4.04.01 – Experimental Cancer Immunology and Therapy
Dr S.H. van der Burg
( Dr. T. van Hall )
Aim and focus
The aim of our Experimental Cancer Immunology and Therapy program is to optimally implement immunotherapy as treatment modality for patients with solid tumors. The program is focused on the exploration of key factors in host-tumor interactions that determine successes and failures in immune control of cancer in order to drive the improvement of our immunotherapeutic strategies against solid tumors.
Position in international context
Collaborations exist with the universities of Cambridge, Southampton, Mainz, Tuebingen, Stockholm, Copenhagen, Erlangen, Nantes, Lausanne, New York and the Cancer Immunotherapy Consortium (a union between the Ludwig Institute for Cancer Research, the Cancer Research Institute and many other immunotherapy-focused universities and companies). Furthermore, we co-founded the CIMT Immunoguiding program group (24 laboratories in 8 European countries) within the Association of the Immunotherapy of Cancer, for the optimization, validation and harmonization of immunomonitoring techniques in clinical trials. Based on our contributions, we were involved in the organization of the 25th International Papilloma Virus Conference 2009 in Sweden and will organize the Progress in Vaccines against Cancer 2013 meeting in the Netherlands.
Content / highlights / achievements
Current efforts comprise strategies to exploit the in vivo anticancer effect of T-cells directed against tumors with defects in the antigen processing machinery as vaccination with TEIPP (T-cell epitopes associated with impaired peptide processing) peptides mediate protection against TAP-deficient tumors. Recently, we developed a TAP-impaired DC-based cellular vaccine able to induce protective T-cell responses against escaped tumors in mice and man. New studies elucidate non-classical MHC-restricted TEIPP and human TEIPP. For this research two grants (KWF, AICR) were obtained.
Comprehensive patient cohort studies are used to study the presence, type and impact of systemic and local immune response on cancer. In Human Papilloma Virus-induced neoplasia we identified immunecorrelates of protective immunity and unraveled several levels of immune failure in patients. Notably, we were the first to isolate HPV-specific suppressor T-cells and to establish the ratio between tumor-infiltrating CD8+ T-cells and suppressor T-cells as an independent prognostic factor for cervical cancer. Within this context we have started to study other tumor types. For this research 3 grants (KWF, NWO) were obtained.
Several phase I/II vaccine trials to study the capacity of HPV16- or p53-synthetic long peptide vaccines to restore tumor-immunity in different stages of HPV-induced cervical or colorectal cancer were completed. A high number of complete clinical responses, strongly correlated to the strength of vaccine-induced immunity, were observed in vaccinated patients with HPV-induced high grade neoplasia of the vulva. Notably, failure to induce a clinical response was associated with the vaccine-induced enhancement of HPV-specific suppressor T-cells. Furthermore, a phase II study on the adoptive transfer of tumor-specific ex-vivo expanded T-cells for the treatment of melanoma gained momentum. A growing number of melanoma-specific T-cell batches, obtained by stimulation of PBMC with autologous tumor cells, are infused into patients. Preliminary data indicate clinical successes in 5 of 10 patients who completed treatment. A similar protocol for the treatment of end-stage cervical cancer has now been initiated. For these studies 3 research grants (KWF, NWO) were obtained. Most recently a large program grant from the KWF was obtained to study the concept of combined chemo-immunotherapy.
We have published on the concept of Immunoguiding- the process where the results obtained by immunomonitoring bear a strong impact on decisions made with respect to developmental aspects of vaccines and the design of the immunotherapeutic treatments. In view of this we have co-founded the CIMT Imunoguiding program for the harmonization of the use of popular immune assays. For this we received a large grant from the Wallace Coulter Foundation.
ImmunoChemotherapy; Local immunity in relation to chemokines/receptors; HPV-related disease susceptibility; Response prediction.
Cohesion within LUMC
The immunotherapy of cancer is a long standing program within the LUMC. Clinical Oncology strongly collaborates with IHB with whom we have a joint weekly work discussion as well as with Gynecology, Surgery, and Pathology, all with whom we obtained several grants. More recent collaborations exist with Virology, Ophthalmology, Dermatology, Head & Neck Surgery, and KFT.
