Midterm report 2015 K.G. Jensen center for cancer immunotherapy 2014 by Millimeterpress as

K.G. Jebsen Center for Cancer Immunotherapy - mid-term report 2015

Overcoming immune tolerance to target cancer

KG JEBSEN CENTER for Cancer Immunotherapy

Overcoming immune tolerance to target cancer

Design: Millimeterpress AS Front page: Immuno-EM showing a cytotoxic lymphocyte. Courtesy of Jodie Goodridge and Andreas Brech Foto: Terje Heiestad, Millimeter Press AS og Peter Holgersson: www.peterholgersson.se Print: Rolf Ottesen

m id - t e rm re p o r t 20 1 5

index Directors comment 4 Visions 5 Key concepts 6 Scienticfic highlights 8 Future outlook 9 Research groups 10 Kolstad group 12 Lund-Johansen group 16 Malmberg group 20 Olweus group 24 Schumacher group 28 TaskĂŠn group 32 The patients 36 Innovation 38 Publications 40 Education and Career 44 SAB 46 Key Events 48 Visiting professors 50 Facts about JCIT 51 Communication to the public 56 Our sponsors 58 mid- t er m r e p o r t 2015

Directors comments The K.G. Jebsen Center for Cancer Immunotherapy (JCIT) opened in June 2013, and the present report will thus cover highlights from the first (close to) 2 years in the life of JCIT. The formation of the center allowed six partnering groups at the University of Oslo/ Oslo University hospital and the Netherlands Cancer Institute to join forces to develop new strategies in cancer immunotherapy, and the first period has been very active. Immunotherapy was long regarded safe, but ineffective. However, in 2013, Science highlighted “Cancer Immunotherapy” as one of the breakthrough areas of the year. This was mainly due to the undisputable clinical success of therapeutic strategies releasing the power of T cells, including genetically engineered T cells and antibodies blocking checkpoint molecules. The timing for the formation of a Norwegian center focused on cancer immunotherapy was therefore excellent. The expertise of the six consortium PIs; Arne Kolstad, Fridtjof Lund-Johansen, Karl-Johan Malmberg, Johanna Olweus, Kjetil Taskén and Ton Schumacher, and their groups spans from basic immunology to clinical oncology, as reflected in a translational and interdisciplinary research program. Although the center has only been operational for two years, the synergies of coming together to address key bottlenecks in the field are already obvious. The organization into a center has inspired a large number of new collaborative projects between the partners. The physical

proximity of the Oslo partners facilitates close interactions, while multiple exchange visits occur between Oslo-Amsterdam. In particular, the center partners have given each other access to, and created patent-pending, frontline technologies that give the projects a highly competitive edge. A number of co-publications between partners have already emerged - many in high-impact journals - and several studies are near completion. Our international partner can also show to a commercial success story; the acquisition by Kite Pharmaceuticals of the T-Cell Factory B.V, founded by Ton Schumacher and colleagues, strengthening its TCR gene therapy platform. The overarching goal of all our activities is to develop new and more effective therapies for patients with refractory cancer. A major accomplishment in 2014 was thus the completion of the LYMVAC clinical trial. A novel experimental immunotherapy protocol was administered to patients with follicular lymphoma, an incurable cancer by standard treatment. The intra-tumoral therapy resulted in clinical responses in 36% of the patients. For the first time, a reduction in tumor volume was demonstrated to correlate with vaccination-induced T-cell mediated anti-tumor reactivity. A new clinical trial – LYMVAC-2 – will start in 2015. Promising results have also been achieved in another ongoing phase I/II clinical trial, based on

m id - t e rm re p o r t 20 1 5

vision:

To create novel immunotherapeutic strategies that overcome immunological tolerance to cancer

Johanna Olweus the adoptive transfer of haploidentical NK cells to patients with high-risk hematological malignancies (MDS and AML) who have no other treatment options. These clinical results and plans represent a major inspiration. The in-house technological platform, combined with longitudinal sampling of the treated patients, allow us to penetrate the mechanisms even deeper, paving the way for new and improved immunotherapy strategies. In 2014, we organized an international Cancer Immunotherapy Symposium; “Harnessing innate and adaptive immunity in cancer therapy” for 150 delegates at Holmenkollen Park Hotel. The symposium was a success, and attracted a number of top international speakers, including Carl June, Martin

mid- t er m r e p o r t 2015

Pule, Jeff Miller and Rolf Kiessling, as well as “our own” Ton Schumacher. And Oslo showed itself from the sunny side. The meeting not only inspired our own center members, but also represents an example on the many positive effects that the center formation has on the general research community. Among important internal activities, I would like to emphasize that the center got valuable input from our Scientific Advisory Board, including the internationally leading scientists Fred Falkenburg, Rolf Kiessling and Hans Stauss, during the SAB meeting in November 2014. Moreover, our sense of a common direction and purpose has been further enforced during our retreats, the last one at Geilo in April, combining scientific discussions and presentations with fun in the snow. We are very grateful for this opportunity given to us by the K.G. Jebsen Foundation, and by the University of Oslo (UiO). UiO represents the hosting institution for JCIT, which in partnership with Oslo University Hospital and the Netherlands Cancer Institute provide an excellent framework and infrastructure to facilitate our activities. We are confident that we are well positioned to bring even more exciting results to the benefit of cancer patients during the coming two years.

Approach 1. Use allo-reactivity to overcome self-tolerance We use novel strategies to discover T-cell epitopes from cell type-specific antigens and identify high-affinity T-cell receptors (TCRs) that recognize these in context of foreign HLA. The aim is to utilize cell-type specific TCRs to re-direct patient-derived T cells that are infused into the patient to target cancer cells. Another cell type that is triggered upon transfer across HLA barriers is RR the natural killer (NK) cell. Here we exploit insights into R the molecular specificity of NK cells in the design of cell therapy trials against refractory leukemia.

RR R

R LLL LL KILLING LL antigen

T DC

NK Educated L

KIR2DL3

Cancer cell

KILLING

C2C2 KIR2DL1

LL LL HLA-A2

Educated LL

R RR RR R R

RR RR R R

R R LLL LLL LL LL KILLING KILLING LL LL antigen antigen

L L ce cell

m id - t e rm re p o r t 20 1 5

Key concepts

L cell Self-specific LLL L

KILLING

T INHIBITION

Treg

L LLL L

Approach 2. Identify and target cancer-specific neo-antigens Mutated antigens in cancer are foreign to the immune system and therefore potentially immunogenic. By identifying neo-antigen specific T-cell receptors, we plan to endow patient-derived T cells with the ability to specifically target the malignant cells.

Approach 3. Enhance effector T-cell function by overcoming inhibitory mechanisms The activity of T cells with the ability to recognize the tumor will be enhanced in three different ways: i) Modulation of the suppression mediated by so-called regulatory T cells (Tregs) ii) Reversing the effect of the inhibitory inflammatory mediator PGE2, which we have shown inhibits tumor growth and anti-tumor immune function in vivo, iii) Selection of effector T cells based on expression profiles of inhibitory receptors.

Illustration: Erlend StrĂ¸nen mid- t er m r e p o r t 2015

Scientific highlights

n Completing a clinical trial (Lymvac-1) using a novel local immunotherapy strategy to treat patients with follicular lymphoma, an incurable cancer by standard treatment. Clinical responses were seen in 36% of the patients, and the degree of tumor reduction correlated well with vaccine-induced anti-tumor T cell responses in peripheral blood. Kolstad et al, Blood 2015 n Inventing a technology platform for high-throughput discovery of T-cell epitopes and demonstrating that self-peptides are far more frequent recognition elements than previously believed. Demonstrating the utility of a number of novel self-epitopes as targets for cancer immunotherapy. Kumari et al, PNAS 2014

n Developed technology for the high-throughput profiling of tumor antigen-specific CD8+ and CD4+ T cell immunity, and for highthroughput identification of their T-cell receptor sequences. Linnemann et al, Nat Med, 2015, and Linnemann et al Nat Med 2013 n Identified DNAM-1 as an intrinsic marker for functionally educated NK cells. By providing inside-out signaling to LFA-1, this activating receptor contributes to enhance conjugate formation with target cells. These findings pave the way for manipulating NK cells in cancer therapy. Enqvist et al, J. Immunol. 2015.

nA new pipeline for high throughput protein expression paves way for the next generation human protein arrays. Optimized robotics and a new cell-based expression system are used to produce 400 proteins per week. Protein arrays open entirely new possibilities to detect immunerecognition elements in cancer cells. n Demonstrated for the first time by examination of malignant ascites from cancer ovary patients that tumor-associated regulatory T cells are activated and therfore would be highly suppressive. Landskron et al. Cancer Immunol. Immunother. 2015

m id - t e rm re p o r t 20 1 5

Future outlook

n Gain further insights into the molecular specificity of systemic anti-tumor T cell responses in patients responding to immunotherapy with a particular focus on the Lymvac-1 trial n Launch Lymvac-2 for patients with refractory follicular lymphoma, combining the regimen used in Lymvac-1 with the checkpoint inhibitor anti-PD-1

mid- t er m r e p o r t 2015

n Advance the pipeline for genetic modification of T and NK cells for proof-of-principle studies of thus far identified T cell receptors in vitro and in vivo

n Produce the first bead-based human protein array for massive screening of auto-antibodies in serum from patients with autoimmune disease and cancer.

n Coordinate the first Nordic NK cell trial based on transfer of HLA mismatched NK cells to patients with very high risk MDS

n Advance the characterization of hits from our new screening for modulators of expression levels of the regulatory T cell (Treg) lineagespecific transcription factor FoxP3 that determines Treg suppressive activity.

10 LUND-JOHANSEN Group Fridtjof Lund-Johansen

MALMBERG Group Karl-Johan Malmberg

research KOLSTAD Group Arne Kolstad

m id - t e rm re p o r t 20 1 5

Taskén Group Kjetil Taskén

SCHUMACHER Group Ton Schumacher

OLWEUS Group Johanna Olweus

groups mid- t er m r e p o r t 2015

Kolstad group Our primary focus is to conduct clinical studies with novel immunotherapies and translational research in lymphoma. Scientific summary The primary scientific focus of the Kolstad group is to conduct clinical studies with novel immunotherapies and translational research in lymphoma. Kolstad has been involved in many studies in malignant lymphoma at Oslo University Hospital (OUS). He is leader of Focus Area Cancer Immunotherapy awarded by OUS in 2014. The main objective of this consortium is to facilitate translation of novel preclinical concepts into early exploratory clinical studies. A major goal for Kolstad within the K.G Jebsen Center (WP 6) has been to conduct and complete an early exploratory study with a novel in-house in situ vaccine strategy in a cohort of patients with stage III/IV incurable follicular non-Hodgkin`s lymphoma (Lymvac-I study). This work has been in collaboration between the Lymphoma group at OUS with Kolstad as principal investigator, and the group of Johanna Olweus, and results were recently published in Blood. Further work within the JCIT consortium between Kolstad and the groups of Olweus and Schumacher has now been initiated to dissect tumor-specific mutations and potential epitopes targeted by tumor-reactive T cells in peripheral blood from clinical responders in the vaccine trial. Based on the platform used for intranodal immunotherapy in the Lymvac-1 trial, the

aim of the follow-up study (Lymvac-2) is to enhance anti-tumor T-cell responses and corresponding clinical responses by adding the check-point inhibitor pembrolizumab (anti-PD-1). The company Merck will provide pembrolizumab for a study on 20 patients with follicular lymphoma over a period of 2-3 years. In-depth monitoring of anti-tumor T-cell responses will be performed by the Olweus group, as for Lymvac-1, and identification of neo-antigens as described above will be done in collaboration with Schumacher. In preparation of another study with CD20 peptide/HLA-A2-restricted T-cell receptors in lymphoma, preclinical work by the Olweus group with characterization and optimization of TCRs for GMP production in clinical trials is ongoing. KEY ACHIEVEMENTS â&#x20AC;˘ The Lymvac-1 cancer vaccine study for patients with stage III/IV incurable follicular lymphoma was conducted within the KG Jebsen Center for Cancer Immuntherapy as a collaboration with the Immunology group of Olweus at the Institute of Cancer Research. Kolstad invented the strategy, wrote the protocol and was PI for this early exploratory single institution study. Of 14 patients treated, 5 showed objective responses (36%) of which 2 had durable complete responses. Responding patients had strong CD8 T cell activity against autologous tumor cells in peripheral blood.

m id - t e rm re p o r t 20 1 5

mid- t er m r e p o r t 2015

Kolstad group

•

Kolstad A, Kumari S, Walczak M, .. Olweus J. Sequential intranodal immunotherapy induces anti-tumor immunity and correlated regression of disseminated follicular lymphoma. Blood 2015;125(1):82-9. Epub 2014 Oct 7. A commentary was written in the same issue of Blood by Bhardwaj N, Brody JD Dendritic cells and lymphoma cells: come together right now. Blood 2015; 125(1):5-7 A phase II Nordic Lymphoma Group study with radioimmunotherapy (RIT) as part of conditioning prior to autologous stem cell transplantation in mantle cell lymphoma and transitional studies. Kolstad A, Laurell A, Jerkeman M,. . Geisler CH. Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma. Blood. 2014;123(19):2953-2959. Husby S, Ralfkiaer U, Garde C, ..Kolstad A, …. Grønbæk K. miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. Blood. 2015 Mar 3. pii:blood-2014-06-584193. [Epub ahead of print]

Nordström L, Sernbo S, Eden P, .. Kolstad A, …Ek S. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma--a Nordic Lymphoma Group study. Br J Haematol.2014 Jul;166(1):98-108.

Hadzidimitriou A, Agathangelidis A, .. Kolstad A, …. Stamatopoulos K. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood. 2011 Sep 15;118(11):3088-95.

•

Phospho-specific flow cytometry to study intracellular signaling in tumor cells and tumor-infiltrating T cells in lymphoma. This is a collaboration with the group of June Myklebust at OUS, Anne Husebekk and Egil Blix at University of Tromsø,

Ron Levy at Stanford and Jonathan Irish at Vanderbilt University. Myklebust JH, Irish JM, Brody J,.. Kolstad A. . . Levy R. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood. 2013;121(8):1367-1376.

