perception of the rules’ restrictive impact. This is outlined in Chapter Two. Then in the first part of Chapter Three, I consider the justificatory potential of these factors, exploring how far these elements are able to change the analysis as to whether or not the rules can be justified. It is argued that when they are judged against the standard of effective judicial protection as it emerges from some of the relevant cases then a possible, qualified justification can emerge. However, any such position is qualified by virtue of the various substantive and methodological difficulties with this approach. Secondly, this thesis contends that when we look at the standard of practical access to justice, the rules remain unjustifiable (even when we see them with the benefit of the contextual factors identified); in this sense they remain ‘overly narrow’. Consequently, the final part of Chapter Three offers some qualified avenues of reform for amending this context and improving the practical impact of these standing rules for the individual applicant.

Published
2022

34. The future shape of EU energy law and policy

Author

Johnston, A, Arnull, A, Barnard, C, Dougan, M, and Spaventa, E

Abstract

Before I had even arrived in Cambridge as a young lecturer in my first full-time academic post, Alan Dashwood had extended the hand of friendship. Soon after I arrived, we began our first coauthored project together, and I have been fortunate to enjoy his guidance, support and friendship ever since. He has always kindly indulged my perhaps more maverick legal interests, yet has also consistently insisted that energy law does not fall into that category. I am immensely grateful for all of this and hope that I may crave his indulgence one more time with this contribution on the future of EU energy law and policy. The twin themes of this chapter will be, first, the need for careful accommodation at the EU level of the diversity of Member State interests and concerns in the energy field (thus respecting the nature of the EU as a ‘constitutional order of states’) and, second, the slow but real shift in EU (and some national) energy law and policy away from reliance upon market mechanisms and towards more complex regimes (involving market and other regulatory tools) to achieve a myriad of public interest goals.

Published
2022

35. Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease

Author

Guy Ben-Betzalel, Wei Qiao, Justine V. Cohen, Sarah A. Weiss, Lisa Manuzzi, Ibraheim Hajir, Mark P. Lythgoe, Douglas B. Johnson, Sai Ching J. Yeung, David Faleck, Gal Markel, Michael Dougan, Dwight H. Owen, Jiajia Zhang, Giulia Costanza Leonardi, Mark M. Awad, Christina A. Arnold, Robin B. Mendelsohn, Hamzah Abu-Sbeih, MacLean C. Sellers, Giuseppe Lamberti, Nick Powell, Elad Sharon, Biagio Ricciuti, Abdul Rafeh Naqash, Jarushka Naidoo, David J. Pinato, Yinghong Wang, Aanika Balaji, Abu-Sbeih H., Faleck D.M., Ricciuti B., Mendelsohn R.B., Naqash A.R., Cohen J.V., Sellers M.C., Balaji A., Ben-Betzalel G., Hajir I., Zhang J., Awad M.M., Leonardi G.C., Johnson D.B., Pinato D.J., Owen D.H., Weiss S.A., Lamberti G., Lythgoe M.P., Manuzzi L., Arnold C., Qiao W., Naidoo J., Markel G., Powell N., Yeung S.-C.J., Sharon E., Dougan M., Wang Y., and Wellcome Trust

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Immune checkpoint inhibitors, Immunology, MEDLINE, Inflammatory bowel disease, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Internal medicine, Neoplasms, Original Reports, medicine, Humans, In patient, Adverse effect, Aged, Retrospective Studies, Science & Technology, business.industry, Cancer, Retrospective cohort study, Middle Aged, medicine.disease, Inflammatory Bowel Diseases, 030104 developmental biology, Multicenter study, N/A, 030220 oncology & carcinogenesis, Female, Immunotherapy, business, Life Sciences & Biomedicine
Abstract

PURPOSE The risk of immune checkpoint inhibitor therapy–related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors. PATIENTS AND METHODS We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events. RESULTS Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn’s disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event–related deaths were recorded. Anti–cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively). CONCLUSION Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.

