Rolf Kiessling's Group
Using the immune system to treat cancer.
General Area of Research
A series of recent discoveries in molecular biology and immunology have resulted in new principles for the treatment of cancer, including gene transfer and immune therapy for activation of the host T cell system. Recent evidence indicate that vaccination with therapeutic vaccines based on peptides, plasmid DNA, heat-shock proteins or dendritic cells (DC) transduced with tumor antigens can lead to objective tumor responses in experimental animals and in a varying proportion of patients with metastatic disease. At the IGT lab we are defining new tumor antigens and vaccination methods to be used in immune and gene therapy. These are tested experimentally and in clinical trials in cancer patients at Radiumhemmet. A better understanding of how tumors can escape detection of the host immune system is also among our aims.
I. Development and Optimization of Cancer Vaccines
A. T cell and innate immunity based approaches
Cytotoxic CD8+ T cells (CTLs) are key effector cells of the immune system and critical components of protective immunity against infectious diseases and cancer. CTLs have the potential to eradicate cancer cells with high specificity when are present in enough amounts. Therefore, induction of effective and long-term CTL immunity is a major goal of cancer vaccines. DNA vaccination represents a safe and advantageous approach to delivers plasmid-encoded tumor-associated antigens that has shown to be effective in inducing protective CTL immunity in animal models, but has thus far failed to translate into clinical success. Therefore, efficient delivery systems and powerful adjuvants that activate innate immunity are needed for cancer DNA vaccines to overcome tumor-specific tolerance. We are using the in vivo electroporation (EP), which has emerged as a simple, efficient and tolerable method for delivering DNA vaccines that greatly enhances plasmid uptake, antigen expression and elicited T cell immunity. Moreover, DNA EP activates innate immunity resulting in massive infiltration of immune cells and the production of proinflammatory cytokines and chemokines that may contribute to the induction of the immune responses. We are also exploring different strategies to potentiate the intrinsic adjuvant properties of bacterial plasmids used for DNA vaccines by boosting key signaling pathways and downstream transcription factors that activate innate immunity.
B. Antibody and NK cell based approaches
Different strategies of tumor vaccination based on the oncogene HER2/neu (HER2), which is expressed in a proportion of human breast carcinomas and other types of cancer, are being tested. These include plasmid DNA vaccines and adenoviral vaccine approaches. The contribution to tumor protection by NK cells active in Antibody mediated Cellular Cytotoxicity (ADCC) is a major focus of this research. In order to test experimentally HER2 based therapies, we are establishing novel orthotopic and transgenic mouse models of HER2 expressing breast cancer.
II. Clinical Vaccination Studies
Combined dendritic cell-vaccination and adoptive T cell transfer in patients with advanced malignant melanoma
There is an urgent need to find new treatments for patients suffering from advanced malignant melanoma, which today face a poor prognosis and limited therapeutic options.
We are performing a clinical trial that combines vaccination with dendritic cells (DC) and adoptive T cell transfer. DC loaded with the material from the patients own tumor is injected to stimulate an anti-tumor immune response. To further amplify this response in absence of suppressive tumor-derived factors we will stimulate and expand patient lymphocytes in vitro, so that large numbers of trained and activated cells can be re-infused to fight the cancer.
III. Immune Escape
A. Myeloid derived suppressor cells in cancer patients
Tumors employ a wide array of mechanisms to hide from the immune system. One such tumor immune escape mechanism is the recruitment of so called myeloid derived suppressor cells (MDSC). These cells are a mixed population of mainly immature myeloid cells that can interfere with lymphocytes proliferation and function, and thereby hamper tumor-specific immunity. MDSC have been much studied in mice, but are difficult to define in cancer patients due to their heterogeneity. We examine the phenotype and suppressive mechanisms of MDSC isolated from cancer patients, with a focus on individuals with advanced malignant melanoma. A better understanding of MDSC biology is needed to develop therapeutic approaches targeting this immune-suppressive cell population.
B. Immune-networks in breast cancer
Immunological analyses in humans are often limited to tests than can be performed with blood cells. However, many recent reports suggest that the immunological situation within the tumor is not accurately reflected by studying cell populations in the blood. We therefore aim to gain an improved understanding of how local or systemic immunity is influenced by the presence of a tumor. To this end we will characterize the presence, frequency, phenotype and functionality of numerous immune cell populations in the tumor, tumor-draining and non-draining lymph nodes and the blood of breast cancer patients.
C. Oxidative stress
Cancer patients have a suppressed immune response induced by the tumor, and research in our group aims at understanding the underlying molecular mechanisms. Our recent findings indicate interesting links between immunosuppression and anti-oxidative properties in regulatory immune cells, which we would like to investigate further.
Oxidative stress is an extensively studied phenomenon in tumor immunology. The detrimental effects of the so-called reactive oxygen species on the cells of the immune system are profound and associated to tumor escape from the immunologic control.
D. HER receptors and their role in tumor immunity
The EGF-receptor family constitutes molecules for anti-cancer drugs and immunotherapy. Drug resistance and a poorly functioning immune system in cancer patients are major causes for a poor outcome of these therapies. Our goal is to examine the family of HER receptors in melanoma and breast cancer, and study their contribution in tumor induced immune-escape mechanisms and chemo-resistance.
Immune Modulatory Therapies for Autoimmunity and Cancer (IMTAC)
R.K. is the director of a Thematic Center for "Immune Modulatory Therapies for Autoimmunity and Cancer (IMTAC)" awarded and funded by Karolinska Institutet.