Blix ES, Irish JM, Husebekk A,..Kolstad A. Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma. BMC Cancer. 2012 Oct 16;12:478.

Blix ES, Irish JM, Husebekk A, .., Kolstad A. Altered BCR and CD40 signalling are associated with clinical outcome in small lymphocytic lymphoma/chronic lymphocytic leukaemia and marginal zone lymphoma patients. Br J Haematol. 2012 Dec;159(5):604-8.

•

Results from a single center phase II study with reduced intensity allogeneic stem cell transplantation in lymphoma with Kolstad as PI and last author.

Fløisand Y, Brinch L, Gedde-Dahl T,..Kolstad A. Ultra-short course sirolimus contributes to effective GVHD prophylaxis after reduced-intensity allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2012 Dec;47(12):1552-7.

•

Influenza vaccination in lymphoma patients treated with rituximab. A prospective study with Kolstad as PI was conducted comparing response to influenza vaccine (H1N1, swine flu) in lymphoma patients treated with rituximab and healthy controls. Rituximab blocked serological responses to this vaccine, and most likely this is also the case for other common vaccines.

Yri OE, Torfoss D, Hungnes O, Tierens A, ….. Kolstad A. Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. Blood. 2011 Dec 22;118(26):6769-71.

m id - t e rm re p o r t 20 1 5

For the first time, a reduction in tumor volume was demonstrated to correlate with vaccination-induced T-cell mediated anti-tumor reactivity.

mid- t er m r e p o r t 2015

Lund-Johansen group Our main focus is to build large scale assays for detection or autoantibodies in serum. Scientific summary Our main focus is to build large scale assays for detection or auto-antibodies in serum. Microsphere-based arrays with content of full-length human proteins open for high throughput screening of auto-antibodies in serum from cancer patients. The assays will allow near genome-wide screening of self-proteins that are recognized as foreign by the humoral immune system. The information is used to identify candidate targets for immunotherapy and to monitor effects of the treatment. The focus of the Lund-Johansen group is development of array-based proteomics. Microsphere affinity proteomics (MAP) is based on the use of bead-based arrays and flow cytometry. The technology was invented by FLJ, and the throughput is 200 times higher than mass spectrometry (MS). Our main effort within the context of JCIT is production of MAP protein arrays. These will be used as tools to identify auto-antibodies in patient sera. Patients with cancer often produce auto-antibodies, but it is not clear to what extent these responses predict T-cell-mediated cytotoxicity of tumor-cells. Within the JCIT we have a unique opportunity to address this

important question. Research conducted by PIs Olweus, Schumacher and Kolstad leads to identification of T- cell recognition elements in newly diagnosed patients. Protein array analysis of serum from the patients will determine to what extent the same proteins stimulate an antibody response. We expect to see a correlation, and if this hypothesis is confirmed, protein arrays will provide a â&#x20AC;&#x153;short-cutâ&#x20AC;? for high throughput identification of candidate T cell targets. Importantly, the arrays will then also be useful for monitoring of therapies targeted to the same proteins. During 2013-2014, we have streamlined high throughput protein production and developed new and better procedures for coupling of proteins. We are currently in the production phase, with a weekly output of 400 full length human proteins from mammalian cell expression. Thus, we are on schedule with our plans to cover half of the human proteome by the end of 2015. During 2015, we expect to use smallscale custom-made arrays to measure antibody-responses to protein targets recognized by tumor-reactive T cells KG Jebsen Center for Inflammation Research, where the arrays will be used with sera from patients with auto-immune disease.

m id - t e rm re p o r t 20 1 5

mid- t er m r e p o r t 2015

Lund-Johansen group

m id - t e rm re p o r t 20 1 5

We are now in a production phase, with a weekly output of 400 full length human proteins from mammalian cell expression the use of 96 well plates and robotics. We are now in a production phase, with a weekly output of 400 full length human proteins from mammalian cell expression. The yields are sufficient for production of thousands of arrays, and the costs are approximately 10% of those of cell-free expression.

Key achievements • High throughput plasmid production. We have obtained a collection of 10.000 cDNA clones encoding full-length human proteins from the University of Arizona. We expect to extend coverage to 12000 by the end of 2015. We have now established high throughput plasmid DNA production from bacteria in 96 well plates using liquid handing robots

mid- t er m r e p o r t 2015

•

Implementation of robotics in all steps of the production. During the past year, we have obtained three new liquid handling robots. These have now been implemented in tasks such as production, normalization and arraying of plasmid DNA, cell-free production of proteins in small volumes, and production of arrays.

•

Protein expression in mammalian cells. The plasmids used to express proteins for this project were designed for use with cellfree expression kits. Cell-free expression is simple and rapid, but very costly. We have now successfully established expression from these plasmids in the hamster cell line BSR-T7/5. This cell line has stable ectopic expression of the T7 polymerase, which is essential for expression from the plasmids. Mammalian cell expression is expected to yield proteins that are more similar to those targeted by autoantibodies in vivo. Importantly, the new cellular system is compatible with

•

Improved coupling chemistry for protein arrays. The recombinant human proteins are fused with the small bacterial protein Glutathione S Transferase (GST). The tag allows all proteins to be immobilized to microspheres coupled with a anti-GST antibody. Before this project started the anti-GST antibody was coupled covalently to the microspheres. In 2014, we have demonstrated that bindng of biotinylated anti-GST to streptavidin beads is more effective and reproducible than covalent coupling. Thus, we have streamlined all components in array production from protein production to the coupling chemistry.

•

Successful production and testing of a pilot array with 400 human proteins. Using the modified chemistry for immobilization of recombinant proteins to produce a pilot protein array with 400 human proteins. The functionality of the array was tested using commercially available antibodies to human proteins. Signal to noise ratios of 2 logs were routinely obtained.

Malmberg group Developing the next generation natural killer (NK) cell therapy Scientific summary Research in the Malmberg group aims at understanding the mechanisms governing the formation of human NK cell repertoires and their functional tuning by killer cell immunoglobulin-like receptors (KIR)/HLA interactions. In an interdisciplinary effort, molecular studies of human NK cell repertoires at the single cell level are combined with an integrative cellular profiling of the NK cell repertoire in healthy individuals and in patients with cancer (Lund-Johansen, Taskén, Olweus). New insights into NK cell biology are implemented in the design of cell therapy protocols involving transfer of specific NK cell populations across HLA barriers. During the past two years we have, together with colleagues at the Karolinska Institutet (KI) completed a first Phase I/II trial based on adoptive transfer of haploidentical NK cells to patients with refractory high-risk myeloid malignancies including MDS and AML. Six of fifteen patients evaluated so far reached complete remission (CR) and as a consequence, five of these have proceeded to an allogeneic stem cell transplant. Based on these preliminary positive results we plan to launch a Nordic NK cell trial for patients with very high-risk MDS in an upfront setting as bridge to transplant (Kolstad). Within the frame of the KG Jebsen Center, we have explored different strategies for engineering primary NK cells. Although the initial focus has been on well-characterized chimeric antigen receptor (CAR) constructs, we plan to extend this to explore the potential of retargeting human NK cells with neo- and self-specific TCRs generated by the (Olweus/ Schumacher).

KEY ACHIEVEMENTS • Over the past years we have established a methodological tool-box for robust and sensitive analysis of NK cell repertoire diversity in terms of receptor expression and functional responsiveness. In a number of recent publications the Malmberg group has delineated the principles behind the formation of complex receptor repertoires on human NK cells, including the emergence of adaptive NK cells in the context of latent viral infections. In collaboration with John Trowsdale at the University of Cambridge we demonstrated a profound effect of KIR gene copy number on global NK cell repertoires, which may have implications for genetic disease association involving epistatic interactions between KIR and HLA.

Bjørkstrøm et al., Blood 2012. Beziat et al., Blood 2013a, and Beziat et al., Blood 2013b. Based on the above studies we have filed a patent regarding the possibility to selectively expand educated NK cells for cancer therapy. The proof of principle project developed around this discovery received additional funding from the RCN during 20142016.

m id - t e rm re p o r t 20 1 5

mid- t er m r e p o r t 2015

Malmberg group

•

Developed an algorithm for tracing adaptive NK cell responses in the human. A recent development in NK cell biology is the description of adaptive NK cell responses involving clonal-like expansion and differentiation of subpopulations of NK cells.

Beziat V, Traherne J, Malmberg JA, Ivarsson MA, Bjorkstrom NK, Retiere C, Ljunggren HG, Michaelsson J, Trowsdale J, Malmberg KJ. Tracing dynamic expansion of human NK-cell subsets by high-resolution analysis of KIR repertoires and cellular differentiation. European journal of immunology. 2014;44(7):2192-6. Epub 2014/04/12. PMID: 24723455.

•

Launched a Phase I/II trial based on adoptive transfer of NK cells across HLA barriers (Performed at KI). This trial enrolls patients with refractory high-risk MDS and AML. Fifteen patients have been evaluated so far. The treatment has been well tolerated with minimal non-infectious complications. Although preliminary, we have noted some promising clinical responses with 6 patients reaching CR. Notably, clinical responses correlated with the transient detection of donor-derived NK cells 7 days after infusion. Based on these preliminary data we are now in the process of designing a Nordic NK cell trial.

•

Described the emergence of polyclonal adaptive NK cell responses in patients with TAP-deficiency, displaying low levels of HLA class I. Thus, interactions with self-HLA class I molecules shape the repertoire of expanding NK cells during adaptive NK cell responses, but are not a prerequisite for the response to occur. The emergence of adaptive NK cells in TAP-deficient patients may contribute to anti-viral immunity and their unexpectedly low incidence of severe viral infections.

Polyclonal Expansion of NKG2C+ NK Cells in TAP-deficient Patients. Vivien Béziat, Marwan Sleiman, Jodie Goodridge, Mari Kaarbø, Halvor Rollag, Hans-Gustaf Ljunggren, Jacques Zimmer, Karl-Johan Malmberg. Manuscript submitted.

•

We have showed that CAR transfection of primary NK cells is feasible and lead to potent recognition of CD19+ targets. The functional hierarches of discrete NK cell subsets is maintained following CAR transfection, implying that variation in donor NK cell repertoires might influence the overall efficacy of NK cell-based CAR engineering.

Chimeric Antigen Receptors in Primary NK Cells: Deciphering the Role of NK Education. Vincent Oei Yi Sheng, Hanna Julie Hoel, Yang Weiwen, Hilde Almåsbak, Johanna Olweus, Jon-Amund Kyte, Karl-Johan Malmberg. Manuscript in preparation.

m id - t e rm re p o r t 20 1 5

Deciphering cellular and molecular mechanisms of NK cell education

mid- t er m r e p o r t 2015

Olweus group Our main focus is to develop new strategies for T-cell based cancer immunotherapy and to perform penetrating mechanistic analyses of the immune responses in clinical immunotherapy trials Scientific summary Our main focus is to develop new strategies for T-cell based cancer immunotherapy and to perform penetrating mechanistic analyses of the immune responses in clinical immunotherapy trials. We identify T-cell receptors that mediate efficient immune responses to self-antigens or neo-antigens for future genetic engineering of T cells for adoptive cell therapy. The focus of theâ&#x20AC;&#x2122; group is to develop new strategies for T-cell based immunotherapy of cancer, with the main emphasis on leukemia and lymphoma. Our main approaches aim at targeting 1) wild-type self-antigens with cell-type restricted expression, and 2) altered peptides encoded by cancer-specific mutations, so-called neo-antigens. A single self-antigen can potentially be used as a target in a large number of patients. The challenge is to overcome tolerance. In a series of articles, we have demonstrated that T cells that recognize self-peptides on allogeneic (foreign) HLA-A2 with high avidity and specificity can be obtained by priming with dendritic cells engineered to express allogeneic HLA-A2 complexed with self-peptides. Within the Center, this method has been further developed into a new technology platform that allows high-throughput identification of T-cell epitopes and reactive T cells, in collaboration with the Schumacher group. The Schumacher group uses their new technology to identify the TCR sequenc-

es from a large number of these T cells. This provides a basis for TCR gene transfer. Two TCRs used to re-direct peripheral blood T cells specifically killed HLA-A2pos B cells, shown in collaboration with Kolstad and the Malmberg group. Studies are ongoing to test these TCRs in murine models. A major effort to target neo-antigens is centered around clinical trials on follicular lymphoma conducted by Kolstad. In LYMVAC-1, the patients were treated with experimental local immunotherapy (see â&#x20AC;&#x153;The Patientsâ&#x20AC;?). Clinical responses were strongly correlated with systemic CD8 T-cell mediated anti-tumor responses, as measured in a novel setup designed by the Olweus group. In an ongoing collaboration with Schumacher, tumor mutations and potential T-cell targets among these will be characterized in biobanked material from the responder patients, alongside comparative TCR repertoire analyses in tumor and peripheral blood. Anti-tumor antibodies in serum from the responder patients will be characterized using a novel flow cytometry-based protein array developed by Lund-Johansen. Moreover, Olweus and Schumacher have demonstrated the possibility to target an unused repertoire of patient-derived neo-antigens using T cells from healthy donors. This approach opens new possibilities to enable effective personalized immunotherapy.

m id - t e rm re p o r t 20 1 5

A novel technology platform was designed for T-cell epitope and TCR discovery

mid- t er m r e p o r t 2015

Olweus group

Key achievements • A novel technology platform was designed for T-cell epitope and TCR discovery, and the strategy was used to identify a large number of CTL epitopes from the leukemia-associated self-antigens CD20 and MPO

Kumari S, Walchli S, Fallang LE, Yang W, Lund-Johansen F, Schumacher TN, Olweus J. Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes. Proc Natl Acad Sci U S A. 2014;111(1):403-408. Selected by Faculty of 1000 Prime: http://f1000. com/prime/718206020?bd=1 (Two stars)

A patent application protecting the technology and epitopes described above was filed

•

An experimental clinical trial was completed (see “The patients” by Arne Kolstad) in which we demonstrated 36% clinical responses that were strongly correlated with T-cell mediated anti-tumor immunity induced by the local vaccination regime.