Published
2019

37. The transformation of the euro

Author

Borger, V., Van den Bogaert, S.C.G., Rijpma, J.J., Middelaar, L.J. van, Dougan, M., Mendes, J., Smulders, B.M.P., and Leiden University

Subjects
EU law constitutional transformation, Political obligation, Euro, Monetary union, ECB
Abstract

Over the past years, during the debt crisis, the euro has changed profoundly. As a result, it now differs fundamentally from what it was when it was introduced in the early 1990s by the Treaty of Maastricht. Characteristic of this change is a broadening of the currency union’s conception of stability. Whereas it used to grant overriding importance to price stability, it now also explicitly takes into account financial stability. Financial assistance operations for distressed member states and government bond purchases by the European Central Bank are the essential manifestations of this change. Surprisingly, this has come about with hardly any formal amendment to the Union’s ‘basic constitutional charter’, the Treaties. How, then, to understand this change? This dissertation argues that the Union has gone through a constitutional transformation, which occurs when constitutions change shape without formal amendment. Using solidarity as its lens, it conceptualises the unity between the member states and analyses how it was preserved during the crisis. It then goes on to show how this substantively changed the euro’s set-up and why, ultimately, the Court of Justice could not turn against this change in Pringle and Gauweiler.

Published
2018

39. ‘Wish You Weren’t Here…’ New Models of Social Solidarity in the European Union

Author

Eleanor Spaventa, Michael Dougan, Spaventa, E., and Dougan, M.

Subjects
European Union law, Social welfare, Union citizenship, SOCIAL WELFARE, Wish, EU LAW, EUROPEAN CITIZENSHIP, Social Welfare, European law, European studies, Social solidarity, Solidarity, EU LAW, SOCIAL WELFARE, SOLIDARITY, EUROPEAN CITIZENSHIP, Political economy, Political science, SOLIDARITY, European integration, media_common.cataloged_instance, European union, Economic system, media_common
Published
2014

43. Peptide-MHC-targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells.

Author

Xu EJK, Smith BE, Conce Alberto WD, Walsh MJ, Lim B, Hoffman MT, Qiang L, Dong J, Garmilla A, Zhao QH, Perez CR, Gaglione SA, Dobson CS, Dougan M, Dougan SK, and Birnbaum ME

Abstract

Tumor-infiltrating-lymphocyte (TIL) therapy has demonstrated that endogenous T cells can be harnessed to initiate an effective anti-tumor response. Despite clinical promise, current TIL production protocols involve weeks-long ex vivo expansions which can affect treatment efficacy. Therefore, additional tools are needed to engineer endogenous tumor-specific T cells to have increased potency while mitigating challenges of manufacturing. Here, we present a strategy for pseudotyping retroviral vectors with peptide-major histocompatibility complexes (pMHC) for antigen-specific gene delivery to CD8 T cells and examine the efficacy of these transduced cells in immunocompetent mouse models. We demonstrate that pMHC-targeted viruses are able to specifically deliver function-enhancing cargoes while simultaneously activating and expanding anti-tumor T cells. The specificity of these viral vectors enables in vivo engineering of tumor-specific T cells, circumventing ex vivo manufacturing processes and improving overall survival in B16F10-bearing mice. Altogether, we have established that pMHC-targeted viruses are efficient vectors for reprogramming and expanding tumor-specific populations of T cells directly in vivo , with the potential to substantially streamline engineered cell therapy production for a variety of applications.

Published
2024
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44. Enhancing Precision in Detecting Severe Immune-Related Adverse Events: Comparative Analysis of Large Language Models and International Classification of Disease Codes in Patient Records.

Author

Sun VH, Heemelaar JC, Hadzic I, Raghu VK, Wu CY, Zubiri L, Ghamari A, LeBoeuf NR, Abu-Shawer O, Kehl KL, Grover S, Singh P, Suero-Abreu GA, Wu J, Falade AS, Grealish K, Thomas MF, Hathaway N, Medoff BD, Gilman HK, Villani AC, Ho JS, Mooradian MJ, Sise ME, Zlotoff DA, Blum SM, Dougan M, Sullivan RJ, Neilan TG, and Reynolds KL

