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Immunotherapy Laboratory

Immunotherapy 


Introduction to the research
The Immunotherapy laboratory of the Department of Medical Oncology of the VU University Medical Center studies the possibility to exploit the immune system to specifically recognize, attack and eradicate tumor cells. Key components in a successful immune reaction are two types of immune effector cells: the Dendritic Cells (DCs) and the T cells. DCs are the sentinels of our immune system which, in case of danger (e.g. viral or bacterial infections, inflammation or tumor growth), become activated and release factors that recruit other immune cells to contribute to an effective anti-tumor immune response. A central role in the immune-mediated elimination of tumors is played by Cytotoxic (or ?killer?) T Lymphocytes (CTLs). In lymph nodes that drain tumor sites these CTLs are instructed by DCs (migrated from the tumor) to recognize and kill tumor cells. A major obstacle in this process is caused by immune suppressive factors produced by the tumor that hamper the development and proper activation of both DCs and CTLs. As a result, patients are more susceptible to microbial infections and unable to mount an effective immune response to their tumor. Much of our research is aimed at overcoming this immune suppression.

Composition of the group and collaborations

Over the past decade the Immunotherapy laboratory has proven a fruitful and close collaborative effort between the departments of Medical Oncology and Pathology, supervised by Dr. Fons van den Eertwegh (clinic) and Dr. Tanja de Gruijl (lab) from the Medical Oncology and Prof. Rik Scheper from the Pathology department. The group maintains close collaborative ties with the departments of Hematology, Rheumatology, Dermatology, Surgical Oncology and Molecular Cell Biology and Immunology: all concerning the function of DCs and T cells in the anti-tumor immune response.

Translational research

By performing both pre-clinical and clinical research, we aim to rapidly translate findings in the lab to novel or improved clinically applicable therapies, but also to further submit clinical findings to experimental testing in the lab. Close contact between the medical doctors in the clinic and scientists in the lab facilitates this ?bench-to-bedside? and ?bedside-to-bench? approach. A  recent example is a clinical trial in which prostate cancer patients were vaccinated with a DC-stimulating tumor vaccin in combination with a CTL-activating antibody. In this trial several promising clinical responses were found. By studying the immune responses in these patients we hope to find the underlying cellular mechanisms in order to be able to design still better vaccins.          

Some recent research highlights
Saskia Santegoets received a Clinical Young Investigator Award from the Prostate Cancer Foundation (PCF) for her research on DC and T cell functions in men with prostate cancer, who received the Prostate GVAX vaccine combined with the anti-CTLA4 antibody ipilimumab. This prize was presented to her by Dr Howard Soule, the Executive Vice-President and Scientific Officer of the PCF, during the Annual Conference of the American Association of Cancer Research, held in San Diego in April 2008.

The identification of molecular processes that underlie hampered DC development and activation among others in brain tumors enables the modulation of these processes by small-molecule inhibitors that are applied in the clinic. With this knowledge viral vectors are also designed that can be utilized as DC-targeted cancer vaccine vehicles. This research line, financed by the Dutch Organisation for Scientific Research (NWO), is carried out by Dinja Oosterhoff, Jelle Lindenberg, Hester van Cruijsen and Sinéad Lougheed.

Rieneke van de Ven made the important observation that a molecular pump on the surface of skin DCs (i.e. MRP4) is crucial for the migration of these DCs from the skin to draining lymph nodes: a bottleneck in the efficacy of DC-based cancer vaccines (financed by the Dutch Cancer Society, KWF).

Clinical studies on the immunopotentiation of melanoma Sentinel Lymph Nodes were continued by Berbel Sluijter and Mari van den Hout, while a new project was started by Basav Hangalapura to develop novel DC-targeted vaccines for the therapy of prostate cancer. This project is carried out in close collaboration with the group of Prof Yvette van Kooyk and is financed by a grant from CCA/V-ICI/Stichting Avanti-STR. In a novel research line initiated by Hans van der Vliet, Famke Schneiders started on her graduate research concerning the potential use of NKT and V.d T cells for cancer immunotherapy.

publications list: 

Tanja de Gruijl

Fons van den Eertwegh

Hans van der Vliet

 

Recent publications

2015

Rosalia RA, Cruz LJ, van Duikeren S, Tromp AT, Silva AL, Jiskoot W, de Gruijl T, Löwik C, Oostendorp J, van der Burg SH, Ossendorp F. CD40-targeted dendritic cell delivery of PLGA-nanoparticle vaccines induce potent anti-tumor responses. Biomaterials 2015; 2014 Nov 26. pii: S0142-9612(14)01117-X. doi: 10.1016/j.biomaterials.2014.10.053.