•

Kolstad A, Kumari S, Walczak M, Madsbu U, Hagtvedt T, Bogsrud TV, . . Olweus J. Sequential intranodal immunotherapy induces anti-tumor immunity and correlated regression of disseminated follicular lymphoma. Blood 2015;125(1):82-9. Epub 2014 Oct 7.

Lossius A, Johansen JN, Vartdal F, Robins H, Benth JS, Holmoy T, Olweus J. High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8 T cells. Eur J Immunol. Nov;44(11):3439-52

A patent application protecting the approach for identification of disease-driving antigens was filed

•

We demonstrated that Invariant chain incorporating epitopes from MART-1 and CD20 can be used to efficiently activate and prime CD8+T cells, with potential implications for vaccination strategies.

Walchli S, Kumari S, Fallang LE, Sand KM, Yang W, Landsverk OJ, . . . Olweus J*, Gregers TF*. Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T-cell activation. Eur J Immunol. 2014;44(3):774-784.

*Shared senior authors. Front cover. Commentary in Eur J Immunol 2014, V44, p650. Selected by Faculty of 1000 Prime: http://f1000.com/ prime/718194774?bd=1&ui=28053

Walseng E, Wälchli S, Fallang LE, Yang W, Vefferstad A, Areffard A, Olweus J. Soluble T-cell Receptors produced in Human Cells for targeted Delivery. PLoS One, in press

•

CD20p/HLA-A2-restricted T-cell receptors specifically target B cells. Peripheral blood-derived T cells retrovirally transduced with TCRs recognizing CD20p/HLA-A2 specifically and efficiently recognize B cells, including patient-derived follicular lymphoma cells, from HLA-A2pos but not HLA-A2neg individuals (ms in prep co-authored by Malmberg and Kolstad).

•

Enabling personalized immunotherapy using donor-derived neo-antigen specific T cells (ms in prep co-authored by Schumacher)

A commentary was written in the same issue of Blood by Bhardwaj N, Brody JD Dendritic cells and lymphoma cells: come together right now. Blood 2015; 125(1):5-7 A new approach to identify disease-driving antigens by TCR repertoire analysis was designed: We generated TCRb chain reference libraries from sorted peripheral blood T cells responding to EBV, and used these libraries to quantify EBV-specific TCRs identified from the low T cell numbers found in CSF from the same patient.

m id - t e rm re p o r t 20 1 5

mid- t er m r e p o r t 2015

Schumacher group

The group aims to understand what the critical antigens are for human tumor regression Scientific summary The Schumacher group is focused on the analysis and manipulation of tumor-specific T cell responses. Using in-house developed technologies, the group aims to understand what the critical antigens are for human tumor regression The focus of the Schumacher group is twofold: I) To understand what T cells ‘see’ on cancer cells in clinically effective immunotherapies, and II) To develop approaches for the genetic engineering of tumor-specific T cell immunity when otherwise lacking. With the development of approaches to interrogate T cell responses against patient-specific mutant antigens, the former line of research has expanded substantially over the past 2 years. General goals in this research line are to understand how T cell responses against patient-specific antigens are influenced by clinical interventions

(in one project together with Kolstad and Olweus), whether T cells directed against neo-antigens are of a superior quality as compared to T cells against shared antigens, and whether the size of the mutanome predicts the activity of cancer immunotherapies. In addition to these goals, we are also exploiting our MHC-based tools to identify T cells/ TCRs against a series of shared antigens, in collaboration with Olweus. Related to this, we are using our TCR identification technologies (initially from pools of cells, now also from single T cells) to develop TCRs against novel hematological target antigens in an experimental effort led by the Olweus group. Finally, in a joint project with the Olweus group, we have married their in vitro T-cell induction strategy with our cancer exome analysis capacities to investigate whether it is feasible to target a ‘neglected’ repertoire of patient-derived neo-antigens with T cells from healthy donors.

m id - t e rm re p o r t 20 1 5

We have developed technology for the high-throughput profiling of tumor antigen-specific T cell immunity

mid- t er m r e p o r t 2015

Schumacher group

KEY ACHIEVEMENTS • Developed technology for the high-throughput profiling of tumor antigen-specific CD8+ and CD4+ T cell immunity. Over the past years, our group has developed MHC multimer-based technology to dissect antigen-specific CD8+ T cell responses in cancer patients. More recently, we have also developed a strategy to analyze (neo-antigen specific) CD4+ T cell responses, which is based on the use of oncogene-immortalized autologous APCs (Linnemann et al., Nat Med 2015). A main use of these technologies has been to describe tumor antigen specific T cell responses in melanoma and more recently NSCLC patients upon therapy (see below). In parallel, this toolbox has been used to isolate T cell populations specific for a number of lineage antigens (PNAS 2014, co-publication w/ Olweus and Lund-Johansen). Following validation, TCRs isolated from such T cells can be utilized to generate gene-modified T cell populations to target hematological malignancies. Linnemann C, van Buuren MM, Bies L, Verdegaal EM, Schotte R, Calis JJ, Behjati S, Velds A, Hilkmann H, el Atmioui D, Visser M, Stratton MR, Haanen JB, Spits H, van der Burg SH and Schumacher TN. High throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T-cells in human melanoma. Nat Med Jan;21(1):81-5 (2014). E-pub Dec 22, 2014. Commentary in Nat Med 21,12–14(2015) by Overwijk, W. Human CD4+ T cells spontaneously detect somatic mutations in cancer cells. S. Kumari, S. Wälchli, L.E. Fallang, W. Yang, F. Lund-Johansen, T.N. Schumacher, J. Olweus. Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes. Proc Natl Acad Sci USA. 111:403-8 (2014). • Described the frequent occurrence of neo-antigen specific CD8+ T cell and CD4+ T cell responses in melanoma. Using the above-mentioned toolbox, we have demonstrated that both neo-antigen specific CD4+ and CD8+ T cell responses are frequent in melanoma patients (CD8: 6 out of 8 patients analyzed; CD4: 4 out of 5 patients analyzed) (van Rooij et

al, JCO 2013, Linnemann et al., Nat Med 2015). Based on the mutational load in melanoma relative to that in other tumor types (Nature 2013), these data can also be utilized to predict the formation of neo-antigen repertoires in other human tumor types.

N. van Rooij, M. van Buuren, D. Philips, A. Velds, M. Toebes, B. Heemskerk, L. van Dijk, S. Behjati, H. Hilkmann, D. el Atmioui, M. Nieuwland, M.R. Stratton, R.M. Kerkhoven, C. Kesmir, J.B. Haanen, P. Kvistborg, and T.N. Schumacher. Tumor exome analysis reveals neo-antigen-specific T cell reactivity in an Ipilimumab responsive melanoma. J. Clin. Oncol. 31:e439-42 (2013).

• Provided evidence for a role of neo-antigen specific T cell reactivity in the clinical effects of checkpoint blockade and personalized immunotherapy. We have analyzed the effect of anti-CTLA4 treatment and anti-PD1 treatment in a melanoma and NSCLC patient who showed clinical responses to checkpoint blockade (van Rooij et al, JCO 2013, Rizvi et al. Science 2015). These analyses demonstrate that both types of checkpoint blockade can result in enhanced neo-antigen specific CD8+ T cell immunity. We have furthermore obtained data in collaboration with T. Chan, MSKCC showing that in NSCLCs treated with anti-PD1, a high nonsynonymous mutation burden is strongly predictive of clinical efficacy. These data provide additional support for the notion that neo-antigen recognition forms an important ingredient of the effects of anti-checkpoint therapies in tumors such as melanoma and NSCLC. This work further relates to data showing that personalized immunotherapy can be enabled using donor-derived neo-antigen specific T cells (ms in prep co-authored by Olweus) N.A. Rizvi, M.D. Hellmann, A. Snyder, P. Kvistborg, V. Makarov, J.J. Havel, W. Lee, J. Yuan, P. Wong, T.S> Ho, M.L. Miller, N. Rekhtman, A.L. Moreira, F. Ibrahim, C. Bruggeman, B. Gasmi, R. Zappasodi, Y. Maeda, C. Sander, E.B. Garon, T. Merghoub, J.D. Wolchok, T.N. Schumacher, T.A. Chan. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015 Mar 12. pii: aaa1348. [Epub ahead of print] PubMed PMID: 25765070.

m id - t e rm re p o r t 20 1 5

We have demonstrated a role of neo-antigen specific T cell reactivity in the clinical effects of personalized immunotherapy mid- t er m r e p o r t 2015

Taskén group The inhibition of Treg activity will enhance the effectiveness of adoptive T-cell therapies being developed in the centre Scientific summary Our main focus is to understand why the immune system sometimes turns off its ability to recognize and kill cells in an expanding malignant tumor. We aim to understand how tumors develop immune evasion strategies, what mechanisms operate in different cancers and how we can perturb such immunoinhibitory signals to boost anti-tumor immunity. Regulatory T cells (Tregs) have been demonstrated to suppress immune responses to cancer cells, and their removal improves anti-tumor immunity in most cancers. Based on our current understanding of Treg function, it is plausible that the inhibition of Treg activity will enhance the effectiveness of adoptive T-cell therapies being developed in the centre by the Olweus and Schumacher groups. The Taskén group is currently delineating the signaling cascades of inhibitory Tregs as compared with activating effector T cells, thereby aiming to identify molecules in Tregs that can be specifically targeted by small molecule inhibitors. Furthermore, the role of Tregs in suppression of anti-tumor immunity has been assessed in ovarian cancer and in pancreatic, gastric and hepatocellular carcinoma. In addition, a new potential mechanism of regulation of Treg mediated immunosuppression via gap junctions has been characterized and a chemical biology screen has delivered a set of candidate compounds to perturb this mechanism (continuing work).

The Taskén group has observed that cancer cells, as well as monocytes and Tregs, may secrete high levels of the inflammatory mediator PGE2, which suppresses effector T cell signaling and immune function. Team members have established analyses to assess effects of PGE2 on the phosphoproteome of T-cell subsets and using phosphoflow analysis in a systems biology approach developed in (ongoing), and have examined the impact on T cell signaling in patients with colorectal cancer. These studies as well as similar studies on Treg align well with ongoing studies in the Lund-Johansen (multiplexed analyses of T cell proteomics) and Malmberg (NK cell CyTOF analyses ao) groups. Proof-of-concept that perturbing the PGE2 pathway inhibits tumor growth is already available from animal experiments and targeting strategies are being tested. Clinical impact of perturbing the PGE2 pathway by existing drugs in colorectal cancer has been assessed in a registry study coupling data from the Cancer Registry of Norway and the Norwegian Prescription Database. Key achievements • Signaling networks elicited by T cell co-stimulation by CD28 and CD2 have been mapped in detail by phosphoflow cytometry, showing differences in activation of the proximal and distal signals, and the mechanisms have now largely been mapped (ongoing). A detailed mapping of human Treg effects on T-cell signalling has also been finalized showing how effector T cells may become suppressed or escape depending on the level of suppression.

m id - t e rm re p o r t 20 1 5

Examination of malignant ascites from cancer ovary patients demonstrates elevated levels of active Tregs mid- t er m r e p o r t 2015

Taskén group

Skånland, S.S., Moltu, K., Berge, T., Aandahl, E.M., Taskén, K. (2014) T-cell co-stimulation through CD2 and CD28 induces distinct signaling responses. Biochem. J., 460:399-410.

Gunasekaran, S.C., Lieske, N.V., Hagness, M., Line, P.D., Taskén, K., Aandahl, E.M. Activation status of human regulatory T cells controls TCR signaling and susceptibility to suppression in CD4+ T cells. In press.

ology has been used to establish a new screening for modulators of expression levels of FoxP3, a transcription factor that defines Tregs and is linked to their level of activation. Ongoing work now assesses hits from the first part of this screening approach for ability to modulate Treg function.

Ellinger, B., Silber, J., Prashar, A., Landskron, J., Weber, J., Rehermann, S., Müller, F.-J., Smith, S., Wrigley, S., Taskén, K., Gribbon, P., Labes, A., Imhoff. J.F. (2014) A phenotypic screening approach to identify novel anti-cancer compounds derived from marine fungi. Assay Drug Dev. Technol., 12:162-75.

• Examination of malignant ascites from cancer ovary patients demonstrates elevated levels of active Tregs in malignant ascites and methods to monitor Treg in clinical samples have been developed.

Landskron, J., Helland, Ø., Torgersen, K.M., Aandahl, E.M., Gjertsen, B.T. Bjørge, L., Taskén, K. Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients. Cancer Immunol. Immunother., 64:337-47.

Spurgeon, B.E.J., Aburima, A., Oberprieler, N.G., Taskén, K., Naseem, K.M. (2014) Multiplexed Phosphospecific Flow Cytometry Enables Large-scale Signaling Profiling and Drug Screening in Blood Platelets. J. Thromb. Haemostasis, 12:1733-43.

Santegoets, S.J.A.M., Dijkgraaf, E.M., Battaglia, A., Beckhove, P., Britten, C.M., Gallimore, A., Gouttefangeas, C., de Gruijl, T.D., Koenen, H.J.P.M., Scheffold, A., Shevach, E.M., Staats, J., Taskén, K., Whiteside, T.L., Kroep, J.R., Welters, M.J.P., van der Burg, S.H. Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry. Submitted.

Landskron, J., Taskén, K. Phosphoprotein detection by high-throughput flow cytometry. Invited Chapter in Methods in Molecular Biology (Springer) “Phosphoproteomics – Methods and Protocols” (Ed. Louise von Stechow). In press.

• A chemical proteomics approach and peptide disruptor/siRNA characterization in throphoblast primary cultures have identified ezrin as the A kinase anchoring protein (AKAP) that regulates GAP junction communication through formation of a PKA/ezrin/Cx43/ZO1 complex. PKA and ezrin regulation of Cx43 opening may have application in immune regulation as one mechanism of Treg suppression is by Gap junction communication.