Abstract

Purpose: Current approaches to accurately identify immune-related adverse events (irAEs) in large retrospective studies are limited. Large language models (LLMs) offer a potential solution to this challenge, given their high performance in natural language comprehension tasks. Therefore, we investigated the use of an LLM to identify irAEs among hospitalized patients, comparing its performance with manual adjudication and International Classification of Disease (ICD) codes., Methods: Hospital admissions of patients receiving immune checkpoint inhibitor (ICI) therapy at a single institution from February 5, 2011, to September 5, 2023, were individually reviewed and adjudicated for the presence of irAEs. ICD codes and an LLM with retrieval-augmented generation were applied to detect frequent irAEs (ICI-induced colitis, hepatitis, and pneumonitis) and the most fatal irAE (ICI-myocarditis) from electronic health records. The performance between ICD codes and LLM was compared via sensitivity and specificity with an α = .05, relative to the gold standard of manual adjudication. External validation was performed using a data set of hospital admissions from June 1, 2018, to May 31, 2019, from a second institution., Results: Of the 7,555 admissions for patients on ICI therapy in the initial cohort, 2.0% were adjudicated to be due to ICI-colitis, 1.1% ICI-hepatitis, 0.7% ICI-pneumonitis, and 0.8% ICI-myocarditis. The LLM demonstrated higher sensitivity than ICD codes (94.7% v 68.7%), achieving significance for ICI-hepatitis ( P < .001), myocarditis ( P < .001), and pneumonitis ( P = .003) while yielding similar specificities (93.7% v 92.4%). The LLM spent an average of 9.53 seconds/chart in comparison with an estimated 15 minutes for adjudication. In the validation cohort (N = 1,270), the mean LLM sensitivity and specificity were 98.1% and 95.7%, respectively., Conclusion: LLMs are a useful tool for the detection of irAEs, outperforming ICD codes in sensitivity and adjudication in efficiency.

Published
2024
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45. Blockade of IL1β and PD1 with Combination Chemotherapy Reduces Systemic Myeloid Suppression in Metastatic Pancreatic Cancer with Heterogeneous Effects in the Tumor.

Author

Oberstein PE, Dias Costa A, Kawaler EA, Cardot-Ruffino V, Rahma OE, Beri N, Singh H, Abrams TA, Biller LH, Cleary JM, Enzinger P, Huffman BM, McCleary NJ, Perez KJ, Rubinson DA, Schlechter BL, Surana R, Yurgelun MB, Wang SJ, Remland J, Brais LK, Bollenrucher N, Chang E, Ali LR, Lenehan PJ, Dolgalev I, Werba G, Lima C, Keheler CE, Sullivan KM, Dougan M, Hajdu C, Dajee M, Pelletier MR, Nazeer S, Squires M, Bar-Sagi D, Wolpin BM, Nowak JA, Simeone DM, and Dougan SK

Subjects
Humans, Male, Female, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized pharmacology, Aged, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Deoxycytidine therapeutic use, Deoxycytidine administration & dosage, Middle Aged, Gemcitabine, Tumor Microenvironment immunology, Tumor Microenvironment drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, Paclitaxel therapeutic use, Paclitaxel administration & dosage, Paclitaxel pharmacology, Neoplasm Metastasis, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal immunology, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology, Pancreatic Neoplasms immunology, Interleukin-1beta antagonists & inhibitors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells drug effects, Myeloid-Derived Suppressor Cells metabolism, Programmed Cell Death 1 Receptor antagonists & inhibitors
Abstract

Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Herein, we report clinical and translational results from a phase Ib trial testing whether IL1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n = 10) were treated with canakinumab, a high-affinity monoclonal human antiinterleukin-1β (IL1β), the PD1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSC) by flow cytometry for patients in the trial but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor, we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD1 and IL1β blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment., (©2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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46. Mandating COVID-19 Vaccination on Campus: A Qualitative Analysis of a Cross-Sectional Study of California College Students.