1 Marloes J.M. Gooden, Margit H. Lampen, Ekaterina S. Jordanova, Ninke Leffers, J. Baptist Trimbos, Sjoerd H. van der Burg, Hans W. Nijman, Thorbald van Hall (2011) HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8+ T lymphocytes, Proc. Natl. Acad. Sci USA, 108:10656-10661 (IF 9.77)
2 Moniek Heusinkveld, Peggy J. de Vos van Steenwijk, Renske Goedemans, Tamara H. Ramwadhdoebe, Arko Gorter, Marij J.P. Welters, Thorbald van Hall, Sjoerd H. van der Burg (2011) M2 macrophages induced by PgE2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells. J. Immunol., 187:1157-1165 (IF 5.75)
3 Els M.E.Verdegaal, Marten Visser, Tamara H. Ramwadhdoebe, Caroline E. van der Minne, Jeanne A.Q.M.J. van Steijn, Ellen H.W. Kapiteijn, John B.A.G. Haanen, Sjoerd H. van der Burg , Hans J.W.R. Nortier and Susanne Osanto (2011) Successful treatment of metastatic melanoma by adoptive transfer of blood-derived polyclonal tumor-specific CD4+ and CD8+ T cells in combination with Interferon-alpha. Cancer Immunol. Immunotherapy, 60:953-963 (IF 4.3)
4 Jan Pander, Moniek Heusinkveld, Tahar van der Straaten, Ekaterina Jordanova, Renée Baak-Pablo, Hans Gelderblom, Hans Morreau, Sjoerd H. van der Burg, Henk-Jan Guchelaar, Thorbald van Hall (2011) Activation of tumor-promoting type 2 macrophages by EGFR-targeting antibody cetuximab, Clin Cancer Res, 17:5668-5673 (IF 7.34)
5 Rezaul Karim, Craig Meyers, Claude Backendorf, Kristina Ludigs, Ekaterina Jordanova, Mariette van Poelgeest, Rienk Offringa, Gert-Jan van Ommen, Cornelis Melief, Sjoerd van der Burg, and Judith Boer. (2011) Human Papillomavirus Infection Deregulates the Response of a Cellular Network Comprising of Chemotactic and Proinflammatory Genes . PloS One, 6(3):e17848 (IF 4.41)
6 Peggy J. de Vos van Steenwijk, Moniek Heusinkveld, Tamara H. Ramwadhdoebe, Margriet J. Löwik, Jeanette M. van der Hulst, Renske Goedemans, Sytse J. Piersma, Gemma G. Kenter, Sjoerd H. van der Burg. (2010) An unexpectedly large polyclonal repertoire of HPV-specific T cells are poised for action in patients with cervical cancer. Cancer Res, 70(7):2707-17 (IF 7.51)
7 Claudia C. Oliveira, Peter A. van Veelen, Bianca Querido, Arnoud de Ru, Sandra Laban, Sjoerd H. van der Burg, Rienk Offringa, Thorbald van Hall (2010) The nonpolymorphic MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects. J. Exp. Med., 207:207-221 (IF 15.5)
8 Marij J.P. Welters, Gemma G. Kenter, Peggy J. Vos van Steenwijk, Margriet J.G. Lowik, Dorien M.A. Berends-van der Meer, Farah Essahsah, Linda F.M. Stynenbosch, Annelies P.G. Vloon, Tamara H. Ramwadhdoebe, Sytse J. Piersma, Jeanette M. van der Hulst, A. Rob P.M. Valentijn, Lorraine M. Fathers, Jan Wouter Drijfhout, Kees L.M.C. Franken, Jaap Oostendorp, Gert Jan Fleuren, Cornelis J.M. Melief and Sjoerd H. van der Burg (2010) Success or failure of vaccination for HPV16-positive vulvar lesions correlate with kinetics and phenotype of induced T-cell responses. Proc. Natl. Acad. Sci. USA,107: 11895-11899 (IF 9.77)
9 Margit H. Lampen , Marieke C. Verweij , Bianca J. Querido , Sjoerd H. van der Burg , Emmanuel J.H.J Wiertz and Thorbald van Hall (2010) CD8+ T cell responses against TAP-deficient cells are readily detected in the human population. J. Immunol. , 185:6508-6517 (IF 5.75)
10 Sytse J Piersma, Jeanette M. van der Hulst, Kitty M.C. Kwappenberg, Renske Goedemans, Caroline E van der Minne, Sjoerd H. van der Burg (2010) Influenza M1-specific human CD4+ FOXP3+ and FOXP3- T-regulatory cells can be detected long after viral clearance. Eur. J. Immunol, 40:3064-3074 (IF 4.94)
11 Frank M. Speetjens, Peter J.K. Kuppen, Marij J.P. Welters, Farah Essahsah, Annemarie M.E.G. Voet, M. Graziella Kallenberg, A. Rob P.M. Valentijn, Jaap Oostendorp, Lorraine M. Fathers, Hans W. Nijman, Jan Pander, Jan Wouter Drijfhout, Cornelis J.H. van de Velde, Cornelis J. Melief, Sjoerd H. van der Burg (2009) Induction of p53-specific immunity by a p53 synthetic long peptide vaccine in patients treated for metastatic colorectal cancer. Clin Cancer Res, 15:1086-1095 (IF 6.25)
12 Reza Karim, Ekaterina S. Jordanova, Sytse J. Piersma, Gemma G. Kenter, Lieping Chen, Judith M. Boer, Cornelis J.M. Melief, Sjoerd H. van der Burg (2009) Tumor-expressed B7-H1 and B7-DC in relation to PD1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin. Cancer Res., 15:6341-6347 (IF 6.75)
13 G.G. Kenter, M.J.P. Welters, A.R.P.M. Valentijn, M.J.G. Lowik, T.M.A. Berends-van der Meer, A.P.G. Vloon, F. Essahsah, L.M. Fathers, R. Offringa, J.W. Drijfhout, A.R. Wafelman, J. Oostendorp, G.J. Fleuren, S.H. van der Burg and C.J.M Melief (2009) Effective treatment of vulvar intraepithelial neoplasia by vaccination against the oncoproteins E6 and E7 of human papillomavirus type 16. New England Journal of Medicine, 361:1838-1847 (IF 50)
14 Cornelis J. M. Melief & Sjoerd H. van der Burg (2008) Immunotherapy of established (pre-) malignant disease by synthetic long peptide vaccines. Nature Rev. Cancer, 8:351-360 (IF 31.6)