Clinical Oncology 1

Experimental Cancer Immunology and Therapy

Principal investigator

Dr S.H. van der Burg (Dr T. van Hall, Dr Ir. E. Verdegaal)

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.

Position in international context

Collaborations exist with the universities of Cambridge, Southampton, Mainz, Tuebingen, Stockholm, Copenhagen, Erlangen, Nantes, Lausanne,  New York and the Cancer Vaccine Collaborative. Furthermore, we co-founded the CIMT Immunoguiding program group (24 laboratories in 8 European countries) for the optimization, validation and harmonization of immunomonitoring techniques in clinical trials.

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 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 3 grants (KWF, NWO) were obtained.

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 for the treatment of melanoma gained momentum. Preliminary data indicate durable clinical successes in 4 of 5 patients who completed treatment.  A similar protocol for the treatment of end-stage cervical cancer has now been initiated. For this three grants (KWF, NWO) 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
• Local immunity
• 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, and Pathology, all with whom we obtained several grants. More recent collaborations exist with Virology, Ophthalmology, Dermatology, Head & Neck Surgery, and KFT.

Key publications

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

M.J.P. Welters, G.G. Kenter, S.J. Piersma, A.P.G. Vloon, M.J.G. Löwik, T.M.A. Berends-van der Meer, J.W. Drijfhout, A.R.P.M. Valentijn, A.R. Wafelman, J. Oostendorp, G.J. Fleuren, R. Offringa, C.J.M. Melief and S.H. van der Burg (2008) Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by an HPV16 E6 and E7 long-peptide vaccine. Clin. Cancer Res. 14: 178-187
IF 6.25 

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

E.S. Jordanova, A. Gorter, O. Ayachi, F. Prins, L.G. Durrant, G.G. Kenter, S.H. van der Burg G.J. Fleuren. (2008) HLA class I, MICA and CD8⁺/regulatory T-cell ratio: which parameter determines survival of cervical cancer patients?. Clin. Cancer Res, 14:2028-2035
IF 6.25

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 6.25

Chambers B, Grufman P, Fredriksson V, Andersson K, Roseboom M, Laban S, Camps M, Wolpert EZ, Wiertz EJ, Offringa R, Ljunggren HG, van Hall T. (2007) Induction of protective CTL immunity against peptide transporter TAP-deficient tumors through dendritic cell vaccination. Cancer Res. 67(18):8450-5
IF 7.67

Flierman R, Westerhuis G, Hameetman M, van Duivenvoorde LM, van Hall T, van Laar JM, Fibbe WE, Toes RE. (2007) Targeting host B-cell immune responses by persistent donor NK-cell alloreactivity following nonmyeloablative allogeneic stem cell transplantation. Blood. 109):5524-5525
IF10.9

Martijn S. Bijker, Susan J.F. van den Eeden, Kees L. Franken, Cornelis J.M. Melief, Rienk Offringa, and Sjoerd H. van der Burg. (2007) CD8+ CTL priming by exact peptide-epitopes in IFA induces a vanishing CTL response, while long peptides induce sustained CTL reactivity. J. Immunol., 179: 5033-5040
IF 6.07

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

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