Author

Buckner-Capone A and Dougan M

Subjects
Humans, Cross-Sectional Studies, California, Universities, Male, Female, Young Adult, SARS-CoV-2, Vaccination psychology, Adolescent, Adult, Mandatory Programs, Trust, Health Knowledge, Attitudes, Practice, Students psychology, Qualitative Research, COVID-19 Vaccines administration & dosage, COVID-19 prevention & control
Abstract

The purpose of this study was to examine college student perceptions related to institutional vaccine mandates. We utilized qualitative data ( n = 2,212) from five open-ended questions in a cross-sectional study of students enrolled or intending to enroll in an institute of higher education in California in fall 2021. Data were collected between June and August 2021. Thematic analysis was employed to analyze student beliefs, and four themes were developed from the data: (1) Polarizing views and language, (2) deciding who to trust, (3) conveying rights and risk, and (4) staying focused on education. The themes represented vaccinated and nonvaccinated student perspectives, capturing views about trust, rights, and risk. Many responses were polarizing and included language that was emotional and political. Despite the range of responses, most students expressed appreciation and approval of the vaccination mandate on college campuses. Findings illustrate the important contributions of qualitative research and suggest opportunities for public health practitioners to lead and engage in critical dialogue about science and public health practices as we aim to promote public perceptions of vaccination programs and health promotion practice.

Published
2024
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47. Anti-LAG-3 boosts CD8 T cell effector function.

Author

Kureshi CT, Dougan M, and Dougan SK

Subjects
Humans, Animals, Mice, Melanoma immunology, Melanoma drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Programmed Cell Death 1 Receptor immunology, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Lymphocyte Activation Gene 3 Protein, CD8-Positive T-Lymphocytes immunology, Antigens, CD metabolism, Antigens, CD immunology
Abstract

LAG-3 is the third immune checkpoint pathway successfully targeted for cancer therapy. Although ineffective as a monotherapy, combination of LAG-3 and PD-1 blockade improves survival from advanced melanoma. In this issue of Cell, two studies in mice and a human clinical trial provide insights on LAG-3 in immune regulation., Competing Interests: Declaration of interests S.K.D. received research funding unrelated to this project from Novartis, Bristol-Myers Squibb, and Takeda and is a founder, science advisory board member, and equity holder in Kojin and has equity in Axxis Bio. M.D. has research funding from Eli Lilly; he has received consulting fees from Genentech, ORIC Pharmaceuticals, Partner Therapeutics, SQZ Biotech, AzurRx, Eli Lilly, Mallinckrodt Pharmaceuticals, Aditum, Foghorn Therapeutics, Palleon, and Moderna; and he is a member of the Scientific Advisory Board for Neoleukin Therapeutics, Veravas, and Cerberus Therapeutics and has equity in Axxis Bio., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
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48. Novel endoscopic scoring system for immune mediated colitis: a multicenter retrospective study of 674 patients.

Author

Wang Y, Abu-Sbeih H, Tang T, Shatila M, Faleck D, Harris J, Dougan M, Olsson-Brown A, Johnson DB, Shi C, Grivas P, Diamantopoulos L, Owen DH, Cassol C, Arnold CA, Warner DE, Alva A, Powell N, Ibraheim H, De Toni EN, Philipp AB, Philpott J, Sleiman J, Lythgoe M, Daniels E, Sandhu S, Weppler AM, Buckle A, Pinato DJ, Thomas A, and Qiao W

Subjects
Humans, Retrospective Studies, Male, Female, Middle Aged, Adult, Immunosuppressive Agents therapeutic use, Aged, Immunotherapy methods, Sensitivity and Specificity, Ulcer pathology, Colitis pathology, Severity of Illness Index, Colonoscopy methods
Abstract