Pidoux, G., Gerbaud, P., Dompierre, J., Lygren B., Solstad, T., Evain-Brion, D., Taskén, K. (2014) The A kinase anchoring protein ezrin interacts with connexin 43 to facilitate protein kinase A control of gap junction communication in cell fusion. J. Cell Sci., 127:41724185.

Patent application filed. • The Taskén group has in 2014 delivered a new unique setup and roboticized pipeline for flow cytometry-based chemical biology screening that has been tested and put into production. This method-

• COX-2 / PGE2 mediated immunosuppression inhibits anti-tumor immune activity in patients with colorectal cancer. Our prospective studies of patients with metastatic colorectal cancer undergoing liver surgery showed that Treg-mediated suppression by PGE2 predicts clinical outcome (Cancer Immunol Immunother, 2012) and a follow-up study on patients has examined signalling defects. A registry study coupling the Norwegian Cancer Registry and Prescription Database shows a highly significant secondary preventive affect of acetyl salicylic acid probably due to this effect. A clinical intervention trial is now starting.

Moltu, K., Henjum, K., Oberprieler, N.G., Bjørnbeth, B.A., Taskén, K. Proximal signaling responses in peripheral T cells from colorectal cancer patients are affected by high concentrations of circulating prostaglandin E2. Resubmitted, PLoS One.

Bains, S.J., Mahic, M., Småstuen, M.C., Yaqub, S., Dørum, L.M., Bjørnbeth, B.A., Møller, B., Brudvik, K.W., Taskén, K. Impact of Aspirin as Secondary Prevention in an Unselected Cohort of 25,644 Patients with Colorectal Cancer – A Population-Based Study. Submitted.

m id - t e rm re p o r t 20 1 5

COX-2 / PGE2 mediated immunosuppression inhibits anti-tumor immune activity in patients with colorectal cancer

mid- t er m r e p o r t 2015

The patients Treating patients with novel immunotherapy â&#x20AC;&#x201C; a JCIT commitment Foto: Terje Heiestad, MillimeterPress AS.

Arne Kolstad.

Lymvac-1: Treating follicular lymphoma with local immunotherapy to achieve systemic effects

A major goal of the JCIT consortium has been to create new immunologic therapies that will benefit cancer patients. Recently, an early exploratory study with a novel inhouse in situ vaccine strategy was conducted with Arne Kolstad as principal investigator (Lymvac-1 trial). The target population for this trial was patients with disseminated untreated or relapsed follicular non-Hodgkin`s lymphoma (FL). Patients with disseminated disease stage III or IV and are considered to be incurable by standard therapies available today. Remissions can be achieved with monoclonal antibody therapy, chemotherapy or the combination of both. However, relapses tend to occur with closer intervals and in the end treatment options are scarce. There is evidence to support that immune surveillance is of importance in FL and we therefore decided to conduct a study aiming to overcome tolerance against the cancer by a novel immunostimulatory approach. Local immunotherapies administered intra-tumorally have thus far not received much attention relative to systemic immunotherapies. In our study we investigated the possible concerted actions of local radiation and in situ immunostimulatory strategies to induce T-cell mediated immune responses resulting in clinical effects. Fourteen patients with stage III/IV follicular lymphoma (FL) grade I-IIIA, of which the majority were previously untreated, received sequential intranodal immunotherapy targeting single lymph nodes. Three different treatment modalities were combined; radiotherapy (RT), injections of low-dose rituximab (5 mg) and immature autologous dendritic cells (DCs). Clinical responses were observed in five out of fourteen patients (36%), and two patients had durable complete remissions. For this study, the group of Johanna Olweus designed a new

assay to monitor T-cell mediated anti-tumor reactivity. Notably, vaccination-induced systemic CD8 and also CD4 T-cell mediated responses against autologous tumor cells were detected in peripheral blood in responding patients. Reduction in total tumor volume was closely correlated with the magnitude of vaccination-induced systemic CD8 T-cell mediated responses, and immune responders showed prolonged time to next treatment compared to non-responders. Our in situ vaccine strategy could override local suppression of T-cell responses targeting tumor. Moreover, activated tumor-reactive T cells were rendered resistant to further suppression. We hypothesize that pre-conditioning of the lymphoma node by radiotherapy provides an ample source of â&#x20AC;&#x153;danger signalsâ&#x20AC;? to facilitate DC maturation and presentation of tumor-antigens to T cells. Memory T cells migrating into the irradiated lymph nodes can then make contact with and become primed by the injected and matured DCs. Moreover, intranodally administrered DCs can migrate to distal lymph nodes, opening the possibility that DCs bring tumor-antigen to distant sites for further T-cell priming. In some patients, this resulted in the elimination of bulky tumor masses, likely caused by T-cell migration to distant tumor sites. Results from this study were published in Blood 2014 with Kolstad as first author and Olweus as last author. The study received considerable attention, and a Commentary by Josh Brody appeared in the same issue of Blood. Kolstad and Olweus furthermore discussed potential mechanisms of action in an invited Author-view article in Oncoimmunology, 2015.

Lymvac-2 - A follow-up study of Lymvac-1

The majority of FL patients who achieved immune responses and clinical responses by local immunotherapy have relapsed during follow-up. Hence, our next goal will be to

m id - t e rm re p o r t 20 1 5

37 tt PET-scan before start of treatment shows advanced stage follicular lymphoma. PET-scan one year uu after treatment is normal. Patient is still in complete remission 5 Â˝ years after treatment.

improve and prolong the effects observed in Lymvac-1. A new study is planned to start in 2015 (Lymvac-2) where we keep the local immunotherapy platform unchanged, but add on a check-point inhibitor administered systemically. The pharmaceutical company Merck has agreed to provide the anti-PD1 antibody Pembrolizumab free of charge for 20 patients with FL. In this phase II study patients will be recruited from all regions in Norway and treated at Oslo University Hospital Radiumhospitalet. As in Lymvac-1, the major end-points will be clinical and immunological responses. Recruitment time is estimated to be 2 years. We expect shorter accrual time for Lymvac-2 than Lymvac-1, given the attention results from Lymvac-1 have received in the scientific community and media. Harnessing Natural Killer Cells in Cancer Therapy KJM is the co-ordinating investigator of a first phase I/II clinical trial based on adoptive transfer of haploidentical NK cells to patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who have no other treatment options. This trial is carried out at the Karolinska Institutet (KI). The treatment has been well tolerated. Interestingly, six patients achieved complete remission (CR) that lasted at least 3 months. Four of these patients were transplanted within 6 months after NK cell treatment. Notably, the clinical responses correlated with the emergence of donor-derived NK cells at day 7 post adoptive transfer. Based on the positive results in this first trial we aim to establish generic models for national and international scale-up of NK cell-based cell therapy strategies, either alone or in combination with other treatment modalities such as antibodies. To pave the way for a more generic platform, we propose to launch a multicenter Nordic Phase II trial that capitalizes on the promising results of the completed Phase I/ II trial. The Nordic trial will be co-ordinated from the K.G. Jebsen Center at the University of Oslo.

mid- t er m r e p o r t 2015

Treatment schedule and proposed mechanism of action in the LYMVAC clinical trial.

Innovation

Schumacher’s biotech company T Cell Factory B.V acquired by Kite Pharma. Kite Pharma has acquired T cell factory BV (TCF), previously owned by Schumacher and the NKI. Financial terms of Kite’s acquisition of TCF include an upfront payment of up to Euro 20.0M. Kite Pharma, founded in 2009, is a clinical-stage biopharmaceutical company focused on the development and commercialization of novel cancer immunotherapy products. Schumacher has been appointed Chief Scientific Officer of Kite’s European headquarters. Scientists from the Schumacher laboratory will work closely with Kite scientists to develop new TCR candidates against mutated proteins and thereby generate truly tumor-specific therapy. The agreement greatly strengthens the possibilities for translating discoveries made by researchers in the JCIT into new therapies.

Olweus group and Inven2 have filed a patent for new technology to discover immune-recognition elements in cancer cells Identification of immune-recognition elements, or epitopes, is a bottleneck in immuno-therapy. Established methods for discovery of T cell epitopes involve screening of peptide libraries or detection of MHCbound peptides by mass spectrometry. In an article published in the prestigious journal the Proceedings of the National Academy of Sciences USA, the Olweus group describes a new approach that eliminates these laborious and time-consuming steps. The method is in part a novel combination of technologies previously described by the Olweus and Schumacher groups. Results obtained using the method show that the number of immune-recognition elements is far greater than previously expected. The group has received an innovation grant from the BIOTEK2021 program of the Research Council of Norway to pursue therapeutic applications of T-cell receptors reactive to peptides identified using the technology.

m id - t e rm re p o r t 20 1 5

Lund-Johansen group has validated the commercial potential of their protein array technology Lund-Johansen and Inven2 are currently finalizing an innovation project, which aims to explore the commercial potential of FLJ’s protein array technology. The project is funded by the FORNY programme of the Research Council of Norway. In collaboration with US antibody manufacturer Novus Biologicals, Lund-Johansen has shown that his array technology can be applied for high-throughput validation of antibodies. Validation is the bottleneck in antibody production, and poorly validated antibodies represent a frequent cause of irreproducibility of bio-medical research. Inven2 and Lund-Johansen are currently negotiating with several candidate industry partners. The aim is to establish a Norwegian biotech company based on the array technology.

mid- t er m r e p o r t 2015

The Taskén group has identified hit compounds that inhibit the activity of regulatory T cells (Treg). Previously, the Taskén group has shown that prostaglandin E2 (PGE2) activates Treg cells via a pathway that involves protein kinase A (PKA). Direct targeting of PKA has proven to be difficult due to the ubiquitous expression of the kinase and the lack of oral bioavailability of cAMP antagonists that target the PKA regulatory subunit (cAMP receptor) expressed lymphocytes. However, the Taskén group has discovered cell type-specific adaptor and anchoring proteins that have a role in scaffolding signalling enzymes downstream of PKA in effector T cells and regulatory T cells. The group receives grants from the Norwegian Cancer Society and the University of Oslo to pursue development of compounds that interfere with the immunomodulaing signalling machinery.

Publications During the short existence of JCIT, scientists at JCIT have authored or co-authored 83 papers, of which 77 papers are in international peer-reviewed journals. Among these, 17 papers were published in journals with an impact factor above 10, and 26 papers in journals with an impact factor between 5 and 10. International, as well as national, collaborations are an important part of the daily research activities at JCIT and highly valued by all group leaders. Thus, 40 out of the 83 publications are a direct result of collaborations with international research institutions. All publications are listed on page 40-43. National/international collaborators are listed on page 53-54.

Distrubution by impact factor

7% (6)

20%

41%

(17)

(34)

Walseng, E., Walchli, S., Fallang, L. E., Yang, W., Vefferstad, A., Areffard, A. & Olweus, J. Soluble T-cell receptors produced in human cells for targeted delivery. PLoS One 10, e0119559 (2015).

Schlums, H., Cichocki, F., Tesi, B., Theorell, J., Beziat, V., Holmes, T. D., Han, H., Chiang,S. C., Foley, B., Mattsson, K., Larsson, S., Schaffer, M., Malmberg, K. J., Ljunggren, H. G., Miller, J. S. & Bryceson, Y. T. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42, 443-456 (2015).

Vesterhus, M., Hov, J. R., Holm, A., Schrumpf, E., Nygard, S., Godang, K., Andersen, I. M., Naess, S., Thorburn, D., Saffioti, F., Vatn, M., Gilja, O. H., Lund-Johansen, F., Syversveen, T., Brabrand, K., Pares, A., Ponsioen, C. Y., Pinzani, M., Farkkila, M., Moum, B., Ueland, T., Rosjo, H., Rosenberg, W., Boberg, K. M. & Karlsen, T. H. Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis. Hepatology (2015). Sobecks, R. M., Wang, T., Askar, M., Gallagher, M. M., Haagenson, M., Spellman, S., Fernandez-Vina, M., Malmberg, K. J., Muller, C., Battiwalla, M., James, G., Verneris, M. R., Ringden, O., Marino, S. R., Davies, S., Dehn, J., Bornhauser, M., Inamoto, Y., Woolfrey, A., Shaw, P., Pollack, M., Weisdorf, D., Miller, J., Hurley, C. K., Lee, S. J. & Hsu, K. C. Impact of KIR and HLA Genotypes on Outcomes after Reduced-Intensity Conditioning Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant (2015). Smeland, K. B., Kiserud, C. E., Lauritzsen, G. F., Fagerli, U. M., Falk, R. S., Fluge, O., Fossa, A., Kolstad, A., Loge, J. H., Maisenholder, M., Kvaloy, S. & Holte, H. Conditional survival and excess mortality after high dose therapy with autologous stem cell transplantation for adult refractory or relapsed Hodgkin lymphoma in Norway. Haematologica (2015).

No IF availabe

(26)

Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69-74 (2015).

Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J. J., Lee, W., Yuan, J., Wong, P., Ho, T. S., Miller, M. L., Rekhtman, N., Moreira, A. L., Ibrahim, F., Bruggeman, C., Gasmi, B., Zappasodi, R., Maeda, Y., Sander, C., Garon, E. B., Merghoub, T., Wolchok, J. D., Schumacher, T. N. & Chan, T. A. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124-128 (2015). Lunemann, S., Malone, D. F., Grabowski, J., Port, K., Beziat, V., Bremer, B., Malmberg, K. J., Manns, M. P., Sandberg, J. K., Cornberg, M., Ljunggren, H. G., Wedemeyer, H. & Bjorkstrom, N. K. Effects of HDV infection and pegylated interferon alpha treatment on the natural killer cell compartment in chronically infected individuals. Gut 64, 469-482 (2015). Landskron, J., Helland, O., Torgersen, K. M., Aandahl, E. M., Gjertsen, B. T., Bjorge, L. & Tasken, K. Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients. Cancer Immunol Immunother 64, 337347 (2015).

5-10 <5

31%

Kolstad, A., Olweus, J. â&#x20AC;&#x153;In situâ&#x20AC;? vaccination for systemic effects in follicular lymphoma. Oncoimmunology (In press).