De Remigis A, de Gruijl TD, Uram JN, Tzou SC, Iwama S, Talor MV, Armstrong TD, Santegoets SJ, Slovin SF, Zheng L, Laheru DA, Jaffee EM, Gerritsen WR, van den Eertwegh AJ, Le DT, Caturegli P. Development of thyroglobulin antibodies after GVAX immunotherapy is associated with prolonged survival. Int J Cancer 2015; 136: 127-137.

Heeren AM, Koster BD, Samuels S, Ferns DM, Chondronasiou D, Kenter GG, Jordanova ES, de Gruijl TD. High and interrelated rates of PD-L1+CD14+ antigen-presenting cells and regulatory T cells mark the microenvironment of metastatic lymph nodes from patients with cervical cancer. Cancer Immunol Res 2015; pii: canimm.0149.2014.

2014

Würdinger T, Deumelandt K, van der Vliet HJ, Wesseling P, de Gruijl TD. Mechanisms of intimate and long-distance cross-talk between glioma and myeloid cells: How to break a vicious cycle. BBA Rev Cancer 2014; 1846: 560-575.

Lameris R, de Bruin RC, Schneiders FL, van Bergen-Henegouwen PM, Verheul HM, de Gruijl TD, van der Vliet HJ. Bispecific antibody platforms for cancer immunotherapy. Crit Rev Hematol Oncol 2014; 92: 153-165.

Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR; CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15: 700-712.

Schneiders FL, Prodöhl J, Ruben JM, O'Toole T, Scheper RJ, Bonneville M, Scotet E, Verheul HM, de Gruijl TD, van der Vliet HJ. CD1d-restricted antigen presentation by V?9Vd2-T cells requires trogocytosis. Cancer Immunol Res 2014; 2: 732-740.

Fehres CM, Bruijns SC, van Beelen AJ, Kalay H, Ambrosini M, Hooijberg E, Unger WW, de Gruijl TD, van Kooyk Y. Topical rather than intradermal application of the TLR7 ligand imiquimod leads to human dermal dendritic cell maturation and CD8+ T-cell cross-priming.  Eur J Immunol 2014; 44: 2415-2424.

Lindenberg JJ, van de Ven R, Oosterhoff D, Sombroek CC, Lougheed SM, Stam AG, Koenen HJ, van den Eertwegh AJ, Scheper RJ, de Gruijl TD. Induction of dendritic cell maturation in the skin microenvironment by soluble factors derived from colon carcinoma. Hum Vaccin Immunother 2014; 10(6).

Lameris R, Schneiders FL, de Gruijl TD, van der Vliet HJ. Exploiting the CD1d-iNKT cell axis for potentiation of DC-based cancer vaccines. Methods Mol Biol 2014; 1139: 155-165.

Ruben JM, van den Ancker W, Bontkes HJ, Westers TM, Hooijberg E, Ossenkoppele GJ, de Gruijl TD, van de Loosdrecht AA. Apoptotic blebs from leukemic cells as a preferred source of tumor-associated antigen for dendritic cell-based vaccines. Cancer Immunol Immunother 2014; 63: 335-345.

Lanzi A, Fehres CM, de Gruijl TD, van Kooyk Y, Mastrobattista E. Effects of antigen-expressing immunostimulatory liposomes on chemotaxis and maturation of dendritic cells in vitro and in human skin explants. Pharm Res 2014; 31: 516-526.

2013

van de Ven R, Lindenberg JJ, Oosterhoff D, de Gruijl TD. Dendritic cell plasticity in tumor-conditioned skin: CD14+ cells at the cross-roads of immune activation and suppression. Front Immunol 2013; 4: 403.

Yanagisawa K, Yue S, van der Vliet HJ, Wang R, Alatrakchi N, Golden-Mason L, Schuppan D, Koziel MJ, Rosen HR, Exley MA. Ex vivo analysis of resident hepatic pro-inflammatory CD1d-reactive T cells and hepatocyte surface CD1d expression in hepatitis C. J Viral Hepat 2013;20: 556-565.

van den Ancker W, Wijnands PG, Ruben JM, Westers TM, Punt B, Bachas C, Ravenshorst N, van Wetering S, Kruisbeek AM, Bontkes HJ, Ossenkoppele GJ, van de Loosdrecht AA, de Gruijl TD. Procedures for the expansion of CD14(+) precursors from acute myeloid leukemic cells to facilitate dendritic cell-based immunotherapy. Immunotherapy 2013; 5: 1183-1190.  

Ruben JM, Visser LL, Bontkes HJ, Westers TM, Ossenkoppele GJ, de Gruijl TD, van de Loosdrecht AA. Targeting the acute myeloid leukemic stem cell compartment by enhancing tumor cell-based vaccines. Immunotherapy 2013; 5: 859-568.

