Title Participants Abstract "Paving the way for immunotherapy in pancreatic cancer by unravelling its tumour microenvironment and exploring a novel combination immunotherapy consisting of a CD40 agonist and interleukin-15" "Jonas Van Audenaerde" "Pancreatic Ductal Adenocarcinoma (PDAC) has the worst 5-year survival of all cancers nowadays and is projected to become the 2nd leading cause of cancer-related death by the end of this decade. Despite hopeful breakthroughs in new treatment options for other cancer types, no improvement has been made for pancreatic cancer patients. The unique tumour microenvironment (TME) of PDAC is held responsible for the great amount of therapy resistance towards current and novel treatment schemes. More specifically, a profound desmoplastic reaction, orchestrated by activated pancreatic stellate cells (PSC), causes shielding of the tumour and an extremely high intra-tumoural pressure. This leads to a virtually impenetrable tumour resulting in this dismal prognosis for PDAC patients. Therefore, new treatment options targeting not only the tumour but also this particular TME are urgently needed. Hence, this thesis focusses on the development of new combination strategies to address the highly unmet medical need. Recently, immunotherapy has booked unseen successes in the treatment of patients with malignant melanoma, non-small-cell lung cancer and kidney cancer. More specifically, activating T cells by using so-called immune checkpoint inhibitors like PD-(L)1 and CTLA-4 unlocked an unseen potential for treatment of cancer. The Nobel Prize 2018 for this discovery underlines the significance of this finding. However, despite their success, these checkpoint inhibitors failed to improve survival in PDAC patients. Therefore, I focussed in this thesis on the potential of Natural Killer (NK) cells to attack both tumour and its TME. As professional cancer killing cells, they are prime candidates for battling cancer. From the plethora of cytokines that could stimulate NK cells, Interleukin(IL)-15 is deemed to be one of the most attractive, evidenced by its third place on the cancer immunotherapy trials network (CITN) priority list of immunotherapy agents. Hence, I sought to investigate the potential of IL-15 stimulated NK cells to kill not only PDAC cancer cells (PCC) but especially also the stromal PSC. Here, I demonstrated that NK cells are capable of killing both cell types and this to a significantly greater extent after IL-15 stimulation. This contact-dependent killing was partially regulated by the NKG2D receptor but the full mechanism still has to be further clarified. I confirmed these results in an ex vivo assay using human tumour-derived PSC and autologous NK cells, underlining the potential of IL-15 for future PDAC treatments. Next, I investigated the potential of combining IL-15 with a CD40 agonist for the treatment of cancer. The latter has the specific capacity to prime the immune system and has already proven anti-cancer and anti-stromal effects in PDAC. Using two different mouse models of PDAC, I showed that when these agents are combined, they invigorate each other resulting in profound anti-tumour responses and significantly prolonged survival with the majority of mice becoming tumour-free in both models. In-depth research revealed that this combination of immunotherapeutic agents resulted in increased numbers of both NK cells and CD8 T cells and a reduction of regulatory T cells in the tumour. In summary, this thesis provides evidence for inclusion of NK cell targeting therapies in the treatment of PDAC. In particular, IL-15 shows great potential to accomplish improved treatment outcome. I provided a solid foundation for initiation of an early phase clinical trial investigating IL-15 combined with a CD40 agonist." "Paving the way for immunotherapy in pancreatic cancer by exploring a novel combination immunotherapy consisting of a CD40 agonist and interleukin-15" "Jonas Van Audenaerde, Geert Roeyen, Marc Peeters, Evelien Smits" "Pancreatic Ductal Adenocarcinoma (PDAC) has the worst 5-year survival of all cancer types. Treatment options for these patients are limited and consist mainly of chemotherapy. However, the unique tumour microenvironment with its dense, fibrotic shield causes resistance to current and novel therapies. Tackling this stromal shield is therefore deemed crucial for making progress in PDAC treatment. We investigated in this thesis the potential of Natural Killer (NK) cells to address this high medical need. Firstly, our systematic review revealed strong evidence of their importance in PDAC and how the tumour renders them into a suppressed and less functional state. Based on this information, we sought to stimulate NK