>10

Linnemann, C., van Buuren, M. M., Bies, L., Verdegaal, E. M., Schotte, R., Calis, J. J., Behjati, S., Velds, A., Hilkmann, H., Atmioui, D. E., Visser, M., Stratton, M. R., Haanen, J. B., Spits, H., van der Burg, S. H. & Schumacher, T. N. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat Med 21, 81-85 (2015). cover-nm0115.indd 1

12/19/14 2:14 PM

Husby, S., Ralfkiaer, U., Garde, C., Zandi, R., Ek, S., Kolstad, A., Jerkeman, M., Laurell, A., Raty, R., Pedersen, L. B., Pedersen, A., Ehinger, M., Sundstrom, C., Karjalainen-Lindsberg, M. L., Delabie, J., Clasen-Linde, E., Brown, P., Cowland, J. B., Workman, C. T., Geisler, C. H. & Gronbaek, K. miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. Blood 125, 2669-2677 (2015).

m id - t e rm re p o r t 20 1 5

41 van Buuren, M. M., Dijkgraaf, F. E., Linnemann, C., Toebes, M., Chang, C. X., Mok, J. Y., Nguyen, M., van Esch, W. J., Kvistborg, P., Grotenbreg, G. M. & Schumacher, T. N. HLA micropolymorphisms strongly affect peptide-MHC multimer-based monitoring of antigen-specific CD8+ T cell responses. J Immunol 192, 641-648 (2014). VOLUME 125 NUMBER 1 1 JANUARY 2015

Clinical Review Series on Aggressive B-Cell Lymphomas (p 1, p 22, p 33, p 40, p 48) X-linked tumor suppressor in T-ALL (p 3, p 13) CDK6 regulates normal and leukemic stem cell proliferation (p 7, p 90)

EVI1 rearrangement defines a single MDS/AML entity with frequent RAS mutation (p 9, p 133, p 140) Distinguishing GATA2 deficiency disorders from aplastic anemia (p 56) HIT antibodies, the serotonin-release assay, and plasma exchange (p 155, p 195)

Cover: SLAP and SLAP2 inhibit platelet reactivity in arterial thrombosis and stroke (p 185) www.bloodjournal.org

Kolstad, A., Kumari, S., Walczak, M., Madsbu, U., Hagtvedt, T., Bogsrud, T. V., Kvalheim, G., Holte, H., Aurlien, E., Delabie, J., Tierens, A. & Olweus, J. Sequential intranodal immunotherapy induces antitumor immunity and correlated regression of disseminated follicular lymphoma. Blood 125, 82-89 (2015). Ferrara, F., Dâ&#x20AC;&#x2122;Angelo, S., Gaiotto, T., Naranjo, L., Tian, H., Graslund, S., Dobrovetsky, E., Hraber, P., Lund-Johansen, F., Saragozza, S., Sblattero, D., Kiss, C. & Bradbury, A. R. Recombinant renewable polyclonal antibodies. MAbs 7, 32-41 (2015). Enqvist, M., Ask, E. H., Forslund, E., Carlsten, M., Abrahamsen, G., Beziat, V., Andersson, S., Schaffer, M., Spurkland, A., Bryceson, Y., Onfelt, B. & Malmberg, K. J. Coordinated Expression of DNAM-1 and LFA-1 in Educated NK Cells. J Immunol 194, 4518-4527 (2015). Blix, E. S., Kildal, A. B., Bertelsen, E., Waage, A., Myklebust, J. H., Kolstad, A. & Husebekk, A. Content of endothelial progenitor cells in autologous stem cell grafts predict survival after transplantation for multiple myeloma. Biol Blood Marrow Transplant 21, 840-847 (2015). Becattini, S., Latorre, D., Mele, F., Foglierini, M., De Gregorio, C., Cassotta, A., Fernandez, B., Kelderman, S., Schumacher, T. N., Corti, D., Lanzavecchia, A. & Sallusto, F. T cell immunity. Functional heterogeneity of human memory CD4(+) T cell clones primed by pathogens or vaccines. Science 347, 400-406 (2015). Westerhuis, G., de Witte, M., Schumacher, T. N., Toes, R. E. & Fibbe, W. E. Barriers to chimerism after major histocompatibility complex-mismatched stem cell transplantation: a potential role for heterologous immunity. Exp Hematol 42, 753-760 (2014). Walchli, S., Kumari, S., Fallang, L. E., Sand, K. M., Yang, W., Landsverk, O. J., Bakke, O., Olweus, J. & Gregers, T. F. Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T-cell activation. Eur J Immunol 44, 774-784 (2014).

mid- t er m r e p o r t 2015

van Buuren, M. M., Calis, J. J. & Schumacher, T. N. High sensitivity of cancer exome-based CD8 T cell neo-antigen identification. Oncoimmunology 3, e28836 (2014). Taraldsrud, E., Fevang, B., Aukrust, P., Beiske, K. H., Floisand, Y., Froland, S., Rollag, H. & Olweus, J. Common variable immunodeficiency revisited: normal generation of naturally occurring dendritic cells that respond to Toll-like receptors 7 and 9. Clin Exp Immunol 175, 439-448 (2014). Spurgeon, B. E., Aburima, A., Oberprieler, N. G., Tasken, K. & Naseem, K. M. Multiplexed phosphospecific flow cytometry enables large-scale signaling profiling and drug screening in blood platelets. J Thromb Haemost 12, 1733-1743 (2014). Skanland, S. S., Moltu, K., Berge, T., Aandahl, E. M. & Tasken, K. T-cell co-stimulation through the CD2 and CD28 co-receptors induces distinct signalling responses. Biochem J 460, 399-410 (2014). Singh, M., Singh, P., Vaira, D., Torheim, E. A., Rahmouni, S., Tasken, K. & Moutschen, M. The RIAD peptidomimetic inhibits HIV-1 replication in humanized NSG mice. Eur J Clin Invest 44, 146-152 (2014). Shugay, M., Britanova, O. V., Merzlyak, E. M., Turchaninova, M. A., Mamedov, I. Z., Tuganbaev, T. R., Bolotin, D. A., Staroverov, D. B., Putintseva, E. V., Plevova, K., Linnemann, C., Shagin, D., Pospisilova, S., Lukyanov, S., Schumacher, T. N. & Chudakov, D. M. Towards error-free profiling of immune repertoires. Nat Methods 11, 653-655 (2014).

cellular barcoding experiments. Cell Rep 6, 617-624 (2014). Nordstrom, L., Sernbo, S., Eden, P., Gronbaek, K., Kolstad, A., Raty, R., Karjalainen, M. L., Geisler, C., Ralfkiaer, E., Sundstrom, C., Laurell, A., Delabie, J., Ehinger, M., Jerkeman, M. & Ek, S. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma--a Nordic Lymphoma Group study. Br J Haematol 166, 98-108 (2014). Munneke, J. M., Bjorklund, A. T., Mjosberg, J. M., Garming-Legert, K., Bernink, J. H., Blom, B., Huisman, C., van Oers, M. H., Spits, H., Malmberg, K. J. & Hazenberg, M. D. Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease. Blood 124, 812-821 (2014). Lossius, A., Johansen, J. N., Vartdal, F., Robins, H., Jurate Saltyte, B., Holmoy, T. & Olweus, J. High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells. Eur J Immunol 44, 3439-3452 (2014). Laurell, A., Kolstad, A., Jerkeman, M., Raty, R. & Geisler, C. H. High dose cytarabine with rituximab is not enough in first-line treatment of mantle cell lymphoma with high proliferation: early closure of the Nordic Lymphoma Group Mantle Cell Lymphoma 5 trial. Leuk Lymphoma 55, 1206-1208 (2014). Kvistborg, P., Philips, D., Kelderman, S., Hageman, L., Ottensmeier, C., Joseph-Pietras, D., Welters, M. J., van der Burg, S., Kapiteijn, E., Michielin, O., Romano, E., Linnemann, C., Speiser, D., Blank, C., Haanen, J. B. & Schumacher, T. N. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci Transl Med 6, 254ra128 (2014).

Rogne, M. & Tasken, K. Compartmentalization of cAMP signaling in adipogenesis, lipogenesis, and lipolysis. Horm Metab Res 46, 833-840 (2014). Possik, P. A., Muller, J., Gerlach, C., Kenski, J. C., Huang, X., Shahrabi, A., Krijgsman, O., Song, J. Y., Smit, M. A., Gerritsen, B., Lieftink, C., Kemper, K., Michaut, M., Beijersbergen, R. L., Wessels, L., Schumacher, T. N. & Peeper, D. S. Parallel in vivo and in vitro melanoma RNAi dropout screens reveal synthetic lethality between hypoxia and DNA damage response inhibition. Cell Rep 9, 1375-1386 (2014). Pidoux, G., Gerbaud, P., Dompierre, J., Lygren, B., Solstad, T., Evain-Brion, D. & Tasken, K. A PKA-ezrin-Cx43 signaling complex controls gap junction communication and thereby trophoblast cell fusion. J Cell Sci 127, 4172-4185 (2014). Perie, L., Hodgkin, P. D., Naik, S. H., Schumacher, T. N., de Boer, R. J. & Duffy, K. R. Determining lineage pathways from

Kumari, S., Walchli, S., Fallang, L. E., Yang, W., Lund-Johansen, F., Schumacher, T. N. & Olweus, J. Alloreactive cytotoxic T cells provide means to decipher the im-

Publications and patents munopeptidome and reveal a plethora of tumor-associated self-epitopes. Proc Natl Acad Sci U S A 111, 403-408 (2014). Kolstad, A., Laurell, A., Jerkeman, M., Gronbaek, K., Elonen, E., Raty, R., Pedersen, L. B., Loft, A., Bogsrud, T. V., Kimby, E., Hansen, P. B., Fagerli, U. M., Nilsson-Ehle, H., Lauritzsen, G. F., Lehmann, A. K., Sundstrom, C., Karjalainen-Lindsberg, M. L., Ralfkiaer, E., Ehinger, M., Delabie, J., Bentzen, H., Schildt, J., Kostova-Aherdan, K., Frederiksen, H., Brown Pde, N., Geisler, C. H. & Nordic Lymphoma, G. Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma. Blood 123, 2953-2959 (2014). Kelderman, S., Heemskerk, B., van Tinteren, H., van den Brom, R. R., Hospers, G. A., van den Eertwegh, A. J., Kapiteijn, E. W., de Groot, J. W., Soetekouw, P., Jansen, R. L., Fiets, E., Furness, A. J., Renn, A., Krzystanek, M., Szallasi, Z., Lorigan, P., Gore, M. E., Schumacher, T. N., Haanen, J. B., Larkin, J. M. & Blank, C. U. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 63, 449-458 (2014). Husoy, M. A., Brinch, L., Tjonnfjord, G. E., Gedde-Dahl, T., Jr., Heldal, D., Holme, P. A., Dybedal, I., Kolstad, A., Akkok, C. A., Rollag, H., Gaustad, P., Bergan, S., Egeland, T., Josefsen, D., Kvalheim, G. & Floisand, Y. [Allogeneic stem-cell transplantation in adults 1985-2012: results and development]. Tidsskr Nor Laegeforen 134, 1569-1575 (2014). Hoppes, R., Oostvogels, R., Luimstra, J. J., Wals, K., Toebes, M., Bies, L., Ekkebus, R., Rijal, P., Celie, P. H., Huang, J. H., Emmelot, M. E., Spaapen, R. M., Lokhorst, H., Schumacher, T. N., Mutis, T., Rodenko, B. & Ovaa, H. Altered peptide ligands revisited: vaccine design through chemically modified HLA-A2-restricted T cell epitopes. J Immunol 193, 4803-4813 (2014). Halvorsen, B., Smedbakken, L. M., Michelsen, A. E., Skjelland, M., Bjerkeli, V., Sagen, E. L., Tasken, K., Bendz, B., Gullestad, L., Holm, S., Biessen, E. A. & Aukrust, P. Activated platelets promote increased monocyte expression of CXCR5 through prostaglandin E2-related mechanisms and enhance the anti-inflammatory effects of CXCL13. Atherosclerosis 234, 352-359 (2014). Gubin, M. M., Zhang, X., Schuster, H., Caron, E., Ward, J. P., Noguchi, T., Ivanova, Y., Hundal, J., Arthur, C. D., Krebber, W. J., Mulder, G. E., Toebes, M., Vesely, M. D., Lam, S. S., Korman, A. J., Allison, J. P., Freeman, G. J., Sharpe, A. H., Pearce, E. L., Schumacher, T. N., Aebersold, R., Rammensee, H. G., Melief, C. J., Mardis, E. R., Gillanders, W. E., Artyomov, M. N. & Schreiber, R. D. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577-581 (2014).