Co-director Anders Österborg, Cancercenter Karolinska, Karolinska Institutet.
Members and group leaders in IMTAC are;
- Håkan Mellstedt, Cancercenter Karolinska, Karolinska Institutet.
- Ola Winqvist, Department of Medicine, Karolinska Institutet
- Klas Kärre, Microbiology and Tumor Biology Center, Karolinska Institutet
- Kalle Malmberg, Department of Medicine, Karolinska Institutet
- Annika Scheynius, Department of Medicine, Karolinska Institutet.
- Petter Höglund, Microbiology and Tumor Biology Center, Karolinska Institutet
Additional examples of collaborators at Karolinska Institutet
- Giuseppe Masucci, Cancer Centrum Karolinska, Karolinska Institutet
- Johan Hansson, Cancer Centrum Karolinska, Karolinska Institutet
- Katarina Le Blanc, Clinical Immunology, Karolinska Institutet
- Kalle Malmberg, Centre of Infectious Medicine, Karolinska Institutet
- Lars Holmgren, Cancer Centrum Karolinska, Karolinska Institutet
- Olle Larsson, Cancer Centrum Karolinska, Karolinska Institutet
- Stefan Seregard, St. Erik Eye Hospital, Karolinska Institutet
- Tina Dalianis, Cancer Centrum Karolinska, Karolinska Institutet
- Andrew Quest, University of Chile, Santiago, Chile
- Barbara Seliger, Martin-Luther University, Halle-Wittenberg, Germany
- Brahm H. Segal, Roswell Park Cancer Institute, University of Buffalo, USA
- Federica Cavallo, University of Turin, Italy
- Flavio Salazar-Onfray, University of Chile, Santiago, Chile
- Göran Stenman, University of Gothenburg, Sweden
- Guido Forni, University of Turin, Italy
- Jehad Charo, Max-Delbruck Center for Molecular Medicine Berlin, Germany
- Koji Kono, Yamanashi Medical University, Yamanashi, Japan
- Kousako Mimura, Yamanashi Medical University, Yamanashi, Japan
- Michael I. Nishimura, Medical University of South Carolina, USA
- Takashi Ando, Yamanashi Medical University, Yamanashi, Japan
- Wei-Zen Wei, Karmanos Cancer Center, Wayne State University, USA
- Riki Okita, Kawasaki Medical School, Kurashiki, Japan
Collaborators in Industry
- BioInvent International AB, Sweden
- Cyto-Pulse Science, Inc, Stockholm, Sweden
- Mabtech AB, Nacka, Sweden
- Philochem AG, Switzerland
- Protagen AG, Dortmund, Germany
- ThromboGenics NV, Belgium
- ALF-Project grant from the Stockholm City Council
- Cancer Society of Stockholm
- DC-Thera Network of Excellence (6th European Union framework program)
- EUCAAD collaborative project (7th European Union framework program)
- German Research Association
- IMTAC thematic center grant from the Karolinska Institutet
- Swedish Cancer Society
- Swedish Medical Research Council
Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells.
Okita R, Wolf D, Yasuda K, Maeda A, Yukawa T, Saisho S, et al
PLoS ONE 2015 ;10(10):e0139809
Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms.
Mao Y, Poschke I, Wennerberg E, Pico de Coaña Y, Egyhazi Brage S, Schultz I, et al
Cancer Res. 2013 Jul;73(13):3877-87
HER2/HER3 signaling regulates NK cell-mediated cytotoxicity via MHC class I chain-related molecule A and B expression in human breast cancer cell lines.
Okita R, Mougiakakos D, Ando T, Mao Y, Sarhan D, Wennerberg E, et al
J. Immunol. 2012 Mar;188(5):2136-45
High expression of GCLC is associated with malignant melanoma of low oxidative phenotype and predicts a better prognosis.
Mougiakakos D, Okita R, Ando T, Dürr C, Gadiot J, Ichikawa J, et al
J. Mol. Med. 2012 Aug;90(8):935-44
Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress.
Mougiakakos D, Johansson CC, Jitschin R, Böttcher M, Kiessling R
Blood 2011 Jan;117(3):857-61
Antibody-dependent natural killer cell-mediated cytotoxicity engendered by a kinase-inactive human HER2 adenovirus-based vaccination mediates resistance to breast tumors.
Triulzi C, Vertuani S, Curcio C, Antognoli A, Seibt J, Akusjärvi G, et al
Cancer Res. 2010 Oct;70(19):7431-41
Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign.
Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R
Cancer Res. 2010 Jun;70(11):4335-45
Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death.
Mougiakakos D, Johansson CC, Kiessling R
Blood 2009 Apr;113(15):3542-5
Transduction with the antioxidant enzyme catalase protects human T cells against oxidative stress.
Ando T, Mimura K, Johansson CC, Hanson MG, Mougiakakos D, Larsson C, et al
J. Immunol. 2008 Dec;181(12):8382-90
Tumor-induced changes in the phenotype of blood-derived and tumor-associated T cells of early stage breast cancer patients.
Poschke I, De Boniface J, Mao Y, Kiessling R
Int. J. Cancer 2012 Oct;131(7):1611-20
Tumor-dependent down-regulation of the ζ-chain in T-cells is detectable in early breast cancer and correlates with immune cell function.
Boniface JD, Poschke I, Mao Y, Kiessling R
Int. J. Cancer 2012 Jul;131(1):129-39