Santegoets SJ, Turksma AW, Powell Jr DJ, Hooijberg E, de Gruijl TD. IL-21 in cancer immunotherapy: At the right place at the right time. Oncoimmunology 2013; 2(6):e24522.

Kuijk LM, Verstege MI, Rekers NV, Bruijns SC, Hooijberg E, Roep BO, de Gruijl TD, van Kooyk Y, Unger WW. Notch controls generation and function of human effector CD8+ T cells. Blood 2013; 121: 2638-2646.

Lindenberg JJ, Oosterhoff D, Sombroek CC, Lougheed SM, Hooijberg E, Stam AG, Santegoets SJ, Tijssen HJ, Buter J, Pinedo HM, van den Eertwegh AJ, Scheper RJ, Koenen HJ, van de Ven R, de Gruijl TD. IL-10 conditioning of human skin affects the distribution of migratory dendritic cell subsets and functional T cell differentiation. PLos One 2013; 8(7): e70237.

Oosterhoff D, Heusinkveld M, Lougheed SM, Kosten I, Lindstedt M, Bruijns SC, van Es T, van Kooyk Y, van der Burg SH, de Gruijl TD. Intradermal delivery of TLR agonists in a human explant skin model: preferential activation of migratory dendritic cells by polyribosinic-polyribocytidylic acid and peptidoglycans. J Immunol 2013; 190: 3338-3345.

Kerkhoff N, Bontkes HJ, Westers TM, de Gruijl TD, Kordasti S, van de Loosdrecht AA. Dendritic cells in myelodysplastic syndromes: from pathogenesis to immunotherapy. Immunotherapy 2013; 5: 621-637.

van den Ancker W, Ruben JM, Westers TM, Wulandari D, Bontkes HJ, Hooijberg E, Stam AG, Santegoets SJ, Ossenkoppele GJ, de Gruijl T, van de Loosdrecht A. Priming of PRAME- and WT1-specific CD8+ T cells in healthy donors but not in AML patients in complete remission: Implications for immunotherapy. Oncoimmunology 2013; 2(4): e23971.

Turksma AW, Bontkes HJ, Ruizendaal JJ, Scholten KB, Akershoek J, Rampersad S, Moesbergen LM, Cillessen SA, Santegoets SJ, de Gruijl TD, Leemans CR, Meijer CJ, Hooijberg E. Exploring dendritic cell based vaccines targeting survivin for the treatment of head and neck cancer patients. J Transl Med 2013; 11: 152. Doi: 10.1186/1479-5876-11-152.

Santegoets SJ, Turksma AW, Suhoski MM, Stam AG, Albelda SM, Hooijberg E, Scheper RJ, van den Eertwegh AJ, Gerritsen WR, Powell DJ Jr, June CH, de Gruijl TD. IL-21 promotes the expansion of CD27+CD28+ tumor infiltrating lymphocytes with high cytotoxic potential and low collateral expansion of regulatory T cells. J Transl Med 2013 Feb 12; 11:37. doi: 10.1186/1479-5876-11-37.

Lindenberg JJ, Lougheed SM, Van de Ven R, Zomer A, Santegoets SJ, Griffioen AW, Hooijberg E, Van den Eertwegh AJ, Thijssen VL, Scheper RJ, Oosterhoff D, De Gruijl TD. Functional characterization reveals STAT3 dependence of a dendritic cell-derived CD14+BDCA3/ CD141+ population arising upon IL-10-exposed maturation. Oncoimmunology 2013; 2: e23837.

Verbrugge SE, Al M, Assaraf YG, Niewerth D, van Meerloo J, Cloos J, van der Veer M, Scheffer GL, Peters GJ, Chan ET, Anderl JL, Kirk CJ, Zweegman S, Dijkmans BA, Lems WF, Scheper RJ, de Gruijl TD, Jansen G. Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors. Exp Hematol Oncol 2013 Jan 10; 2: 2. [doi: 10.1186/2162-3619-2-2.

Turksma AW, Bontkes HJ, Ruizendaal JJ, van den Heuvel H, Scholten KB, Santegoets SJ, de Gruijl TD, Meijer CJ, Hooijberg E. Increased cytotoxic capacity of tumor antigen specific human T cells after in vitro stimulation with IL21 producing dendritic cells. Hum Immunol 2013; 74: 506-513.

Lundberg K, Albrekt AS, Nelissen I, Santegoets S, de Gruijl TD, Gibbs S, Lindstedt M. Transcriptional profiling of human dendritic cell populations and models - unique profiles of in vitro dendritic cells and implications on functionality and applicability. Plos One 2013; 8(1) :e52875.