cells in such way that they attack both tumour and surrounding stroma. We show that, upon stimulation with IL-15, NK cells are capable of killing both pancreatic cancer and stellate cells, the drivers of the stromal reaction, in a contact- dependant manner. Increased expression of NKG2D and TIM-3 receptors was partially responsible for this enhanced killing. Furthermore, in our search to potentiate IL-15 stimulation, we combined this with an immune priming CD40 agonist and demonstrated profound anti-tumour effects and prolonged survival in PDAC mouse models. Increased intra-tumoral cytotoxic T cells, NK cells and reduced T regulatory cells combined with increased cross-presenting dendritic cells in the tumour draining lymph nodes are the main effectors of the observed anti-tumour effects. Summarised, our data provide a strong rationale for NK cell-driven cancer immunotherapy where immune stimulation is combined with immune priming. Initiation of an early-phase clinical trials with this novel combination immunotherapy for PDAC patients is warranted." "Playing in three makes it simpler: Mapping the cognitive figure-ground framework onto cancer-immunology and immunotherapy (Review)." "Yori Gidron, L. Vannucci" "The avalanche of research findings in complex multidisciplinary fields, such as cancer immunobiology, requests organizing and practical wol king models for scientists and clinicians. Frameworks from one scientific discipline can be adopted for another one, to clarify and provide new insights into complex findings A 'figure-ground' (FG) perspective was adopted from cognitive sciences to construct a simple organizing tool, which can assist in understanding tumour development and immunotheiapy designing In an FG arena, there is a figure that needs to be contrasted from a background to be seen by a viewer, who may have a mental representation of the figure (i.e. knows what the figure features look like). Applying this framework to cancer, three players emerge: the viewer (immune system components), the figure (tumour), and the background (e Q., normal cells) with their dynamic interactions Various characteristics of tumour development such as reduced expression of major-histocompatilibity complex (MHC) molecules or in by inflammatory cells in its boundaries make tumour-immunity interplay highly suitable to an FG perspective. We describe the basic FG frame-work and immuno-biology of tumour development, thereafter refrained by the FG freamework The term 'antigenic contrast' is introduced to reflect the contrast between the tumour figure and its variable background Antigenic contrast emerges as a main factor enabling the immune system viewer to detect and mount adequate reactions against a tumour figure We provide empirical examples of immunotherapeutic interventions whose results are explained by the FG perspective. For example, vaccines are forms of sharpening the 'mental' representation of the immune viewer concerning the tumour figure, while administering interferons can be seen as enhancing tumour figure salience by rescuing MI-IC expression. This framework highlights important elements in complex networks (e.g., cancer immunobiology), enhances communication between cancer scientists and clinicians, explains experimental and clinical study results, and provides further rationale for combinational immunotherapies." "2019 ARIA Care pathways for allergen immunotherapy" "Jean Bousquet, Oliver Pfaar, Alkis Togias, Holger J Schünemann, Ignacio Ansotegui, Nikolaos G Papadopoulos, Ioanna Tsiligianni, Ioana Agache, Josep M Anto, Claus Bachert, Anna Bedbrook, KarlU+2010Christian Bergmann, Sinthia BosnicU+2010Anticevich, Isabelle Bosse, Jan Brozek, Moises A Calderon, Giorgio W Canonica, Luigi Caraballo, Victoria Cardona, Thomas Casale, Lorenzo Cecchi, Derek Chu, Elisio Costa, Alvaro A Cruz, Wienczyslawa Czarlewski, Stephen R Durham, George Du Toit, Mark Dykewicz, Motohiro Ebisawa, Jean Luc Fauquert, Montserrat FernandezU+2010Rivas, Wytske J Fokkens, João Fonseca, JeanU+2010François Fontaine, Roy Gerth van Wijk, Tari Haahtela, Susanne Halken, Peter Hellings, Despo Ierodiakonou, Tomohisa Iinuma, Juan Carlos Ivancevich, Lars Jacobsen, Marek Jutel, Igor Kaidashev, Musa Khaitov, Omer Kalayci, Jörg Kleine Tebbe, Ludger Klimek, Marek L Kowalski, Piotr Kuna, Violeta Kvedariene, Stefania La Grutta, Désirée LarenasU+2010Linemann, Susanne Lau, Daniel Laune, Lan Le, Karin Lodrup Carlsen, Olga Lourenço, HansU+2010Jørgen Malling, Gert Marien, Enrica Menditto, Gregoire Mercier, Joaquim Mullol, Antonella Muraro, Robyn OU+2019Hehir, Yoshitaka Okamoto, Giovanni B Pajno, HaeU+2010Sim Park, Petr Panzner, Giovanni Passalacqua, Nhan PhamU+2010Thi, Graham Roberts, Ruby Pawankar, Christine Rolland, Nelson