Scientific Report 2003-05


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Scientific Report 2003-05

  1. 1. Tumor Immunology | Scientific Report 2003-05 Per thor Straten, Ph.D. Group Head Tumor Immunology Group The Tumor Immunology Group is at present the only research group in Denmark ha- ving tumor immunology and immunotherapy as its main focus. Through the imple- mentation of “state of the art” techniques in the lab we are also one of very few groups in the country capable of monitoring immune therapeutic trials at present day's stan- dards. I believe our position leaves us with an obligation, not only to conduct experi- mental research, but also to inspire and motivate the clinical and scientific community in Denmark. In this respect, we are directly involved in many clinical projects but I also consider our role as "catalysts" quite important. It goes without saying that - conside- ring our translational research profile - we are obliged to bring our experimental data into the clinic whenever possible. malignancies are characterized by defects in apoptotic Scientific scope and achievements signaling cascades, e.g. an over expression of proteins Our main activities in the period are best described as of the Bcl-2 family (e.g. Bcl-2, Bcl-X(L), or Mcl-1), "Monitoring and characterizing anti-tumor T-cell and the inhibitor of apoptosis proteins (IAP; e.g. sur- responses in cancer patients". It is beyond the scope vivin or ML-IAP). Consequently, these groups of of this short document to describe our research ac- proteins could represent suitable targets for therapeu- tivities in detail, but in very broad and general terms tic vaccination against cancer, provided that peptides we have had a focus 1) Characterization of novel derived from these proteins are recognized by host T CD8 T cell epitopes derived from tumor antigens cells in the context of HLA molecules. playing an important role for the growth and/or sur- vival of cancer cells, and 2) Characterization of spon- To characterize such peptides we have used the re- taneous as well as treatment induced anti-tumor T- verse immunogenetics approach. Thus, selected IAP cell responses in cancer patients. and Bcl-2 family proteins are scanned for the pres- ence of potential binders to specific HLA molecules, Characterization of novel CD8 T cell epitopes and spontaneous T-cell reactivity against such pep- tides is subsequently analyzed in blood samples from Harnessing of the immune system for the battle cancer patients by the EliSpot assay. This highly sen- against cancer has been the focus of tremendous re- sitive assay is ideally suited for detection of low fre- search efforts over the past two decades. Multiple quency T-cell reactivity. means to achieve this goal, including adoptive trans- fer of anti-tumor-reactive T cells, systemic or local- This program was initiated in 1999, and using the ized administration of immune modulating cytokines, above outlines strategy we have been able to describe and the use of therapeutic vaccines have been scruti- spontaneous T cell reactivity against peptides derived nized. The latter aims at inducing cytotoxic T lym- from the proteins survivin, Livin, Bcl-2, Bcl-Xl, and phocytes (CTL) specific for tumor associated anti- Mcl-1. Reactivity has been detected in a vast variety gens (TAA) presented by cancer cells in the context of different cancers; e.g., melanoma, breast cancer, of HLA molecules. Until recently only limited atten- renal cell carcinoma, prostate cancer, and various tion has been focused on elucidating the most suit- hematological cancers (AML, CLL, etc.) Also, in an able targets for induction of clinically relevant anti- associated program focused at identification of im- cancer immune responses. In this regard, anti- munogenic peptides derived from proteins associated apoptotic molecules that enhance the survival of can- with drug resistance (PADR), we have identified reac- cer cells and facilitate their escape from cytotoxic tivity against Taxol resistance-associated gene-3 therapies represent prime candidates. Indeed, most (TRAG-3) (Breast cancer and melanoma). Due to the Danish Cancer Society | Institute of Cancer Biology 27