Turksma A, Bontkes H, van den Heuvel H, de Gruijl T, von Blomberg B, Braakhuis B, Leemans C, Bloemena E, Meijer C, Hooijberg E. Effector memory T-cell frequencies in relation to tumour stage, location and HPV status in HNSCC patients.Oral Dis 2013; 19: 577-584. 

2012

Oprea-Lager DE, Vincent AD, van Moorselaar RJ, Gerritsen WR, van den Eertwegh AJ, Eriksson J, Boellaard R, Hoekstra OS. Dual-phase PET-CT to differentiate [(18)F]Fluoromethylcholine uptake in reactive and malignant lymph nodes in patients with prostate cancer. Plos One 2012; 7: e48430. doi: 10.1371/journal. pone.0048430.

de Gruijl TD, Ginhoux F, Bousso P, Bieber T, Piguet V, von Stebut E, Dudziak D, Chakraverty R. Fondation rene touraine pour la dermatologie. Exp Dermatol 2012; 21: 802-814.

Hoebe EK, Le Large TY, Tarbouriech N, Oosterhoff D, De Gruijl TD, Middeldorp JM, Greijer AE. Epstein-Barr Virus-encoded BARF1 protein is a decoy receptor for macrophage colony stimulating factor and interferes with macrophage differentiation and activation. Viral Immunol 2012; 25: 461-470.

de Gruijl TD, van de Ven R. Adenovirus-based immunotherapy of cancer: promises to keep. Adv Cancer Res 2012;115:147-220. 

Oosterhoff D, Lougheed S, van de Ven R, Lindenberg J, van Cruijsen H, Hiddingh L, Kroon J, van den Eertwegh AJ, Hangalapura B, Scheper RJ, de Gruijl TD. Tumor-mediated inhibition of human dendritic cell differentiation and function is consistently counteracted by combined p38 MAPK and STAT3 inhibition. Oncoimmunology 2012; 1: 649-658.

Santegoets SJ, Stam AG, Lougheed SM, Gall H, Scholten PE, Reijm M, Jooss K, Sacks N, Hege K, Lowy I, Cuillerot JM, von Blomberg BM, Scheper RJ, van den Eertwegh AJ, Gerritsen WR, de Gruijl TD. T cell profiling reveals high CD4(+)CTLA-4 (+) T cell frequency as dominant predictor for survival after Prostate GVAX/ipilimumab treatment. Cancer Immunol Immunother 2012; 2012 Aug 10. [Epub ahead of print].

Ouwehand K, Spiekstra SW, Waaijman T, Breetveld M, Scheper RJ, de Gruijl TD, Gibbs S. CCL5 and CCL20 mediate immigration of Langerhans cells into the epidermis of full thickness human skin equivalents. Eur J Cell Biol 2012; 91: 765-773.

Hadj JO,  Den Braven R, Tillier C, Schrijver HM, Verheul HMW, Van der Vliet HJ.  Reversible posterior leukoencephalopathy syndrome during sunitinib therapy for metastatic renal cell carcinoma. Oncology Lett 2012; 3: 1293-1296.

Dressel AJ, van der Mijn JC, Aalders IJ, Rinkel RN, van der Vliet HJ. Irinotecan-induced dysarthria. Case Rep Oncol 2012; 5 :47-51.

Revicki DA, van den Eertwegh AJ, Lorigan P, Lebbe C, Linette G, Ottensmeier CH, Safikhani S, Messina M, Hoos A, Wagner S, Kotapati S. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcomes 2012; 10: 66.

Unger WW, van Beelen AJ, Bruijns SC, Joshi M, Fehres CM, van Bloois L, Verstege MI, Ambrosini M, Kalay H, Nazmi K, Bolscher JG, Hooijberg E, de Gruijl TD, Storm G, van Kooyk Y. Glycan-modified liposomes boost CD4(+) and CD8(+) T-cell responses by targeting DC-SIGN on dendritic cells. J Control Release 2012; 160: 88-95.

Van den Eertwegh AJ, Versluis J, van den Berg HP, Santegoets SJ, van Moorselaar RJ, van der Sluis TM, Gall HE, Harding TC, Jooss K, Lowy I, Pinedo HM, Scheper RJ, Stam AG, von Blomberg BM, de Gruijl TD, Hege K, Sacks N, Gerritsen WR. Combined immunotherapy with granulocyte -macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13: 509-517.

Hangalapura BN, Timares L, Oosterhoff D, Scheper RJ, Curiel DT, de Gruijl TD. CD40-targeted adenoviral cancer vaccines: the long and winding road to the clinic. J Gene Med 2012; 14: 416-427.