Background and Aims: No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms., Methods: This retrospective, international, 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned 1 point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCESs, and clinical symptoms were graded according to a standardized instrument., Results: A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4. The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo endoscopic subscore of 3 was 74.6%, and the specificity of clinical symptom grading was much lower at 27.4% and 12.3%, respectively. Early endoscopy was associated with timely SIT use (P < .001; r = 0.4084)., Conclusions: This is the largest multicenter study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff of 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC., Competing Interests: Disclosure The following authors disclosed financial relationships: Y. Wang: Consultant for Sorriso Pharma, MabQuest, AzurRx, Sanarentero, Janssen, IOTA, Ilyapharma, Biontech, and Mallinckrodt Pharma. D. Faleck: Consultant for Kaleido Biosciences, AzurRx, Mallinckrodt Pharmaceuticals, Janssen, Teva, Gilead, Ferring, and Equillium. M. Dougan: Research funding Eli Lilly; consulting fees from Genentech, Partner Therapeutics, SQZ Biotech, AzurRx, Eli Lilly, Mallinckrodt Pharmaceuticals, Aditum, Foghorn Therapeutics, Palleon, Sorriso Pharmaceuticals, Generate Biomedicines, Asher Bio, Neoleukin Therapeutics, Moderna, Alloy Therapeutics, Third Rock Ventures, DE Shaw Research, Agenus, and Curie Bio; member of the Scientific Advisory Board for Veravas, Monod Bio, Axxis Bio, and Cerberus Therapeutics. D. B. Johnson: Served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko; research funding from BMS and Incyte; patents pending for the use of MHC-II as a biomarker for immune checkpoint inhibitor response and abatacept as a treatment for immune-related adverse events. P. Grivas: Funding from Acrivon Therapeutics, ALX Oncology, Bavarian Nordic, Bristol-Myers Squibb, Clovis Oncology, Debiopharm; Genentech, Gilead, GlaxoSmithKline, G1 Therapeutics, Merck KGaA, Mirati Therapeutics, MSD, Pfizer, and QED Therapeutics. Consultant for Aadi Bioscience, Abbvie, AstraZeneca, Asieris Pharmaceuticals, Astellas Pharma, Bristol-Myers Squibb, Boston Gene, CG Oncology, Dyania Health, Lucence Health, Fresenius Kabi, G1 Therapeutics, Gilead, Guardant Health, ImmunityBio, Janssen, Merck KGaA, MSD, Pfizer, PureTech, Roche, SeaGen, Strata Oncology, and Silverback Therapeutics. D. Owen: Research funding (to institution) from Merck, BMS, Pfizer, Genentech, Palobiofarma, and Onc.AI. N. Powell: Speaker for Allergan, Bristol Myers Squibb, Falk, Ferring, Janssen, Pfizer, Tillotts, and Takeda; consultant and/or advisory board member for AbbVie, Allergan, Celgene, Bristol Myers Squibb, Ferring, and Vifor Pharma. J. Philpott: Speaker for AbbVie. S. Sandhu: Grants from Novartis/AAA, Astra Zeneca, Merck Sharp and Dohme, and Genentech; personal fees from Astra Zeneca; and personal fees to the institution from Merck Sharp and Dohme, Bristol Myer Squibb, and personal fees to the institution from Astra Zeneca, outside the submitted work. D. J. Pinato: Grant funding from the Wellcome Trust Strategic Fund (PS3416), the Foundation for Liver Research, and the Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG grant ID 25697); support from the NIHR Imperial Biomedical Research Centre, Imperial Experimental Cancer Medicine Centre, and Imperial College Tissue Bank; lecture fees from ViiV Healthcare, Bayer Healthcare, Bristol Myers Squibb, Roche, EISAI, and Falk Foundation; travel expenses from Bristol Myers Squibb, Bayer Healthcare, and Viiv Healthcare; consultant for Bayer Healthcare, Bristol Myers Squibb, Mina Therapeutics, H3B, EISAI, Roche, DaVolterra, Mursla, Exact Sciences, Avamune, and AstraZeneca; and research funding (to his institution) from MSD, Bristol Myers Squibb, and GSK. A. Olsson-Brown: Speaker/consultant for Bristol Myers Squibb, MSD, Novartis, Eiasi, and Merck/Pfizer; speaker for Roche, AZ, GSK, Ipsen, and Boehringer Ingram. C. Cassol: Grant funding from Novartis, Iptacopan Educational Steering Committee, Nephrology, and SBIR. All other authors disclosed no financial relationships. This study was supported by the National Institutes of Health/National Cancer Institute under award number P30CA016672 for institutional review board review service; otherwise, no additional grant support was received for conducting the study., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Published
2024
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49. The Development of Persistent Gastrointestinal Symptoms in Patients With Melanoma Who Have Had an Immune Checkpoint Inhibitor-Related Gastrointestinal Toxicity.

