The ACE Tumor Immunology and Immune Therapy should be considered an emerging ACE, and will coordinate, integrate and accelerate research, education and academic care with respect to immune therapies towards multiple tumor types. To this end, we will select: (1) state-of-the art models and techniques to better understand interactions between tumor development, therapy resistance, and immune system; (2) develop and implement an immune monitoring portfolio to aid patient selections; (3) provide timely education; and (4) initiate new immune (combination) patient trials. The proposed program should ensure progression towards a profile with (inter)national recognition in the field of tumor immunology and immune therapy.
Immune therapies have demonstrated recent and significant efficacy in the treatment of tumors, and are expected to cover a growing part of the (future) treatment portfolio for many tumor types. The success of these therapies critically depends on a better understanding of the tumor micro-environment (TME), particularly with respect to quantity, quality and location of immune cells (or their subsets), and how critical parameters may be reflected in the blood compartment.
Examples of preclinical/translational research that started and is embedded in this ACE:
Setting up advanced techniques, such as: multiplex flow cytometry; multiplex in-situ stainings; and imaging (bioluminescence and opto-acoustic tomography) to facilitate research and immune-monitoring of patients.
Determining immune-related factors that are related to therapy resistance, in particular tumor cell:immune cell interactions related to tumor growth or invasion, and critical spatio-temporal relationships between tumor and immune cell populations.
Providing infrastructure to sample and archive biomaterials; and profiling immune markers of patient blood and tumors of the skin, breast, lung, prostate, bladder, oral cavity, weak tissues and pancreas (acronyms: Multomab; Responder (Merck); Impa (SLO) with cohorts between 100-200 patients).
Developing a universal 'pipeline' to analyze immune profiles, and correlate such profiles to genomic, pathway and clinical parameters (with use of big data structures); and integrating data to better select patients for therapies, and design and perform new immune (combination) trials.
Examples of clinical research that started and is embedded in this ACE:
Checkpoint inhibitors in: bladder cancer (Merck); liver cancer (Pfizer); pancreas cancer; and pre B-ALL (Amgen).
Virotherapy in: prostate cancer (ZonMw; ongoing); glioblastoma (KWF; completed); and pancreas cancer.
T cell therapy in: melanoma and head-and-neck (KWF; scheduled for Q2 2019); multiple myeloma (translational phase); breast cancer (KWF; preclinical phase); and gynaecological tumors (preclinical phase).
DC therapy in: mesothelioma (H2020, Amphera); and pancreas cancer (Amphera; TKI).
Per mid 2018, this ACE has published > 75 immune-oncology manuscripts, of which > 15 involving multiple departments.
This ACE provides education to students ranging from bachelor, master, research master, PhD, scientist, pharmacists, MD, and medical specialist. To this end, leading investigators fulfill key positions, such as faculty memberships of Post Graduate Schools of "Molecular Medicine", "Infection and Immunity", and "Nanobiology", and coordinator of master research for medicine students, and ensure continued innovation with respect to courses and classes in the field of immuno-oncology.
Ongoing educational activities:
organise and lecture courses in above-mentioned research schools (on average 20-60 students per class).
organise laboratory visits during various minors (on average 10-20 students per class).
supervise and guide individual research internships, PhD students and AIOs.
invites of faculties to (inter)national congresses.
contribute to exchange of visiting scientists.
Student evaluations provide high marks for above-mentioned courses.
In addition to education provided to Erasmus MC students and employees, there is substantial involvement in immuno-oncology training at other UMCs as well as other European centers (as part of ITN programs). We will make an inventory of current educational activities related to immuno-oncology (currently ongoing), and restructure the contents with respect to the various student levels.
Societal Relevance to Research, Education and Patient Care
Immune therapies in certain types of cancer are clearly advantageous when compared to chemotherapeutic drugs or small molecule inhibitors, and decades of research have moved multiple immune therapies into standard of care. In example, Nivolumab has recently been registered for the treatment of metastatic melanoma, NSCLC and renal cell carcinoma in the Netherlands, and the same is true for other (combinations of) checkpoint inhibitors. In fact, recent market analyses demonstrate that immune therapies, or therapies combined with immune therapies, will constitute a growing part of the treatment portfolio of cancers (treatment of up to 60% of patients, Citigroup, US).
This ACE will provide Erasmus MC a recognizable profile and aid to the understanding of tumor immunity and maturation of immune therapies. In addition, this ACE aims to make these treatments, often with side effects and costly (in example: per patient cost of checkpoint inhibitors is generally about 80 k€, CVZ, the Netherlands) better and more affordable.
Also, the proposed ACE will valorize novel findings and therapies, and provide coordinated contribution to education and awareness of the general public with respect to immuno-oncology via non-scientific publications, social media, and close contacts with patient organizations. In fact, parts of research of this ACE are supported by different community foundations, such as Stichting Coolsingel.