  2. 2. Tumor Immunology | Scientific Report 2003-05 high frequency of the HLA-A02.01 molecule among IL-2 administration. Caucasians, peptides binding to this molecule have had a center of attention in this line of research. We collaborate with Prof. Hans von der Maase from However, we have also characterized peptides bind- the University Hospital in Århus to conduct monitor- ing to HLA-A1, A3, A24, A11, and B35 as well. ing of melanoma patients receiving intra-tumor injec- tions of an irradiated tumor specific cytotoxic T-cell The main scope of this part of our work has been to clone (C-CURE-709). We are in the process of final- characterize ideally suited peptides for use in thera- izing this study, and compiling the functional and peutic vaccinations against cancer. Obviously, this molecular data. implies subsequent testing in clinical trials. To this end, several clinical trials based on survivin derived At the University Hospital Herlev (Inge Marie Svane) peptides administered with montanide or dendritic three vaccination protocols are ongoing (melanoma, cells are ongoing at clinics in Europe breast cancer, and renal cell carcinoma) in which can- (,, and cer patients are vaccinated with dendritic cells (DC) For some of these trials we loaded with peptide (from survivin, telomerase and have been involved with initiation of the trial, and are p53), or allogeneic tumor cell lysate. These trials in- also conducting the biological monitoring as given clude a total of 120 patients and are ongoing. Our below. data have shown that the treatment indeed induces increased numbers of peptide specific T cells. Characterization of spontaneous as well as treat- ment induced anti-tumor T-cell responses in can- We have been collaborating with Prof. Jürgen C. cer patients Becker (University Hospital in Würzburg, Germany) for a number of years and are still running joint pro- As pointed out above we take advantage of spontane- jects. Presently, we are in the process of analyzing ous T cell reactivity to characterize novel tumor anti- selected patient samples taken over the course of gens. Nevertheless, tumor progression in the face of treatment from a phase I/II vaccination trial a cellular anti-tumor immune response continues to (survivin peptides to HLA-A1, A2, and B35 adminis- puzzle scientists. Obviously, it is important to reveal tered with Montanide as adjuvant) including patients information with regards to this at best partially func- with melanoma, and cervical -, pancreatic -, and co- tional immune response, and gain valuable knowledge lon cancer (n=80). that may pave the way for induction of clinically rele- vant immunity against cancer cells. To this end, we In collaboration with clinicians from the State Uni- conduct studies of the frequency and phenotype of versity Hospital (headed by Dr. Lars Vindelov), we spontaneous anti-cancer T cell responses in cancer recently initiated a program focusing on analyzing T- patients. Moreover, in collaboration with clinicians (- cell reactivity after hematopoietic cell transplantation revise list!!!!!), we conduct several studies in which we (HCT). This treatment modality represents a well monitor immune reactivity before, during and after established treatment option for a number of hema- immune therapy, e.g., therapeutic vaccination against tological malignancies. Importantly, for some hema- cancer. To this end, from the University Hospital in tological malignancies the cure rates are very high, Herlev (Poul Geertsen) we have received numerous and T cells are known to play an important role for blood samples and biopsies from melanoma patients the efficacy of the treatment. Nevertheless, HCT is receiving electro/chemo/IL-2 therapy. A close moni- not uncomplicated. First, despite high cure rates toring of weekly blood samples has been conducted some hematological malignancies are far more prone and compared to responses detected in biopsies, in to respond than others. Thus, for still unresolved order to reveal insight into the presence of induced reasons HCT is not particularly efficient in the treat- anti-tumor T-cell responses over the course of treat- ment of e.g., Myeloma. Second, even concerning pa- ment. Treatment induced T-cell responses have been tients that respond and achieve complete remission, detected in several patients, and, importantly, objec- the adverse side effect of chronic graft versus host tive clinical responses have also been observed. Strik- disease constitutes a life long problem. Therefore, ingly, we found that CTL reactivity decreased during despite efficacy of this treatment modality there is 28 Danish Cancer Society | Institute of Cancer Biology
