Clinical Oncology 1

Experimental Cancer Immunology and Therapy

Principal investigator

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 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, with a special focus on melanoma (skin and uveal), HPV-induced tumors (anogenital and head & neck), colorectal cancer, lung cancer, GIST and ovarian cancer.

Position in international context

Collaborations exist with the universities of Cambridge, Southampton, Mainz, Tuebingen, Stockholm, Copenhagen, Erlangen, Nantes, and Lausanne  as well as with  the Cancer Research Institute . Furthermore, we co-founded  and co-chair the CIMT Immunoguiding program (CIP;  http://www.cimt.eu; 100 participants in Europe and USA) for the optimization, validation and harmonization of immunomonitoring techniques in clinical trials as well as collaboration with the Cancer Immunotherapy Consortium (New York, USA).

Content / highlights / achievements

A strategy to exploit  the in vivo anticancer effect of T-cells directed against tumors with defects in the antigen processing machinery was initiated 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. New studies elucidate non-classical MHC-restricted TEIPP and human TEIPP. For this three 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 and immune escape 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.  New studies on this topic have been financed by 4 grants from KWF and NWO.

Several phase I/II vaccine trials to study the capacity of HPV16- or p53-synthetic long peptide (SLP) vaccines to restore tumor-immunity in different stages of HPV-induced cervical or colorectal cancer were completed. Correlates of immune protection and of immune failure have been found in a recent trial of which a high number of patients showed a complete clinical response after vaccination with HPV16 SLP. Furthermore, a phase II study on the adoptive transfer of tumor-specific ex-vivo expanded T-cells has been published indicating durable 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. Based on the preclinical and clinical studies new trials were initiated in which several forms of immunotherapy are combined (in melanoma, colorectal cancer, ovarian cancer, lung cancer). For this grants from KWF and Reliable Cancer Therapies were obtained.

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.

Future themes

• Chemo-immunotherapy
• Macrophage-T cell interactions
• Response prediction

Cohesion within LUMC

The immunotherapy of cancer is a long standing program within the LUMC. Clinical Oncology strongly collaborates with IHB, Gynecology, Surgery, Pathology, Pulmonology,  Ophthalmology, Head & Neck Surgery, and Clinical Pharmacy & Toxicology. Furthermore, collaborations exist with the Dutch Cancer Institute (NKI, Amsterdam) and the University Medical Center Groningen (Groningen)

Key publications

1      Sjoerd H. van der Burg, Michael Kalos, Cecile Gouttefangeas, Sylvia Janetzki, Christian Ottensmeier, Marij J.P. Welters, Pedro Romero, Cedrik M. Britten, Axel Hoos (2011) Harmonization of immune biomarker assays: Enhanced quality and reproducibility in clinical studies, Science Translational Medicine, 3, 108ps44

2      Cláudia C. Oliveira, Bianca Querido, Marjolein Sluijter, Jens Derbinski, Sjoerd H. van der Burg and Thorbald van Hall (2011) Competition of MHC-I peptide repertoires is governed by peptide transporter TAP, Eur. J. Immunol., 41:3114-3124 (IF 4.942)

3      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)

4      Moniek Heusinkveld, Renske Goedemans, Robert Briet, Hans Gelderblom, Hans Nortier, Arko Gorter, Vincent Smit, Ton Langeveld, Jeroen Jansen, Sjoerd H. van der Burg (2011) Systemic and local human papillomavirus 15-specific T-cell immunity in patients with head and neck cancer. Int. J. Cancer, PMID 22020783 (IF 4.93)

5      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)

6      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)

7      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)

8      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)

9      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)

10     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)

11     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)

12     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)

13     Long V. Ly, Marjolein Sluijter, Mieke Versluis, Gre P.M. Luyten, Sjoerd H. van der Burg, Cornelis J.M. Melief, Martine J. Jager and Thorbald van Hall (2010) Peptide vaccination causes vigorous expansion and effector function of adoptively transferred CD8⁺ T cells in non-conditioned hosts. Cancer Res, 70:8339-8346 (IF 8.23)

14     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)

15     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)

16     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)

17     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)

18     P.J. de Vos van Steenwijk, S.J. Piersma,  M.J.P. Welters, J.M. van der Hulst, G.J. Fleuren, B.W.J. Hellebrekers, G.G. Kenter, S.H. van der Burg (2008) Surgery followed by persistence of high-grade squamous intraepithelial lesions is associated with the induction of a dysfunctional HPV16 specific T-cell response. Clin Cancer Res 2008, 14:7188-7195.(IF 6.48)

19     Sjoerd H. van der Burg, Sytse J. Piersma, Annemieke M. de Jong, Jeanette M. van der Hulst, Kitty M.C. Kwappenberg, Muriel van den Hende, Marij J.P. Welters, Gert Jan Fleuren, Cornelis J.M. Melief, Gemma G. Kenter, Rienk Offringa. (2007) Cervical cancer is associated with the presence of CD4+ regulatory T-cells specific for the high risk human papillomavirus E6 oncoprotein. Proc. Natl. Acad. Sci. USA, 104:12087-12092 (IF 9.6)

20     Sytse J. Piersma, Ekaterina S. Jordanova, Mariëtte I.E. van Poelgeest,  Kitty M.C. Kwappenberg, Jeanette M. van der Hulst, Jan W. Drijfhout, Cornelis J.M. Melief, Gemma G. Kenter, Gert Jan Fleuren, Rienk Offringa, and Sjoerd H. van der Burg. (2007) High numbers of intraepithelial CD8+ tumor-infiltrating lymphocytes are associated with the absence of lymph node metastases in voluminous low stage cervical cancer. Cancer Res., 67:354-361 (IF 7.67)

All publications can be found on  www.lumc.nl