Viability of Research, Education and Patient Care
This ACE has a strong multi-disciplinary character (currently involves 12 departments), and we intend to create a high level of viability through a 'bottom-up' structure. At its base, there is a 'Tumor Immunology Platform' (TIP) (n >30 with more than half being PhD students), where we weekly discuss manuscripts and projects, and intensify collaborations and joint future projects with respect to tumor immunology and immune therapies.
At a higher management level, scientific and clinical opportunities and challenges are discussed at 6 weekly intervals with leading investigators (n=37). The leading investigators well represent research teams and clinical activities from Erasmus MC, and are well balanced with respect to seniority and expertise (i.e., current numbers, clinicians: 15; UHD/professors: 21 (8 also being clinician); UD/postdoctoral fellows: 9), which warrants continuity of this ACE.
Individual departments within ACE, such as depts of Medical Oncology, Pulmonary Disease, and MDL, have already established track records within Immuno-oncology, which will only increase and include other depts. when efforts are combined and coordinated within ACE.
Current opportunities within ACE and other ACEs to further strengthen viability:
Create a shared and unique research agenda (currently drafted) to direct joint studies and grant writing at consortium level.
Make an inventory of equipment; research/animal models; bio-banking; clinical trials; funding; and external collaborators (also currently drafted) to enhance visibility, effectiveness and competitiveness of ACE. In a next step these inventories will be shared and merged with those of interacting ACEs and research facilities.
Make a governance of 'way of working together' to ensure future stability of our team(s).
Key and relevant publications of the last five years
- Lamers C, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R, Gratama J. Treatment of metastatic Renal Cell Carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther, 2013, 21:904.
- Cornelissen R, Hegmans J, Maat AP, Kaijen-Lambers M, Bezemer K, Hendriks R, Hoogsteden H, Aerts J. Extended Tumor Control after Dendritic Cell Vaccination with Low-Dose Cyclophosphamide as Adjuvant Treatment in Patients with Malignant Pleural Mesothelioma. Am J Respir Crit Care Med, 2016, 193:1023.
- Worah K, Mathan TSM, Vu Manh TP, Keerthikumar S, Schreibelt G, Tel J, Duiveman-de Boer T, Sköld AE, van Spriel AB, de Vries IJM, Huynen MA, Wessels HJ, Gloerich J, Dalod M, Lasonder E, Figdor CG, Buschow SI. Proteomics of Human Dendritic Cell Subsets Reveals Subset-Specific Surface Markers and Differential Inflammasome Function. Cell Rep,.2016, 16:2953.
- Buschow SI, Sprengers D, Woltman AM. To target or not to target viral antigens in HBV related HCC? J Hepatol,.2015 62:1449.
- Sideras K, Biermann K, Verheij J, Takkenberg BR, Mancham S, Hansen BE, Schutz HM, de Man RA, Sprengers D, Buschow SI, Verseput MC, Boor PP, Pan Q, van Gulik TM, Terkivatan T, Ijzermans JN, Beuers UH, Sleijfer S, Bruno MJ, Kwekkeboom J. PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma. Oncoimmunology, 2017, 6:e1273309.
- Gracias D, Stelekati E, Hope J, Boesteanu A, Doering T, Norton J, Mueller Y, Fraietta J, Wherry E, Turner M, Katsikis P. The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling. Nat Immunol, 2013, 14:593.
- Lievense L, Hegmans J, Aerts J. Biomarkers for immune checkpoint inhibitors. Lancet Oncol, 2014, 15:e1.
- de Jong M, Essers J, van Weerden W. Imaging preclinical tumour models: improving translational power. Nat Rev Cancer, 2014, 14:481.
- Straetemans T, Berrevoets C, Coccoris M, Treffers-Westerlaken E, Wijers R, Cole D, Dardalhon V, Sewell A, Taylor N, Verweij J, Debets R. Recurrence of melanoma following T cell treatment: continued antigen expression in a tumor that evades T cell recruitment. Mol Ther, 2015 23:396.
- Brahmer J, Reckamp K, Baas P, Crinò L, Eberhardt W, Poddubskaya E, Antonia S, Pluzanski A, Vokes E, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino M, Aerts J, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison C, Lestini B, Spigel D. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med, 2015, 373:123.
- Kunert A, van Steenbergen-Langeveld S, van Brakel M, da Silva M, Coulie P, Lamers C, Sleijfer S, Debets R. MAGE-C2 specific TCRs, in combination with epigenetic drug treatment of target cells, yield tumor-selective therapeutic T cells. J Immunol, 2016 197:2541.
- Kunert A, Obenaus M, Lamers CH, Blankenstein T, Debets R. T cell receptors for clinical therapy: in vitro assessment of toxicity risk. Clin Cancer Res, 2017 23:6012
- Hammerl D, Dietmar R, Martens J, Trajanowski Z, Debets R. Adoptive T cell therapy: not without testing visibility of tumor antigens. Trends Immunol, 2018, in press.
- Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, Pedroza-Gonzalez A, Polak WG, de Jonge J, Gaspersz M, Dong H, Thielemans K, Pan Q, JNM IJ, Bruno MJ, Kwekkeboom J. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Gastroenterology, 2017;153: 1107.