  3. 3. Tumor Immunology | Scientific Report 2003-05 certainly room for improvement; both with regards fact that the peptides previously characterized in the to efficacy but also concerning side effects. It is our The Group are now in clinical trial as given above. hope that we can contribute by increasing current Moreover, in collaboration with oncologists and he- knowledge about the cells and molecules involved in matologists we are planning to initiate a vaccination HCT, and we recently published the first paper in this trial in hematological malignancies using the commer- line of research. Importantly, as given in the "Future cially available adjuvant Montanide (Seppic, France) directions" section we are in the process of moving in combination with peptides derived from the Bcl-2 to the next stage of this program with the aim of family of proteins (Bcl-2, Mcl-1, and Bcl-xl; indica- characterizing minor histocompatibility antigens tion Myeloma). Future collaborations with clinicians (mHag). (Dr. Inge Marie Svane) include a study of immu- nological parameters following adoptive transfer of in We have initiated a study focused on characterizing vitro expanded tumor infiltrating lymphocytes (TIL) functional and molecular aspect of regulatory T cells after conditioning with chemotherapy (indication; (Treg) in cancer. It has recently been realized that cancer of the head and neck). Undoubtedly, more these cells play an important role in regulating T-cell trials will be initiated in the future in which vaccina- responses and thus are important players in auto- tion is combined with other immune modulators immunity as well as in down regulating T cell re- and/or chemotherapy for clearance of Treg. To the sponses against cancer. Ongoing studies combining latter, we have been collecting blood and bone mar- immune histochemistry, sorting and functional analy- row samples form AML patients, before and after ses of Treg will be part of our work over the next chemotherapy. These samples will be studied for years. Our recent data demonstrate that Treg are pre- various immune parameters (e.g., Treg frequency and sent in breast cancer lesions, and also that the fre- function) once sampling is finalized. quency of these cells depend on secretion of specific molecules by the cancer cells. In the monitoring of such studies we will continue to combine analyses of frequency, phenotype (FACS), Future directions and functionality (EliSpot/intra-cellular FACS) with molecular tracking of specific T cells (TCR clonotype Our studies of spontaneous and treatment induced mapping). Thus, we are able to reveal data on longi- T-cell responses bias more and more towards analyz- tudinal studies on specificity, frequency, functional ing treatment induced reactivity - in part due to the capacity, homing capacity and dynamics of T-cell responses before, during and after treatment. Our future monitoring strategy is planned to include cyto- kine bead array analyses (or similar methodologies) of serum samples and culture supernatants. Identification of Treg cells in ductal breast carcinoma. The picture shows membrane staining of CD3 and intracellular staining of Foxp3. Treg cells are identified as double positive for CD3 and Foxp3 expression. Danish Cancer Society | Institute of Cancer Biology 29
  4. 4. Tumor Immunology | Scientific Report 2003-05 Collaboration and administrative We are members of the Nordic Centre of Excellence for development of anti-cancer vaccine concepts co- activities ordinated by Guiseppe Masucci, Karolinska, Stock- The far majority of our work is based on studies of holm.( blood samples and tumor biopsies from cancer pa- tients. Thus, we collaborate with oncologists and cli- We participate in the CIMT monitoring panel aimed nicians from the main University Hospitals in Den- at the development of standardized protocols for mark, to be able to receive sufficient amounts of pa- monitoring of immunotherapy trials. (Initiative by tient material. To this end, we have received more Thomas Wölfel, Mainz:, than 1000 patient samples over the past five years. As given above, we collaborate with oncologists and he- We are founding member of Copenhagen Cluster of matologist at the University Hospitals in Copenha- Immunology, recently granted app. 1.300.000,- Euro gen, Århus and Ålborg. In addition we collaborate over the next 5 years. with scientists and clinicians abroad, in particular Prof. Jürgen C. Becker, Würzburg, Germany, and We are founding member of "Immunological re- Prof. Gustav Gaudernack in Oslo. As given below we search school" recently granted 1.300.000,- Euro over participate in several networks in tumor immunology the next 5 years. ( in Europe. Together with Per Guldberg, Danish cancer Society, We have participated in founding The European So- we organized the 2005 Danish Cancer Society Sym- ciety for Cancer Immunology and Immunotherapy posium on "Immunotherapy of Cancer"; an interna- (ESCII) (Initiative by Prof. Papamichail, Immunology tional meeting on the topic. Center, Athens). 30 Danish Cancer Society | Institute of Cancer Biology