Gomez-Eerland, R., Nuijen, B., Heemskerk, B., van Rooij, N., van den Berg, J. H., Beijnen, J. H., Uckert, W., Kvistborg, P., Schumacher, T. N., Haanen, J. B. & Jorritsma, A. Manufacture of gene-modified human T-cells with a memory stem/central memory phenotype. Hum Gene Ther Methods 25, 277-287 (2014). Ellinger, B., Silber, J., Prashar, A., Landskron, J., Weber, J., Rehermann, S., Muller, F. J., Smith, S., Wrigley, S., Tasken, K., Gribbon, P., Labes, A. & Imhoff, J. F. A phenotypic screening approach to identify anticancer compounds derived from marine fungi. Assay Drug Dev Technol 12, 162-175 (2014). Bunse, M., Bendle, G. M., Linnemann, C., Bies, L., Schulz, S., Schumacher, T. N. & Uckert, W. RNAi-mediated TCR knockdown prevents autoimmunity in mice caused by mixed TCR dimers following TCR gene transfer. Mol Ther 22, 1983-1991 (2014). Blaker, Y. N., Eide, M. B., Liestol, K., Lauritzsen, G. F., Kolstad, A., Fossa, A., Smeland, E. B. & Holte, H. High dose chemotherapy with autologous stem cell transplant for patients with transformed B-cell non-Hodgkin lymphoma in the rituximab era. Leuk Lymphoma 55, 2319-2327 (2014). Blaker, Y. N., Brodtkorb, M., Maddison, J., Hveem, T. S., Nesheim, J. A., Mohn, H. M., Kolstad, A., Geisler, C. H., Liestol, K., Smeland, E. B., Holte, H., Delabie, J. & Danielsen, H. Computerized image analysis of the Ki-67 proliferation index in mantle cell lymphoma. Histopathology (2014). Beziat, V., Traherne, J., Malmberg, J. A., Ivarsson, M. A., Bjorkstrom, N. K., Retiere, C., Ljunggren, H. G., Michaelsson, J., Trowsdale, J. & Malmberg, K. J. Tracing dynamic expansion of human NK-cell subsets by high-resolution analysis of KIR repertoires and cellular differentiation. Eur J Immunol 44, 2192-2196 (2014). Bersvendsen, H., Kolstad, A., Blystad, A. K., Aurlien, E., Fossa, A., Kvaloy, S. O., Holte, H. & Lauritzsen, G. F. Multimodal treatment with ALL-like chemotherapy, Auto-SCT and radiotherapy for lymphoblastic lymphoma. Acta Oncol 53, 680-687 (2014). Bengner, M., Beziat, V., Ernerudh, J., Nilsson, B. O., Lofgren, S., Wikby, A., Malmberg, K. J. & Strindhall, J. Independent skewing of the T cell and NK cell compartments associated with cytomegalovirus infection suggests division of labor between innate and adaptive immunity. Age (Dordr) 36, 571-582 (2014). Azzi, T., Lunemann, A., Murer, A., Ueda, S., Beziat, V., Malmberg, K. J., Staubli, G., Gysin, C., Berger, C., Munz, C., Chijioke, O. & Nadal, D. Role for early-differentiated natural killer cells in infectious mononucleosis. Blood 124, 2533-2543 (2014).

Ariotti, S., Hogenbirk, M. A., Dijkgraaf, F. E., Visser, L. L., Hoekstra, M. E., Song, J. Y., Jacobs, H., Haanen, J. B. & Schumacher, T. N. T cell memory. Skin-resident memory CD8(+) T cells trigger a state of tissue-wide pathogen alert. Science 346, 101-105 (2014). Almagro, J. C., Gilliland, G. L., Breden, F., Scott, J. K., Sok, D., Pauthner, M., Reichert, J. M., Helguera, G., Andrabi, R., Mabry, R., Blery, M., Voss, J. E., Lauren, J., Abuqayyas, L., Barghorn, S., Ben-Jacob, E., Crowe, J. E., Jr., Huston, J. S., Johnston, S. A., Krauland, E., Lund-Johansen, F., Marasco, W. A., Parren, P. W. & Xu, K. Y. Antibody engineering and therapeutics, The Annual Meeting of the Antibody Society: December 8-12, 2013, Huntington Beach, CA. MAbs 6, 577-618 (2014). Vanherberghen, B., Olofsson, P. E., Forslund, E., Sternberg-Simon, M., Khorshidi, M. A., Pacouret, S., Guldevall, K., Enqvist, M., Malmberg, K. J., Mehr, R. & Onfelt, B. Classification of human natural killer cells based on migration behavior and cytotoxic response. Blood 121, 1326-1334 (2013). Vang, T., Landskron, J., Viken, M. K., Oberprieler, N., Torgersen, K. M., Mustelin, T., Tasken, K., Tautz, L., Rickert, R. C. & Lie, B. A. The autoimmune-predisposing variant of lymphoid tyrosine phosphatase favors T helper 1 responses. Hum Immunol 74, 574-585 (2013). van Rooij, N., van Buuren, M. M., Philips, D., Velds, A., Toebes, M., Heemskerk, B., van Dijk, L. J., Behjati, S., Hilkmann, H., El Atmioui, D., Nieuwland, M., Stratton, M. R., Kerkhoven, R. M., Kesmir, C., Haanen, J. B., Kvistborg, P. & Schumacher, T. N. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 31, e439-442 (2013). van der Heijden, I., Gomez-Eerland, R., van den Berg, J. H., Oosterhuis, K., Schumacher, T. N., Haanen, J. B., Beijnen, J. H. & Nuijen, B. Transposon leads to contamination of clinical pDNA vaccine. Vaccine 31, 3274-3280 (2013). Turchaninova, M. A., Britanova, O. V., Bolotin, D. A., Shugay, M., Putintseva, E. V., Staroverov, D. B., Sharonov, G., Shcherbo, D., Zvyagin, I. V., Mamedov, I. Z., Linnemann, C., Schumacher, T. N. & Chudakov, D. M. Pairing of T-cell receptor chains via emulsion PCR. Eur J Immunol 43, 2507-2515 (2013). Storvold, G. L., Landskron, J., Strozynski, M., Arntzen, M. O., Koehler, C. J., Kalland, M. E., Tasken, K. & Thiede, B. Quantitative profiling of tyrosine phosphorylation revealed changes in the activity of the T cell receptor signaling pathway upon cisplatin-induced apoptosis. J Proteomics 91, 344-357 (2013). Sternberg-Simon, M., Brodin, P., Pickman, Y., Onfelt, B., Karre, K., Malmberg, K. J., Hoglund, P. & Mehr, R. Natural killer cell inhibitory receptor expression in humans and mice: a closer look. Front Immunol 4, 65 (2013). m id - t e rm re p o r t 20 1 5

43 Smeland, K. B., Kiserud, C. E., Lauritzsen, G. F., Fossa, A., Hammerstrom, J., Jetne, V., Kolstad, A., Kvalheim, G., Loge, J. H., Lokeland, T., Tangen, J. M., Holte, H. & Kvaloy, S. High-dose therapy with autologous stem cell support for lymphoma--from experimental to standard treatment. Tidsskr Nor Laegeforen 133, 1735-1739 (2013). Smeland, K. B., Kiserud, C. E., Lauritzsen, G. F., Blystad, A. K., Fagerli, U. M., Fluge, O., Fossa, A., Hammerstrom, J., Kolstad, A., Loge, J. H., Maisenholder, M., Ostenstad, B., Kvaloy, S. & Holte, H. High-dose therapy with autologous stem cell support for lymphoma in Norway 1987-2008. Tidsskr Nor Laegeforen 133, 1704-1709 (2013). Scott, J. D., Dessauer, C. W. & Tasken, K. Creating order from chaos: cellular regulation by kinase anchoring. Annu Rev Pharmacol Toxicol 53, 187-210 (2013). Rogne, M. & Tasken, K. Cell signalling analyses in the functional genomics era. N Biotechnol 30, 333-338 (2013). Pollheimer, J., Bodin, J., Sundnes, O., Edelmann, R. J., Skanland, S. S., Sponheim, J., Brox, M. J., Sundlisaeter, E., Loos, T., Vatn, M., Kasprzycka, M., Wang, J., Kuchler, A. M., Tasken, K., Haraldsen, G. & Hol, J. Interleukin-33 drives a proinflammatory endothelial activation that selectively targets nonquiescent cells. Arterioscler Thromb Vasc Biol 33, e4755 (2013). Naik, S. H., Perie, L., Swart, E., Gerlach, C., van Rooij, N., de Boer, R. J. & Schumacher, T. N. Diverse and heritable lineage imprinting of early haematopoietic progenitors. Nature 496, 229-232 (2013). Myklebust, J. H., Irish, J. M., Brody, J., Czerwinski, D. K., Houot, R., Kohrt, H. E., Timmerman, J., Said, J., Green, M. R., Delabie, J., Kolstad, A., Alizadeh, A. A. & Levy, R. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood 121, 13671376 (2013).

Linnemann, C., Heemskerk, B., Kvistborg, P., Kluin, R. J., Bolotin, D. A., Chen, X., Bresser, K., Nieuwland, M., Schotte, R., Michels, S., Gomez-Eerland, R., Jahn, L., Hombrink, P., Legrand, N., Shu, C. J., Mamedov, I. Z., Velds, A., Blank, C. U., Haanen, J. B., Turchaninova, M. A., Kerkhoven, R. M., Spits, H., Hadrup, S. R., Heemskerk, M. H., Blankenstein, T., Chudakov, D. M., Bendle, G. M. & Schumacher, T. N. High-throughput identification of antigen-specific TCRs by TCR gene capture. Nat Med 19, 1534-1541 (2013). Landskron, J. & Tasken, K. CD147 in regulatory T cells. Cell Immunol 282, 17-20 (2013). Hombrink, P., Raz, Y., Kester, M. G., de Boer, R., Weissbrich, B., von dem Borne, P. A., Busch, D. H., Schumacher, T. N., Falkenburg, J. H. & Heemskerk, M. H. Mixed functional characteristics correlating with TCR-ligand koff -rate of MHC-tetramer reactive T cells within the naive T-cell repertoire. Eur J Immunol 43, 3038-3050 (2013). Holte, H., Leppa, S., Bjorkholm, M., Fluge, O., Jyrkkio, S., Delabie, J., Sundstrom, C., Karjalainen-Lindsberg, M. L., Erlanson, M., Kolstad, A., Fossa, A., Ostenstad, B., Lofvenberg, E., Nordstrom, M., Janes, R., Pedersen, L. M., Anderson, H., Jerkeman, M. & Eriksson, M. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol 24, 1385-1392 (2013). Gilchuk, P., Spencer, C. T., Conant, S. B., Hill, T., Gray, J. J., Niu, X., Zheng, M., Erickson, J. J., Boyd, K. L., McAfee, K. J., Oseroff, C., Hadrup, S. R., Bennink, J. R., Hildebrand, W., Edwards, K. M., Crowe, J. E., Jr., Williams, J. V., Buus, S., Sette, A., Schumacher, T. N., Link, A. J. & Joyce, S. Discovering naturally processed antigenic determinants that confer protective T cell immunity. J Clin Invest 123, 1976-1987 (2013).

Moltu, K., Bjørgo, E., Solstad, T., Berge, T., Thiede, B., Taskén, K. A proteomic approach to screening of dynamic changes in detergent-resistant membranes from activated human primary T cells. J. Proteomics Bioinform 6, 072-080 (2013).

Gerlach, C., Rohr, J. C., Perie, L., van Rooij, N., van Heijst, J. W., Velds, A., Urbanus, J., Naik, S. H., Jacobs, H., Beltman, J. B., de Boer, R. J. & Schumacher, T. N. Heterogeneous differentiation patterns of individual CD8+ T cells. Science 340, 635-639 (2013).

Lone, A. M. & Tasken, K. Proinflammatory and immunoregulatory roles of eicosanoids in T cells. Front Immunol 4, 130 (2013).

Dahle, J., Repetto-Llamazares, A. H., Mollatt, C. S., Melhus, K. B., Bruland, O. S., Kolstad, A. & Larsen, R. H. Evaluating antigen targeting and anti-tumor activity of a new anti-CD37 radioimmunoconjugate against non-Hodgkin’s lymphoma. Anticancer Res 33, 85-95 (2013). Cornez, I., Joel, M., Tasken, K., Langmoen, I. A., Glover, J. C. & Berge, T. EGF signalling and rapamycin-mediated mTOR inhibition in glioblastoma multiforme evaluated by phospho-specific flow cytometry. J Neurooncol 112, 49-57 (2013).

mid- t er m r e p o r t 2015

Brudvik, K. W., Bains, S. J., Seeberg, L. T., Labori, K. J., Waage, A., Tasken, K., Aandahl, E. M. & Bjornbeth, B. A. Aggressive treatment of patients with metastatic colorectal cancer increases survival: a scandinavian single-center experience. HPB Surg 2013, 727095 (2013). Beziat, V., Traherne, J. A., Liu, L. L., Jayaraman, J., Enqvist, M., Larsson, S., Trowsdale, J. & Malmberg, K. J. Influence of KIR gene copy number on natural killer cell education. Blood 121, 4703-4707 (2013). Beziat, V., Liu, L. L., Malmberg, J. A., Ivarsson, M. A., Sohlberg, E., Bjorklund, A. T., Retiere, C., Sverremark-Ekstrom, E., Traherne, J., Ljungman, P., Schaffer, M., Price, D. A., Trowsdale, J., Michaelsson, J., Ljunggren, H. G. & Malmberg, K. J. NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood 121, 2678-2688 (2013). Bendle, G. M., Linnemann, C., Bies, L., Song, J. Y. & Schumacher, T. N. Blockade of TGF-beta signaling greatly enhances the efficacy of TCR gene therapy of cancer. J Immunol 191, 3232-3239 (2013). Amore, A., Wals, K., Koekoek, E., Hoppes, R., Toebes, M., Schumacher, T. N., Rodenko, B. & Ovaa, H. Development of a hypersensitive periodate-cleavable amino acid that is methionine- and disulfide-compatible and its application in MHC exchange reagents for T cell characterisation. Chembiochem 14, 123-131 (2013). Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A., Behjati, S., Biankin, A. V., Bignell, G. R., Bolli, N., Borg, A., Borresen-Dale, A. L., Boyault, S., Burkhardt, B., Butler, A. P., Caldas, C., Davies, H. R., Desmedt, C., Eils, R., Eyfjord, J. E., Foekens, J. A., Greaves, M., Hosoda, F., Hutter, B., Ilicic, T., Imbeaud, S., Imielinski, M., Jager, N., Jones, D. T., Jones, D., Knappskog, S., Kool, M., Lakhani, S. R., Lopez-Otin, C., Martin, S., Munshi, N. C., Nakamura, H., Northcott, P. A., Pajic, M., Papaemmanuil, E., Paradiso, A., Pearson, J. V., Puente, X. S., Raine, K., Ramakrishna, M., Richardson, A. L., Richter, J., Rosenstiel, P., Schlesner, M., Schumacher, T. N., Span, P. N., Teague, J. W., Totoki, Y., Tutt, A. N., Valdes-Mas, R., van Buuren, M. M., van ‘t Veer, L., Vincent-Salomon, A., Waddell, N., Yates, L. R., Australian Pancreatic Cancer Genome, I., Consortium, I. B. C., Consortium, I. M.-S., PedBrain, I., Zucman-Rossi, J., Futreal, P. A., McDermott, U., Lichter, P., Meyerson, M., Grimmond, S. M., Siebert, R., Campo, E., Shibata, T., Pfister, S. M., Campbell, P. J. & Stratton, M. R. Signatures of mutational processes in human cancer. Nature 500, 415-421 (2013).