Rosario, Dermot Ryan, Boleslaw Samolinski, Mario SanchezU+2010Borges, Glenis Scadding, Mohamed H Shamji, Aziz Sheikh, Gunter J Sturm, Ana Todo Bom, Sanna ToppilaU+2010Salmi, Maryline ValentinU+2010Rostan, Arunas Valiulis, Erkka Valovirta, MariaU+2010Teresa Ventura, Ulrich Wahn, Samantha Walker, Dana Wallace, Susan Waserman, Arzu Yorgancioglu, Torsten Zuberbier" "Contribution of regulatory T cells to alleviation of experimental allergic asthma after specific immunotherapy" "H Maazi, S Shirinbak, Monique Willart, M Cabanski, L Boon, V Ganesh, AM Baru, G Hansen, T Sparwasser, MC Nawijn, AJM van Oosterhout" "Safety and efficacy of immunotherapy with the recombinant B-cell epitope-based grass pollen vaccine BM32" "Verena Niederberger, Angela Neubauer, Philippe Gevaert, Mihaela Zidarn, Margitta Worm, Werner Aberer, Hans Jørgen Malling, Oliver Pfaar, Ludger Klimek, Wolfgang Pfützner, Johannes Ring, Ulf Darsow, Natalija Novak, Roy Gerth van Wijk, Julia Eckl-Dorna, Margarete Focke-Tejkl, Milena Weber, Hans-Helge Müller, Joachim Klinger, Frank Stolz, Nora Breit, Rainer Henning, Rudolf Valenta" "Cost-effectiveness of immunotherapy in the treatment of seasonal allergic rhinitis : identifying product-specific parameters of relevance for health care decision-makers and clinicians" "Claus Bachert, Jakob Noergaard Andreasen" "How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA-GA2LEN statement" "J Bousquet, HJ Schünemann, PJ Bousquet, Claus Bachert, GW Canonica, TB Casale, P Demoly, S Durham, K-H Carlsen, H-J Malling, G Passalacqua, FER Simons, J Anto, CE Baena-Cagnani, K-C Bergmann, T Bieber, AH Briggs, J Brozek, MA Calderon, R Dahl, P Devillier, R Gerth van Wijk, P Howarth, D Larenas, NG Papadopoulos, P Schmid-Grendelmeier, Torsten Zuberbier" "Is the combination of immunotherapy and radiotherapy in non-small cell lung cancer a feasible and effective approach?" "Mathieu Spaas, Yolande Lievens" "For many years, conventional oncologic treatments such as surgery, chemotherapy, and radiotherapy (RT) have dominated the field of non-small-cell lung cancer (NSCLC). The recent introduction of immunotherapy (IT) in clinical practice, especially strategies targeting negative regulators of the immune system, so-called immune checkpoint inhibitors, has led to a paradigm shift in lung cancer as in many other solid tumors. Although antibodies against programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) are currently on the forefront of the immuno-oncology field, the first efforts to eradicate cancer by exploiting the host's immune system date back to several decades ago. Even then, researchers aimed to explore the addition of RT to IT strategies in NSCLC patients, attributing its potential benefit to local control of target lesions through direct and indirect DNA damage in cancer cells. However, recent pre-clinical and clinical data have shown RT may also modify antitumor immune responses through induction of immunogenic cell death and reprogramming of the tumor microenvironment. This has led many to reexamine RT as a partner therapy to immuno-oncology treatments and investigate their potential synergy in an exponentially growing number of clinical trials. Herein, the authors review the rationale of combining IT and RT across all NSCLC disease stages and summarize both historical and current clinical evidence surrounding these combination strategies. Furthermore, an overview is provided of active clinical trials exploring the IT-RT concept in different settings of NSCLC." "ARIA-Versorgungspfade für die Allergenimmuntherapie 2019 = 2019 ARIA Care pathways for allergen immunotherapy" "J. Bousquet, O. Pfaar, A. Togias, H.J. Schünemann, I Ansotegui, N.G. Papadopoulos, I Tsiligianni, I Agache, JM anto, Claus Bachert, A Bedbrook, KC Bergmann, S Bosnic-Anticevich, I Bosse, J Brozek, M Calderon, GW Canonica, GW Caraballo, V Cardona, T Casale, L Cecchi, DK Chu, E Costa, AA Cruz, W Czarlewski, SR Durham, G Du Toit, M Dykewicz, M Ebisawa, JL Fauquert, M Fernandez-Rivas, WJ Fokkens, J Fonseca, JF Fontaine, R Gerth van Wijk, T Haahtela, S Halken, PW Hellings, D Ierodiakonou, T Iinuma, JC Ivancevich, L Jacobsen, M Jutel, I Kaidashev, M Khaitov, O Kalayci, J Kleine Tebbe, L Klimek, ML Kowalski, P Kuna, V Kvedariene, S La Grutta, D Larenas-Linemann, S Lau, D Laune, L Le, K Lodrup Carlsen, O Laurenço, HJ Malling, G Marien, E Mendito, G Mercier, J Mullol, A Muraro, R O'Herir, Y Okamoto, GB Pajno, HS Park, P Panzner, G Passalacqua, N Pham-Thi, G Roberts, G Rolland, N Rosario, D Ryan, B Samolinski, M Sanchez-Borges, G Scadding, MH Shamji, A Shelkh, GJ Sturm, A Todo Bom, S Toppila-Salmi, M Valentin-Rostan, A Valiulis, E Valevirta, MT Ventura, U Wahn, S Walker, D Wallace, S Waserman, A Yorgancioglu, T Zuberbier"