Dressel AJ, van der Mijn JC, Aalders IJ, Rinkel RN, van der Vliet HJ. Irinotecan-induced dysarthria. Case Rep Oncol 2012; 5: 47-51.

Verbrugge SE, Assaraf YG, Dijkmans BA, Scheffer GL, Al M, den Uyl D, Oerlemans R, Chan ET, Kirk CJ, Peters GJ, van der Heijden JW, de Gruijl TD, Scheper RJ, Jansen G. Inactivating PSMB5 mutations and P-glycoprotein (MDR1/ ABCB1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno) proteasome inhibitors in mononuclear blood cells from rheumatoid arthritis patients. J Pharmacol Exp Ther 2012;  341: 174-182.

Schneiders FL, de Bruin RCG,  van den Eertwegh AJM, Scheper RJ, Leemans CR, Brakenhoff RH, Langendijk JA, Verheul HMW, de Gruijl TD, Molling JW, van der Vliet HJ. Circulating invariant natural killer T-cell numbers predict outcome in head and neck squamous cell carcinoma: updated analysis with 10-year follow-Up. J Clin Oncol 2012; 30: 567-570.

de Weger VA, Turksma AW, Voorham QJ, Euler Z, Bril H, van den Eertwegh AJ, Bloemena E, Pinedo HM, Vermorken JB, Van Tinteren H, Meijer GA, Hooijberg E. Clinical effects of adjuvant active specific immunotherapy differ between patients with microsatellite stable and microsatellite instable colon cancer. Clin Cancer Res 2012;  18: 882-889.

Schneiders FL, de Bruin RC, Santegoets SJ, Bonneville M, Scotet E, Scheper RJ, Verheul HM, de Gruijl TD, van der Vliet HJ. Activated iNKT cells promote Vgamma9Vd2-T cell anti-tumor effector functions through the production of TNF-a. Clin Immunol 2012;  142: 194-200.

Oosterhoff D, Sluijter BJ, Hangalapura BN, de Gruijl TD. The dermis as a portal for dendritic cell-targeted immunotherapy of cutaneous melanoma. Curr Top Microbiol Immunol 2012; 351: 181-220.

van Pul KM, Vuysteke RJ, Bril H, Stockmann HB, de Gruijl TD. Feasibility of flowcytometric quantitation of immune effector cell subsets in the sentinel lymph node of the breast after cryopreservation. J Immunol Methods 2012; 375: 189-195.

van de Ven R, Reurs AW, Wijnands PG, van Wetering S, Kruisbeek AM, Hooijberg E, Scheffer GL, Scheper RJ, de Gruijl TD. Exposure of CD34(+) precursors to cytostatic anthraquinone-derivatives induces rapid dendritic cell differentiation: implications for cancer immunotherapy. Cancer Immnunol Immunother 2012; 61: 181-191.

van de Ven R, Lindenberg JJ, Reurs AW, Scheper RJ, Scheffer GL, de Gruijl TD. Preferential Langerhans cell differentiation from CD34(+) precursors upon introduction of ABCG2 (BCRP). Immunol Cell Biol 2012; 90: 206-215.
 

2011  


Huijts CM, Santegoets SJ, van den Eertwegh AJ, Pijpers LS, Haanen JB, de Gruijl TD, Verheul HM, van der Vliet HJ. Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer. BMC Cancer  2011 Nov 30;11(1):505.

van Cruijsen H, Oosterhoff D, Lindenberg JJ, Lougheed SM, Fehres C, Weijers K, van Boerdonk R, Giaccone G, Scheper RJ, Hoekman K, de Gruijl TD. Glioblastoma-induced inhibition of Langerhans cell differentiation from CD34(+) precursors is mediated by IL-6 but unaffected by JAK2/STAT3 inhibition. Immunotherapy 2011; 3:1051-1061.

Schneiders FL, de Bruin R, Exley MA, van der Vliet HJ. Nuancing the proposed role of NKT cells in aging. Virulence 2011; 2:170; author reply 171.

van de Ven R,  van den Hout MFCM, Lindenberg JJ, Sluijter BJR, PAM van Leeuwen, Lougheed SM, Meijer S, van den Tol MP, Scheper RJ, de Gruijl TD. Characterization of four conventional dendritic cell subsets in human skin-draining lymph nodes in relation to T-cell activation. Blood 2011; 118: 2502-2510.

Hangalapura BN, Oosterhoff D, de Groot J, Boon L, Tuting T, van den Eertwegh AJ, Gerritsen WR, van Beusechem VW, Pereboev A, Curiel DT, Scheper RJ, de Gruijl TD. Potent anti-tumor immunity generated by a CD40-targeted adenoviral vaccine. Cancer Res 2011; 71:5827-5837.