Education and Career JCIT: Fostering Scientific Careers

Johannes Landskron Scientist in the Taskén Group. Recruited in 2008 from University of Regensburg where he worked on Drosophila clock proteins for this PhD. Developed extensive flow cytometry expertise in the Taskén group as a postdoc and researcher and built a robotic pipeline that supports both automated phosphoflow analyses and chemical biology screens by flow cytometry. Project: High throughput screening for novel small molecule regulators of FoxP3 in regulatory T cells. “If our strategy works, we may be able to manipulate levels of Treg activation and thereby suppression of anti-tumor immunity.”

m id - t e rm re p o r t 20 1 5

Erlend Strønen MD and PhD student in Olweus group. Erlend started his research career taking the research curriculum during medical studies at the University of Oslo. He got hooked, and continued research to unravel how non-tolerized T cell repertoires can be utilized to enable cancer immunotherapy. “We believe that inefficient immune responses to cancer in patients can be overcome by adoptive transfer of immunity from healthy donors”.

Jodie Goodridge

Scientist in Malmberg Group. Recruited from Fred Hutchinson Cancer Research Center in 2013. Project: Understanding the cellular basis behind the functional maturation of natural killer cells. “If successful, our work will pave the way for the next generation of NK cell therapy based on guided differentiation of specific NK cell subsets”.

mid- t er m r e p o r t 2015

SAB Helping us improve further â&#x20AC;&#x201C; Scientific Advisory Board visit 2014

Johanna Olweus presenting to the members of the SAB. Foto: Terje Heiestad, Millimeter Press AS

Already at the point when the application for a center was sent to the K.G. Jebsen Foundation, a Scientific Advisory Board (SAB) was in place to guide us in the event that we obtained funding. We feel very fortunate to have Fred Falkenburg (Leiden Medical University, the Netherlands), Rolf Kiessling (Karolinska Institute, Stockholm, Sweden) and Hans Stauss (University College London, UK, and chairman of the SAB) in our SAB. These three scientists are at the international forefront and have a broad competence that matches our translational program perfectly, ranging from basic immunology related to cancer immunotherapy to clinical immunotherapy trials. The first SAB meeting was held in Oslo in November 2014, almost 1.5 years since the opening of

the center. Late enough to evaluate if we were on the right track, and early enough to ensure that suggested improvements can be implemented during the lifetime of the center. After two intense days of scientific presentations and discussions we were strengthened in our belief in the program and inspired to follow advice that can further extend the synergies between the partnering groups and focus our research even further. The recommendations were included in the research plan and progress report for the K.G. Jebsen Foundation submitted in January 2015. â&#x20AC;&#x153;The board was impressed with the quality and the breadth of the translational research programme of the Center, which includes discovery science combined with a clear strategy to move research developments into clinical trials in patientsâ&#x20AC;? Excerpt from the SAB report

m id - t e rm re p o r t 20 1 5

Fred Falkenburg

mid- t er m r e p o r t 2015

Hans Stauss (Chairman of SAB)

Rolf Kiessling

Key Events

Norwegian Cancer Symposium 2014 Norwegian Cancer Symposium 2014 â&#x20AC;&#x153;Harnessing innate and adaptive immunity in cancer therapyâ&#x20AC;? was organized by Malmberg and Olweus June 10-12, 2014 (http://www.cancersymposia.no). Norsk Hydro Fond sponsored the meeting, which attracted many internationally leading scientists in immunotherapy as speakers, such

as Carl June, Ton Schumacher, Cassian Yee, Martin Pule, Rolf Kiessling, Dean Anthony Lee and Jeff Miller. Overlooking the view of the Oslo fjord, approximately 100 delegates enjoyed cutting edge scientific talks and interactive poster sessions at the Holmenkollen Park Hotel. Some even dared ziplining from the top of the Ski Jump.

N O R W EG IA N CANCER SY M P O S IU M

2014

HAR NES SING INN ATE AND ADA PTIV E IMM UNI TY IN CAN CER THE RAP Y

ann u al report 20 1 5

Internal activities Scientific Retreats

April 10th -12th 2015 Dr. Holms hotel at Geilo In April 2015 the center organized yet another successful internal scientific retreat. During this two day event we followed presentations from all of the groups of the center, and participated in interesting scientific discussions. Importantly, we also found the time to enjoy downhill skiing and cross country skiing, facilitating non-scientific interactions between center participants.

April 10th-11th 2014 ThorbjĂ¸rnrud Hotel at Jevnaker This was the first internal scientific retreat organized by the K.G. Jebsen Center for Cancer Immunotherapy. A two day event with scientific presentations and discussions. This was also an opportunity for the different groups of the JCIT to get to know each other better.

mid- t er m r e p o r t 2015

Visiting professors Harlan Robins

Fred Hutchinson Cancer Research Center, Seattle, USA Harlan Robins is an Associate faculty member of computational biology in the Public Health Sciences and Human Biology divisions of Fred Hutchinson Cancer Research Center, where he joined the faculty in 2006 and an Associate Professor in Molecular and Cellular Biology at the University of Washington. He received his doctorate in theoretical particle physics from the University of California Berkeley and then trained in computational biology as a postdoctoral member of the Institute for Advanced Studies in Princeton. He studies the genetics of the human immune system particularly how the immune system responds to pathogens such as viruses and bacteria, as well as the aging process. In 2009, Robins co-founded Adaptive Biotechnologies based on sequencing technology he and a couple of colleagues developed at the Hutchinson Center where he is the Chief Scientific Officer. Adaptive Biotechnologies presently has 160 employees and is headquartered in Seattle.

Sattva Neelapu MD Anderson Cancer Center, Houston, USA. Sattva Neelapu MD, is an Associate Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine and Director of Laboratory and Translational Research, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. He had his Clinical fellowship and Postdoctoral Fellowship in Tumor Immunology at the National Cancer Institute, National Institutes of Health, Bethesda, MD. Dr Neelapu is very well known for translational research and particularly clinical trials in malignant lymphoma.

m id - t e rm re p o r t 20 1 5

Facts about JCIT Facts and Figures

K.G. Jebsen Center for Cancer Immunotherapy (JCIT) was established in April 2013 by a generous donation from the K.G. Jebsen Foundation. JCIT is a translational research program for the development of new strategies for immunotherapy against cancer. Approximately 50 persons are involved in research at JCIT. JCIT actively recruits international talents and currently 19 nationalities are represented at the center. The overall nationality balance at JCIT is 40/60, with an overweight of international members among PhD students, post docs and scientists. The overall gender balance at JCIT is 45/55 with an overweight of female members among PhD students and technicians. The Research Groups JCIT consists of 6 research groups headed by Johanna Olweus, Karl-Johan Malmberg, Kjetil Taskén, Fridtjof Lund-Johansen, Arne Kolstad and Ton Schumacher. Organization and Management The Center has three participating partnering institutions; University of Oslo (UiO), Oslo University Hospital (OUH) and Netherlands Cancer Institute (NKI). The management group consists of the Director Johanna Olweus, Deputy Director KarlJohan Malmberg and one additional PI, Arne Kolstad. The Administrative Head of the Consortium is Head of Department, Institute of Clinical Medicine, University of Oslo, Professor Ivar Gladhaug.The management group oversees daily activities of the center. The center management is supported by an administrative coordinator, Cathrine Fallang Knetter. Scientific Advisory Board JCIT has a scientific advisory board (SAB) consisting of internationally leading scientists, with a broad competence that complements JCITs translational program. The SAB critically evaluates and gives advice on the scientific performance, the synergy between the partnering groups and progress of the center. mid- t er m r e p o r t 2015

• Professor Hans Stauss University College London, UK, chairman of the SAB • Professor Fred Falkenburg, Leiden Medical University, the Netherlands • Professor Rolf Kiessling Karolinska Institute, Stockholm, Sweden Monthly Meetings JCIT arrange monthly interactive project meetings, which are welcome to all group members. For each meeting one of the research groups is responsible for organizing and presenting their resent scientific findings. A PI meeting is taking place after each project meeting. Awards Dr. Ragnar Mørk’s Legats cancer research prize was awarded to Arne Kolstad in 2014. An annual prize which recognizes scientist who have made important discoveries in the field of cancer research. The Olweus group was awarded the Oslo University Hospital award for best article first half of 2014 (Kumari et al, PNAS 2014). Arne Kolstad and Olweus et al were awarded the Oslo University Hospital award for best article for second half of 2014 ( Kolstad et al, Blood 2015, epub ahead 2014). Ton N. Schumacher was awarded the San Salvatore Award in 2014. The award recognizes scientists who have contributed to the progress of cancer therapies and in a substantial manner to scientific research on new anti-tumor therapeutic approaches. Ton N. Schumacher became in 2014 a member of Fellow European Academy of Cancer Sciences Ton N. Schumacher was awarded the Queen Wilhelmina Research Award in 2014. The highest Dutch award for cancer research for his work on understanding the basic mechanisms of cancer immunotherapy. In 2013, Ton Schumacher became a Scientific Advisory Council at The Cancer Research Institute.

Facts about JCIT Patent applications Aronsen, J.M., Sjaastad I. Skogestad, J., Carlson, C.R., Taskén, K. “Serca2-PDE3a interaction peptides and uses thereof.” U.S. Provisional Patent Application no. 62005083.

Malmberg, K-J., Beziat, V. “Selective and controlled expansion of educated NK cells for therapy.” EFS ID 13648024.

Bendle, G.M., Linnemann, C., Schrikkema, B., Schumacher, T.N. “T cell recognized peptide epitopes.” GB1420069.5

Mezzadra, R., Hollenstein, A., Schumacher, T.N. “Method and system for efficient generation and selection of genetically modified cells.” NL2013305.

Bies, L., van Buuren, M.M., Linnemann, C., Schumacher, T.N.M. “Means and Methods for determining T cell recognition.” EP14171396.6

Olweus, J., Holmøy, T., Lossius, A. “Identification of disease-driving antigens.” PCT 14/512,737.

de Boer, M., Linnemann, C., Schumacher, T.N.M. “T cell-based bi-specific immunotherapeutics.” EP15151537.6

Olweus, J., Kumari, S. “CTL peptide epitopes and antigen.specific T cells, methods for their discovery, and uses therof.” INVEN-33567/ US-1/PRO.

de Boer, M.,Linnemann, C., Schumacher, T.N. “T cell-based immunotherapeutics.” EP14190210 Klaveness, J., Taskén, K. “Cyclic Amino Compounds for use in the Treatment of Cardiac Disorders.” U.K. Patent Application Serial No. GB1320506.7. Klaveness, J., Taskén, K. “Cyclic Amino Compounds for Use in the Treatment of Cardiac Disorders.” US Patent Application No. 14/549,414 .

Ovaa, H., Rodenko, B., Hoppes, R., Amore A., Schumacher, T.N. “Immune Restricted Peptides With Increased Efficacy.” PCT/ EP2010/069246. Taskén, K., Lygren, B. Østensen, E., Klaveness, J. “Compounds that regulate phospholamban phosphorylation.” PCT/ EP2013/060263.

Staff Position Group leader

Scientist

Post Doc

annual report 2014

Name Arne Kolstad

Employer OUH

Funding OUH

Fridtjof Lund-Johansen

OUH

Karl-Johan Malmberg

OUH/UiO

Johanna Olweus

OUH/UiO

Ton Schumacher

NKI

Kjetil Taskén

UiO (100%)/OUH (20%)

NCMM (RCN/ HSØ/UiO)

Einar Martin Aandahl

OUH

HSØ

Daniel de la Rosa Carrillo

OUH

Jodie Goodridge

OUH

Terhi Kärpänen

UiO

Jebsen

Johannes Landskron

UiO

Jebsen

Anne Jorunn Stokka

UiO

Kishan Chudasama

OUH

Trevor Clancy Lena Eroukhmanoff Benedikt Jacobs Shraddha Kumari Pia Kvistborg Axel Berg-Larsen Anna Mari Lone Maria-Niki Mylonakou

OUH UiO OUH OUH NKI OUS UiO UiO

Krzysztof Sikorski Sigrid Skånland Mateusz Walczak Fan Ying

UiO UiO OUH OUH

HSØ NCS own funding RCN NKI OUH NCS NCMM (RCN/ HSØ/UiO) Jebsen RCN OUH OUH

m id - t e rm re p o r t 20 1 5

53 Position PhD student

Technical staff/ Engineer

Administration

Name Muhammad Ali

Employer OUH

Funding OUH

Maxi-Lu Böschen

OUH

Jebsen

Stalin Chelappa

UiO

NCS

Aleksandra Dukic

UiO

NCS

Lorenzo Fanchi

NKI

Nora V. Lieske

UiO

RCN

Vincent Oei

UiO

Jebsen

Erlend Strønen

OUH

Michelle Sætersmoen

OUH

Eli Taraldsrud

OUH

Laura Bies

NKI

Jebsen

Raquel Gomez

NKI

Stine Granum

OUH

Hanna Julie Hoel

OUH

David McClymont

UiO

Jorun Solheim

UiO

Mireille Toebes

NKI

Gladys Tjørhom

UiO

NCS

Nienke van Rooij

NKI

Anette Vefferstad

OUH

Merete Thune Wiiger

OUH

Weiwen Yang

OUH

Berit Barkley

UiO

Cathrine Fallang Knetter

OUH

Collaboration National Collaborators Norway Aukrust, Pål. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, and Institute of Clinical Medicine, University of Oslo, and K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway Bakke, Oddmund. Department of Biosciences and Centre for Immune Regulation, University of Oslo, Oslo Barzenje, Dlawer. Fredrikstad Hospital, Fredrikstad Beiske, Klaus. Department of Pathology, Oslo University Hospital Rikshospitalet, Oslo

mid- t er m r e p o r t 2015

Bjørge, Line. Department of Ob-Gyn, Haukeland University Hospital, Bergen Bjørnbeth, Bjørn Atle. Gastrosurgical Department, Oslo University Hospital, Oslo Collas, Philippe. Institute of Basic Medical Sciences, University of Oslo, Oslo de Souza, Gustavo. Head of Proteomics core facility, Department of Immunology, Centre of Immune Regulation, Oslo University Hospital Rikshospitalet, Oslo Dyrhol-Riise, Anne Ma. Department of Infectious Diseases, Oslo University Hospital, Oslo Esgurra, Camila. Biotechnology Centre, University of Oslo, Oslo