Author

Varma S, Sullivan K, DiCarlo J, Coromilas A, Staller K, and Dougan M

Subjects
Humans, Male, Female, Retrospective Studies, Middle Aged, Aged, Incidence, Adult, Diarrhea chemically induced, Diarrhea epidemiology, Constipation chemically induced, Constipation epidemiology, Melanoma drug therapy, Immune Checkpoint Inhibitors adverse effects, Gastrointestinal Diseases chemically induced, Gastrointestinal Diseases epidemiology
Abstract

Introduction: Immune-related adverse events (irAE) secondary to immune checkpoint inhibitors (ICI) have gastrointestinal (GI) manifestations, including gastritis, enteritis, and/or colitis. The long-term sequelae of ICI-associated GI toxicities (GI-irAE), particularly the development of disorders of gut-brain interaction, are not well known. We characterized the incidence of persistent GI symptoms after GI-irAE., Methods: This is a retrospective study of adults with melanoma treated with ICI and diagnosed with GI-irAE at our institution from 2013 to 2021. All patients had endoscopic and histologic evidence of GI-irAE. The primary outcome was incidence of persistent GI symptoms (diarrhea, abdominal pain, bloating, constipation, fecal incontinence, nausea, vomiting) after resolution of GI-irAE. Hazard ratios evaluated the association between parameters and time to persistent GI symptoms., Results: One hundred four patients with melanoma (90% stage IV disease) and GI-irAE met inclusion criteria. Thirty-four percent received anti-cytotoxic T lymphocyte-associated protein-4 therapy, 33% anti-programmed death-1, and 34% dual therapy. Patients were treated for GI-irAE for an average of 9 ± 6 weeks. Twenty-eight (27%) patients developed persistent GI symptoms 1.6 ± 0.8 years after GI-irAE. The most common symptom was constipation (17%), followed by bloating (8%) and diarrhea (5%). Over 453 person-years, the incident rate was 6.2% per 100 person-years. Use of cytotoxic T lymphocyte-associated protein-4 single or dual therapy was associated with a 3.51× risk of persistent GI symptoms (95% confidence interval 1.20-10.23)., Discussion: In this cohort of melanoma patients who experienced GI-irAE, 26% developed persistent GI symptoms, most frequently constipation. Future studies should characterize the GI sequelae after GI-irAE, which may shed light on disorders of gut-brain interaction pathogenesis and improve the lives of cancer survivors., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Published
2024
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50. Tofacitinib is Effective in Treating Refractory Immune Checkpoint Inhibitor Hepatitis.

Author

Wang M, Reynolds KL, Montazeri K, Schaefer EA, Sullivan RJ, and Dougan M

Subjects
Aged, Humans, Middle Aged, Chemical and Drug Induced Liver Injury etiology, Melanoma drug therapy, Protein Kinase Inhibitors therapeutic use, Treatment Outcome, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors adverse effects, Piperidines therapeutic use, Pyrimidines therapeutic use
Abstract

Immune checkpoint inhibitors (ICI) have improved metastatic melanoma outcomes; however, toxicities, such as hepatitis, can be dose-limiting or even fatal. 1 Systemic glucocorticoids and antimetabolite immunosuppressive medications remain the mainstay of treatment for ICI-hepatitis, but options for patients refractory to these therapies are limited. 2 Herein we present 3 cases of glucocorticoid-refractory ICI-hepatitis treated with tofacitinib, an inhibitor of Janus kinase (JAK) 1 and 3. These patients represent consecutive patients referred to the Massachusetts General Hospital Severe Immunotherapy Complications service who were determined by our experts to have treatment failure with systemic glucocorticoid and antimetabolite combination therapy between August 2022 and September 2023. 3 These were the only 3 patients managed by the Severe Immunotherapy Complications service who were treated with tofacitinib for ICI-hepatitis during that time., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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