Ouwehand K, Spiekstra SW, Waaijman T, Scheper RJ, de Gruijl TD, Gibbs S.Technical Advance: Langerhans cells derived from a human cell line in a full-thickness skin equivalent undergo allergen-induced maturation and migration. J Leukocyt Biol 2011; 90:1027-1033.

Schneiders FL, de Bruin R, Exley M, van der Vliet HJ. Nuancing the proposed role of NKT cells in aging. 2011; 2:170.

van de Ven R, Verbrugge SE, Reurs AW, Bontkes HJ, Hooijberg E, Jansen G, Scheper RJ, Scheffer GL, de Gruijl TD. High susceptibility of c-KIT(+)CD34 (+) precursors to prolonged doxorubicin exposure interferes with Langerhans cell differentiation in a human cell line model. Cancer Immunol Immunother 2011; 60:943-951.

Hangalapura BN, Oosterhoff D, Gupta T, de Groot J, Wijnands PG, van Beusechem VW, den Haan J, Tüting T, van den Eertwegh AJ, Curiel DT, Scheper RJ, de Gruijl TD. Delivery route, MyD88 signaling and cross-priming events determine the anti-tumor efficacy of an adenovirus based melanoma vaccine. Vaccine 2011; 29:2313-2321.

van der Veldt AA, Eechoute K, Gelderblom H, Gietema JA, Guchelaar HJ, van Erp N, Van den Eertwegh AJ, Haanen JB, Mathijssen RH, Wessels JA. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 2011; 17:620-629.

Lindenberg JJ, Fehres CM, van Cruijsen H, Oosterhoff D, de Gruijl TD. Cross-talk between tumor and myeloid cells: how to tip the balance in favor of antitumor immunity. Immunotherapy 2011; 3:77-96.

Schneiders FL, Scheper RJ, von Blomberg BM, Woltman AM, Janssen HL, van den Eertwegh AJ, Verheul HM, de Gruijl TD, van der Vliet HJ. Clinical experience with a-galactosylceramide (KRN7000) in patients with advanced cancer and chronic hepatitis B/C infection. Clin Immunol 2011; 140:130-141.

Ouwehand K, Oosterhoff D, Breetveld M, Scheper RJ, de Gruijl TD, Gibbs S. Irritant-Induced Migration of Langerhans Cells Coincides with an IL-10-Dependent Switch to a Macrophage-Like Phenotype. J Invest Dermatol 2011; 131:418-425.

2010

Széles L, Póliska S, Nagy G, Szatmari I, Szanto A, Pap A, Lindstedt M, Santegoets SJ, Rühl R, Dezsö B, Nagy L. Research resource: Transcriptome profiling of genes regulated by RXR and its permissive and nonpermissive partners in differentiating monocyte-derived dendritic cells. Mol Endocrinol 2010; 24:2218-2231.

Van den Ancker W, van Luijn MM, Ruben JM, Westers TM, Bontkes HJ, Ossenkoppele GJ, de Gruijl TD, van de Loosdrecht AA. Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation. Cancer Immunol Immunother 2010 Sep 22. [Epub ahead of print].

Sluijter BJ, van den Hout MF, Stam AG, Lougheed SM, Suhoski MM, van den Eertwegh AJ, van den Tol MP, van Leeuwen PA, Meijer S, Scheper RJ, June CH, de Gruijl TD, Santegoets SJ4-1BB-mediated expansion affords superior detection of in vivo primed effector memory CD8(+) T cells from melanoma sentinel lymph nodes. Clin immunol 2010; 137:221-233.

Hangalapura BN, Oosterhoff D, Aggarwal S, Wijnands PG, van de Ven R, Santegoets SJ, van den Tol MP, Hooijberg E, Pereboev A, van den Eertwegh AJ, Curiel DT, Scheper RJ, de Gruijl TD. Selective transduction of dendritic cells in human lymph nodes and superior induction of high-avidity melanoma-reactive cytotoxic T cells by a CD40-targeted Adenovirus. J Immunother 2010; 33:706-715.

Van den Ancker W, van Luijn MM, Westers TM, Bontkes HJ, Ruben JM, de Gruijl TD, Ossenkoppele GJ, van de Loosdrecht AA. Recent advances in antigen-loaded dendritic cell-based strategies for treatment of minimal residual disease in acute myeloid leukemia. Immunotherapy 2010; 2:69-83.