- de Graaf JF, de Vor L, Fouchier RAM, van den Hoogen BG. Armed oncolytic viruses: A kick-start for anti-tumor immunity. Cytokine Growth Factor Rev, 2018 41:28.
- van den Bossche WBL, Kleijn A, Teunissen CE, Voerman JSA, Teodosio C, Noske DP, van Dongen JJM, Dirven CMF, Lamfers MLM. Oncolytic virotherapy in glioblastoma patients induces a tumor macrophage phenotypic shift leading to an altered glioblastoma microenvironment. Neuro Oncol. 2018, in press.
- Kunert A, Basak E, Hurkmans D, Klaver Y, van Brakel M, Oostvogels A, Lamers C, Bins S, Koolen S, van der Veldt A, Sleijfer S, Mathijssen R, Aerts J, Debets R. CD45RA+CCR7- CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in NSCLC patients responding to nivolumab. Ms submitted.
PhD theses of the last five years
- Towards clinical TCR gene therapy: tumor models and receptors; Straetemans; 2012
- Prognostic Markers in Pancreatic Cancer: the Tumour and its Environment; van der Zee; 2012
- Role of microRNA-155 in CD8+ T cell responses; Gracias; 2012
- Interleukin 7 and patient selection in immunotherapy for prostate cancer; Schroten-Loef; 2013
- Engineering of T cell receptor genes to advance T cell therapy: studies into TCR pairing, signaling and binding strength; Govers; 2013
- Oncolytic Newcastle Disease Virus as Treatment for Pancreatic Cancer; Buijs; 2015
- Combination therapies in a patient-derived Glioblastoma Model; Berghauser Pont; 2015
- The Tumor and its Microenvironment in Mesothelioma; The good, the bad and the ugly; Cornelissen; 2015
- Improving treatment in mesothelioma; Lievense; 2016
- Adoptive T cell therapy against solid tumors: success requires safe TCRs and countering immune evasion; Kunert, 2018
- Potential immune biomarkers in gastrointestinal cancers: immune inhibitory molecules, lymphocytes and tumor antigens; Sideras; 2017.
- Regulation of intra-tumoral T cell immunity in liver cancer; Zhou; 2018.
Non-scientific publications related to the ACE
- Nieuws prostaatkankerstichting; Achter de schermen; https://www.kanker.nl/uploads/file_element/content/15470/Achter_de_schermen_bij_Erasmus_MC.pdf, Riegman; 2013
- Oncotherapie; Immuuntherapie: de doorbraak is er, nu de controle nog; Debets; 2014
- Monitor; Eigen afweer in stelling; Aerts; 2014
- SPKS Leven, doorgang, no. 52; Het is nodig de weg van de immunotherapie in te slaan;van den Hoogen en van Eijck; 2015
- European Cancer Patient Coalition; Biobanks; http://www.ecpc.org/news-categories/project-news/128-eurocanplatform-news/195-biobank-faq-eurocanplatform-wp10; Riegman; 2015
- Telegraaf: Immuuntherapie bij leverkanker; Sprengers en Kwekkeboom; 2015
- Nieuwsbrief Asbestslachtoffers Vereniging Nederland; Opgeleide cel activeert eigen immuunsysteem van de patiënt; van der Leest; 2015
- Telegraaf; Afweercellen tegen asbestkanker; Cornelissen; 2015
- Algemeen Dagblad; Nieuwe behandeling voor asbestkanker (voorpagina); Aerts; 2015
- Erasmus MC Cancer Institute Magazine. Immunotherapy: reinforcing the body’s natural defense against cancer; de Wit, 2017.
- Support Casper. Meet our immune monitoring team; v Eijck; 2018.
- J.G.J.V. Aerts
- C.H. Bangma
- J.L. Boormans
- C.A.B. Boucher
- S.I. Buschow
- J.J. Cornelissen
- S.U. Dalm
- R. de Wit
- J.E.M.A. Debets
- C.M.F. Dirven
- P.J. French
- A. Jager
- P. Katsikis
- J.M. Kros
- W.H.J. Kruit
- J. Kwekkeboom
- C.H.J. Lamers
- L.M. Lamfers
- M.P.J.K. Lolkema
- C.W.G.M. Löwik
- J.W.M. Martens
- P.H.J. Riegman
- P.A.E. Sillevis Smitt
- P. Sonneveld
- D. Sprengers
- T.L.M. ten Hagen
- H.J.G. van de Werken
- B.G. van den Hoogen
- A.A.M. van der Veldt
- C.H.J. van Eijck
- F.J. van Kemenade
- G.J.L.H. van Leenders
- W.M. van Weerden
- C. Verhoef
- H.E. Balcioglu
- C.H. Bangma
- R. Barbosa Marques
- M.J. Bruno
- S.I. Buschow
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- L. Mezzanotte
- D.A.M. Mustafa
- J.P. Pignol
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