GENDER DISTRIBUTION

(45%)

female

(55%)

male

(45%)

female

male

(55%)

NATIONALITY DISTRIBUTION

(59%)

(41%)

(59%)

(41%)

national international national international

Fevang, Børre. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, and Institute of Clinical Medicine, University of Oslo, Oslo Fløisand, Yngvar. Department of Hematology, Oslo University Hospital Rikshospitalet, Oslo Frigessi, Arnoldo. Oslo Centre for Biostatistics, University of Oslo, Oslo Frøland, Stig. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, and Institute of Clinical Medicine, University of Oslo, Oslo Gjertsen, Bjørn Tore. Deptartment of Hematology and Clinical Trials Unit, Haukeland University Hospital, Bergen

Facts about JCIT Halvorsen, Bente. Institute of Internal Medicine Research, Oslo University Hospital, Oslo Haraldsen, Guttorm. Department of Pathology, University of Oslo/Oslo University Hospital, Oslo Holmøy, Trygve. Department of Neurology, Akershus University Hospital, Lørenskog Holte, Harald. Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo Husebekk, Anne. Tromsø University Hospital, Tomsø Staerk, Judith. Centre for Molecular Medicine Norway (NCMM), University of Oslo/ Oslo University Hospital, Oslo Karlsen, Tom Hemming. Research Institute of Internal Medicine, and Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet,and Oslo, Norway and K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo Klaveness, Jo. Section for Medical Chemistry, School of Pharmacy, University of Oslo, Oslo Klinkenberg, Geir. SINTEF Materials and Chemistry, Trondheim

Norwegian Lymphoma Group Rollag, Halvor. Department of Microbiology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo

Hacohen, N. Harvard University, Broad Institute, USA Heck, Albert. The Netherlands Proteomics Centre, Utrecht, The Nederlands

Salvesen, Helga. Department of Ob-Gyn, Haukeland University Hospital, Bergen

Hellström-Lindberg, Eva. Karolinska Institutet, Sweden

Sandlie, Inger. Department of Molecular Biosciences and Centre for Immune Regulation, University of Oslo, and Department of Immunology and Transfusion medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo

Herberg, Friedrich. Universität Kassel, Germany

Sjaastad, Ivar. Institute of Experimental Medical Research, Oslo University Hospital, Oslo Staff, Annetine. Deptartment Ob-Gyn, Oslo University Hospital, Oslo Stenmark, Harald. Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo Sundan, Anders. Insitute for Molecular Medicine and Cancer Research, NTNU, Trondheim Thiede, Bernd. Biotechnology Centre / IBV, University of Oslo, Oslo Tjønnfjord, Geir. Department of Hematology, Oslo University Hospital Rikshospitalet, Oslo

Kvale, Dag. Department of Infectious Diseases, Oslo University Hospital, Oslo

Yndestad, Arne. Institute of Internal Medicine Research, Oslo University Hospital, Oslo

Kvalheim, Gunnar, Department of Cellular Therapies, Oslo University Hospital Radiumhospitalet, Oslo

National Collaborators The Netherlands

Kuntziger, Tomas M. Institute of Basic Medical Sciences, University of Oslo, Oslo

Falkenburg, J. LUMC, Leiden Haanen, J. Netherlands Cancer Institute, Amsterdam

Hirchfield, Gideon. Centre for Liver Research, NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK Irish, Jonathan. Vanderbildt University, USA Kalina Tomas, Department of Pediatric Oncology, Charles University, Prague Kallioniemi, Olli. FIMM, Helsinki, Finland Levy, Ron. Stanford University Hospital, USA Lewis, Joe. Chemical Biology Unit, EMBL Ljunggren, Hans-Gustaf. Karolinska Institutet, Sweden Moutschen, Michel. Liege, Belgium Nordic Lymphoma Group Okkenhaug, Klaus. Babraham Institute, Cambridge, UK Orfao Alberto, University of Salamanca, Spain Parham, Peter. Stanford University, USA Pidoux, Guillaume. Université René Descartes, Paris, France Rizvi, N. Columbia, New York, USA.

Heemskerk, M. LUMC, Leiden

Robins, Harlan. Divisions for Public Health and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, USA

Ovaa, H. Netherlands Cancer Institute, Amsterdam

Russel, David. University of Washington, USA

Peeper, D. Netherlands Cancer Institute, Amsterdam

Saez-Rodrigues, Julio. EMBL-EBI, Hinxton, UK

van der Burg, S. LUMC, Leiden

Schreiber, R. Washington University, St. Louis, USA

International Collaborators

Melum, Espen. Institute of Internal Medicine Research, Oslo University Hospital, Oslo

Scott, John D. University of Washington, Seattle, USA

Anders, Simon. EMBL, Heidelberg, Germany / FIMM, Helsinki, Finland

Trowsdale, John. Cambridge University, UK

Morth, J. Preben. Centre for Molecular Medicine Norway (NCMM), University of Oslo/Oslo University Hospital, Oslo

Bradbury Andrew, Los Alamost National Laboratories, USA

van Veelen, Peter. Leiden University Medical Center, The Netherlands

Busch, D. TUM, Munich, Germany.

Wennerberg, Krister. FIMM, Helsinki, Finland

Lorens, James B. University of Bergen, Bergen Lossius, Andreas. Department of Immunology and Transfusion Medicine and Department of Neurology, Oslo University Hospital, Oslo Løset, Geir Åge. Department of Molecular Biosciences and Centre for Immune Regulation, University of Oslo, and Department of Immunology and Transfusion medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo

Munthe, Ludvig. Institute of Immunology, University of Oslo, Oslo Myklebust, June. Department of Immunology, Institute for Cancer Research, Oslo University Hospital Rikshospitalet, and Center for Cancer Biomedicine, University of Oslo, Oslo

Elofsson, Mikael. MIMS, UmeŒ, Sweden Enerbäck, Sven. Göteborgs Universitet, Sweden Grimbacher, Bodo. Freiburg University, Germany

Wu, C. Harvard University, Broad Institute, USA Önfelt, Björn. The Royal School of Technology, Stockholm, Sweden

m id - t e rm re p o r t 20 1 5

Collaboration between Oslo and Amsterdam

mid- t er m r e p o r t 2015

Communication to the public LG

AS STØRS SIDEN

1999

ORIGINALEN LE

MAGASINET

JCIT profiled in the media OPPLEVEL

Illustrasjon: Lisa Aisato

LØRDAG 7. DESEMBER 2013

Her er din framtid

39 OPPFINNELSER SOM VIL REVOLUSJONERE VERDEN

PÅ TOMANNSHÅND: MARIT CHRISTENSEN

PETTERS PAPPA: JOHN NORTHUG I PORTRETTET

HOBBITEN: MARTIN FREEMAN

SUKKERKAMPEN

n Dagbladets Magasin p 28 December 7th 2013: Johanna Olweus about JCITs research in Dagbladets Magasin. n NRK radio December 17th 2013: Radio interview with Johanna Olweus about the article by JCIT partners published in PNAS “Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes.”

http://www.thelocal.no/20131218/norway-researchers-make-cancer-breakthrough n Journal of the Norwegian Medical Association Feb 2014: “T celler mot kreft” article describing recent research on targeted cancer immunotherapy by JCIT groups. http://tidsskriftet.no/article/3140202

http://radio.nrk.no/ serie/ekko-hovedsending#t=58m48s.

n NRK Viten December 17th 2013: ”Norske forskarar med gjennombrot i målstyrt kreftbehandling” Interview with Johanna Olweus in NRK Viten on JCIT groups’ recent discoveries in the field of targeted cancer immunotherapy. http://www.nrk.no/viten/norsk-gjennombrot-i-immunterapi-1.11422853 n Forskning.no December 18th 2013: ”Norske forskarar med gjennombrot i målstyrt kreftbehandling” Article in Forskning.no online describing recent research on targeted cancer immunotherapy by JCIT groups. http://www.forskning.no/artikler/2013/desember/376229 n The Local, December 18th 2013: “Norway researchers in cancer breakthrough” article describing recent research on targeted cancer immunotherapy by JCIT groups.

n Tara Frisk April 2014: ”Fremtidens kreftbehandling er skreddersydd: Vil gjenoppvekke immunsystemet”. Interview with Johanna Olweus and Arne Kolstad where the scientific strategies and goals of K.G. Jebsen Center for Cancer Immunotherapy are presented alongside results from successful immunotherapy trial.

m id - t e rm re p o r t 20 1 5

n OUH webpage: “ Fremragende artikler med bredde”. Oslo University Hospital award for outstanding research article second half of year 2013. Kumari et al in PNAS “Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated selfepitopes.” http://www.oslo-universitetssykehus. no/aktuelt_/nyheter_/Sider/fremragende-forskningsartikler-2014.aspx n OUH webpage: “Gi rom for de gode ideene”. Interview with Johanna Olweus- Researcher of the month at Health South East Regional Health Autority September 2014: http://www.oslo-universitetssykehus.no/ aktuelt_/nyheter_/Sider/Gi-rom-for-degode-ideene.aspx n Aftenposten Bilag October 31st 2014: “Immunterapi på fremmarsj”. Full page presenting the research performed at K.G. Jebsen Center for Cancer Immunotherapy. http:// www.kreftinformasjon.no/forskning-og-innovasjon/immunterapi-pa-fremmarsj n «Kampen mot kreft» 5th edition: ”Samlet ekspertise mot kreft”. Presentation of K.G. Jebsen Center for Cancer Immunotherapy from Oslo Cancer Cluster. http://ous-research.no/olweus/docs/PDF/OCC_2014-2-12. pdf n Journal of the Norwegian Medical Association 2015;135:225.: “Immunstimulering mot follikulært lymfom?” Article presenting important findings from the article by Arne Kolstad and Johanna Olweus published in Blood 2015. “Sequential intranodal immunotherapy induces antitumor immunity and correlated regression of disseminated follicular lymphoma”. Blood 2015; 125: 82 –9. http://tidsskriftet.no/article/3285666/ n Kreftforeningen.no February 12th 2015: ”Ny kreftvaksine får immunforsvaret til å angripe kreft”. Interview with Arne Kolstad about the important findings from the article together with Johanna Olweus published in Blood 2015. “Sequential intranodal immunotherapy induces antitumor immunity and correlated regression of disseminated follicular lymphoma”. Blood 2015; 125: 82 –9. https://kreftforeningen.no/forskning/ forskningsprosjekter-vi-stotter/ny-kreftvaksine-far-immunforsvaret-til-a-angripe-kreft/ n Cancer Research prize to Arne Kolstad. ”Dr. Ragnar Mørk’s Legats kreftforskningspris ble i år tildelt onkolog Arne Kolstad.” http://www.oslo-universitetssykehus.no/ aktuelt_/nyheter_/Sider/Kreftforskningspris-til-Arne-Kolstad-.aspx

mid- t er m r e p o r t 2015

n Kjetil Taskén - Profiled Researcher in Norwegian Cancer Society Donor Campaign – “We aim to understand why the immune system sometimes turns off its ability to recognize and kill cells in an expanding malignant tumor”, 23 appearances in 9 national newspapers (VG Helg, Dagbladet Magasinet, Aftenposten A-magasinet, Vårt Land, Bergens Tidende, Adresseavisa, Stavanger Aftenblad, Fedrelandsvænnen, Avisa Nordland, Nordlys, Finnmark Dagblad) January 17, 18, 24 and 25, 2014. n Kjetil Taskén - Profiled Researcher in Norwegian Cancer Society Brochure on international cooperation, 2014. n Bedre Helse no. 3, 2014 pp30-31. “Dette visste du ikke om betennelser” Interview with Kjetil Taskén on inflammation research. n Bedre Helse no. 10, 2014 pp-4-5. “Godt immunforsvar – hva er det?” Interview with Kjetil Taskén on the role of our immune system in inflammation, infection and cancer. n Kapital, no. 15, 2014, pp 94-96. “Aspirin reduserer kreftrisikoen ”. Interview with Kjetil Taskén about benefit of aspirin as secondary prevention in colorectal cancer and new intervention trial to start. n Asker og Bærum Budstikke, 29.10.2014, p4 “Får kreftmillioner – Rykkinn-ektepar får penger til å forske”. Interview with Kristin and Kjetil Taskén on the occasion that both received grants from the Cancer Socitety. n Main profile in Norwegian Cancer Society Information Brochure on Personalized Medicine: “Why is cancer difficult to treat?” sent to 600,000 households in Norway in February 2015. n Forskning.no – Ingrid Spilde, March, 2015. “Does our immune defence become stronger after infections?” Interview with Kjetil Taskén and Trude Helen Flo. http://forskning. no/2015/02/blir-immunforsvaret-sterkere-etter-sykdom

We thank our sponsors

Novo Nordic Foundation European Commission Anders Jahre’s fund Danish Science Foundation Dutch Cancer Society EEC/CEC/EU CTMM Netherlands Organization for Scientific Research TOP-GO ERC Advanced Grant HFSP grant Stand up to Cancer Roche WCR NWO http://ous-research.no/olweus/ Øyvind André Stiftelsen Regine Stokke Børge M.S. Erlend Olav Bjørkøy

m id - t e rm re p o r t 20 1 5

Overcoming immune tolerance to target cancer

mid- t er m r e p o r t 2015

K.G. Jebsen Centre for Cancer Immunotherapy

Oslo University Hospital Radiumhospitalet UllernchausĂŠen 70 0310 Oslo Norway

Telephone: +47 22 78 13 25 Fax: +47 22 78 13 45 email: johanna.olweus@medisin.uio.no

KG JEBSEN CENTER for Cancer Immunotherapy

m id - t e rm re p o r t 20 1 5