Bontkes HJ, Moreno M, Hangalapura B, Lindenberg JJ, de Groot J, Lougheed S, van der Vliet HJ, van den Eertwegh AJ, de Gruijl TD, von Blomberg BM, Scheper RJ. Attenuation of invariant Natural Killer T-cell anergy induction through intradermal delivery of alpha-galactosylceramide. Clin Immunol 2010; 136:364-374.

Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with Ipilimumab in patients with metastatic melanoma. New Engl J Med 2010; 363:711-723.

Ouwehand K, Scheper RJ, de Gruijl TD, Gibbs S. Epidermis-to-dermis migration of immature Langerhans cells upon topical irritant exposure is dependent on CCL2 and CCL5. Eur J Immunol 2010; 40:2026-2034.

Ten Brinke A, van Schijndel G, Visser R, de Gruijl TD, Zwaginga JJ, van Ham SM. Monophosphoryl lipid A plus IFNgamma maturation of dendritic cells induces antigen-specific CD8(+) cytotoxic T cells with high cytolytic potential. Cancer Immunol Immunother 2010; 59:1185-1195.

Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, de Gruijl TD, Würdinger T, Middeldorp JM. Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci (USA)
2010; 107:6328-6333.

de Jong MA, de Witte L, Santegoets SJ, Fluitsma D, Taylor ME, de Gruijl TD, Geijtenbeek TB. Mutz-3-derived Langerhans cells are a model to study HIV-1 transmission and potential inhibitors. J Leukocyt Biol 2010; 87:637-643.

Ouwehand K, Spiekstra SW, Reinders J, Scheper RJ, de Gruijl TD, Gibbs S. Comparison of a novel CXCL12/CCL5 dependent migration assay with CXCL8 secretion and CD86 expression for distinguishing sensitizers from non-sensitizers using MUTZ-3 Langerhans cells. Toxicol in Vitro 2010; 24:578-585. 

2009  

van Cruijsen H, Ruiz MG, van der Valk P, de Gruijl TD, Giaccone G. Tissue micro array analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer. BMC Cancer  2009; 9: 180.

van de Ven R, de Groot J, Reurs AW, Wijnands PG, van de Wetering K, Schuetz JD, de Gruijl TD, Scheper RJ, Scheffer GL. Unimpaired immune functions in the absence of Mrp4 (Abcc4). Immunol Lett 2009; 124: 81-87.

Pentinga SE, Bruining HG, Gerritsen WR, van den Eertwegh AJ, Rustemeyer T. A case of delayed-type hypersensitivity to subcutaneously administered drugs during anticancer immunotherapy. Br J Dermatol 2009; 160:1132-1134.

Weber JS, Zarour H, Redman B, Trefzer U, O'Day S, van den Eertwegh AJM, MarshallE, Wagner S. Randomized phase 2/3 trial of CpG oligodeoxy-nucleotide PF-3512676 alone or with dacarbazine for patients with unresect-able stage III and IV melanoma. Cancer 2009; 115: 3944-3954.

Van de Ven R, Lindenberg JJ, Oosterhoff D, van den Tol MP, Rosalia RA, Murakami M, Everts M, Scheffer GL, Scheper RJ, de Gruijl TD, Curiel DT. Selective transduction of mature DC in human skin and lymph nodes by CD80/CD86-targeted fiber-modified adenovirus-5/3. J Immunother  2009; 32: 895-906.

Van Houdt IS, Sluijter BJR, van Leeuwen PAM, Moesbergen LM, Hooijberg E, Meijer CJLM, de Gruijl TD, Oudejans JJ, Boven E. Absence of Granzyme B positive TILs in primary melanoma excisional biopsies is strongly associated with the presence of sentinel lymph node metastasis. Cell Oncol 2009; 31: 407-413.

2008

Van Cruijsen H, van der Veldt AA, Vroling L, Oosterhoff D, Broxterman HJ, Scheper RJ, Giaccone G, Haanen JB, van den Eertwegh AJ, Boven E, Hoekman K, de Gruijl TD. Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival. Clin Cancer Res 2008; 14: 5884-5892.

Molling JW, Moreno M, van der Vliet HJ, van den Eertwegh AJ, Scheper RJ, von Blomberg BM, Bontkes HJ. Invariant natural killer T cells and immunotherapy of cancer. Clin Immunol 2008; 129:182-194.

Van de Ven R, Scheffer GL, Reurs AW, Lindenberg JJ, Oerlemans R, Jansen G, Gillet JP, Glasgow JN, Pereboev A, Curiel DT, Scheper RJ, de Gruijl TD. A role for multidrug resistance protein 4 (MRP4; ABCC4) in human dendritic cell migration. Blood 2008; 112: 2353-2359.

Molenkamp BG, Sluijter BJ, van Leeuwen PA, Santegoets SJ, Meijer S, Wijnands PG, Haanen JB, van den Eertwegh AJ, Scheper RJ, de Gruijl TD. Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients. Clin Cancer Res 2008; 14: 4532-4542.

Moreno M, Molling JW, von Mensdorff-Pouilly S, Verheijen RH, von Blomberg BM, van den Eertwegh AJ, Scheper RJ, Bontkes HJ.- In vitro expanded human invariant natural killer T-cells promote functional activity of natural killer cells. Clin Immunol 2008; 129: 145-154.

Moreno M, Molling JW, von Mensdorff-Pouilly S, Verheijen RH, Hooijberg E, Kramer D, Reurs AW, van den Eertwegh AJ, von Blomberg BM, Scheper RJ, Bontkes HJ.-IFN-gamma-producing human invariant NKT cells promote tumor-associated antigen-specific cytotoxic T cell responses. J Immunol 2008; 181: 2446-2454.

Van Houdt IS, Sluijter BJ, Moesbergen LM, Vos WM, de Gruijl TD, Molenkamp BG, van den Eertwegh AJ, Hooijberg E, van Leeuwen PA, Meijer CJ, and Oudejans JJ. Favorable outcome in clinically stage II melanoma patients is associated with the presence of activated tumor infiltrating T-lymphocytes and preserved MHC class I antigen expression. Int J Cancer 2008; 123: 609-615.

Santegoets SJ, Gibbs S, Kroeze K, van de Ven R, Scheper RJ, Borrebaeck CA, de Gruijl TD, Lindstedt M. Transcriptional profiling of human skin-resident Langerhans cells and CD1a+ dermal dendritic cells: differential activation states suggest distinct functions. J Leukoc Biol 2008; 84: 143-151.

Moreno M, Mol BM, Mensdorff-Pouilly SV, Verheijen RH, von Blomberg BM, van den Eertwegh AJ, Scheper RJ, Bontkes HJ. Toll-like receptor agonists and invariant natural killer T-cells enhance antibody-dependent cell-mediated cytotoxicity (ADCC). Cancer Lett  2008; 272: 70-76.

Santegoets SJ, Bontkes HJ, Stam AG, Bhoelan F, Ruizendaal JJ, van den Eertwegh AJ, Hooijberg E, Scheper RJ, de Gruijl TD. Inducing antitumor T cell immunity: comparative functional analysis of interstitial versus Langerhans dendritic cells in a human cell line model. J Immunol 2008; 180: 4540-4549.

Houtenbos I, Santegoets S, Westers TM, Waisfisz Q, Kipriyanov S, Denkers F, Scheper RJ, de Gruijl TD, Ossenkoppele GJ, van de Loosdrecht AA. The novel bispecific diabody alphaCD40/alphaCD28 strengthens leukaemic dendritic cell-induced T-cell reactivity. Br J Haematol 2008; 142: 273-283.

Molling JW, Moreno M, de Groot J, van der Vliet HJ, von Blomberg BM, van den Eertwegh AJ, Scheper RJ, Bontkes HJ.-Chronically stimulated mouse invariant NKT cell lines have a preserved capacity to enhance protection against experimental tumor metastases. Immunol Lett 2008; 118: 36-43.

De Gruijl TD, van den Eertwegh AJ, Pinedo HM, Scheper RJ. Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines. Cancer Immunol Immunother 2008; 57: 1569-1577.

Santegoets SJ, van den Eertwegh AJ, van de Loosdrecht AA, Scheper RJ, de Gruijl TD. Human dendritic cell line models for DC differentiation and clinical DC vaccination studies. J Leukoc Biol 2008; 84: 1364-1373.

Ouwehand K, Santegoets SJ, Bruynzeel DP, Scheper RJ, de Gruijl TD, Gibbs S. CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis. Eur J Immunol 2008; 38: 3050-3059.


PhD theses

11 January 2008, Barbara Molenkamp: Diagnosing Melanoma and Immunomodulation of the Melanoma Sentinel Lymph Node.
12 March 2008, Saskia Santegoets: Characterization of a human dendritic cell line; a prelude to allogeneic dendritic cell-based tumor vaccination.
23 May 2008, Johan Molling: Invariant natural killer T cells and immunotherapy of cancer.
26 September 2008, María Moreno Jauge: Innate and adaptive tumour immunity: role of invariant natural killer T cells.
26 March 2009, Hester van Cruijsen: Preclinical and clinical studies on the co-regulation of tumor-induced angiogenesis and dendritic cel suppression.
7 April 2009, Rieneke van de Ven: The contribution of ABC transporters to dendritic cell development and function.

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