The Center has been conceived with the vision of creating a "virtual institute" for developing innovative immune-based treatment approaches.
Autoimmune and malignant diseases are the two primary foci for the development of therapeutic applications within this thematic center.
Immunological modalities that we examine for therapeutic applications include: antibodies, vaccines and adoptive transfer of immune cells (T cells, NK cells) modified ex vivo.
Basic research is primarily directed at elucidating new mechanisms and pathways and identifying molecules and structures that may be utilized for therapy.
These basic discoveries will be translated to knowledge-based therapeutic approaches. A select number of these therapeutic entities will then be tested in investigator-initiated clinical trials for safety and efficacy.
One research focus in the group is to understand the molecular mechanisms responsible for immunological tolerance.
In particular, we study natural killer cells in the mouse using a combination of cellular immunology, biophysical imaging and mathematical modeling. The intracellular signals that control functional responses and development under various conditions are studied. A second more recent interest is to ask how various components of the immune system impact on the outcome of erythrocyte and platelet transfusion in humans. One focus is to understand how antibodies to HLA molecules makes patients refractory to platelet transfusions and another is to study natural killer cells in transfusion reactions. The aim is to develop means to avoid such reactions and to improve transfusion practices.
The group of Rolf Kiessling is active both in basic and clinical tumor immunology research.
His clinical research is facilitated by his part time position (25%) as a consultant physician in the melanoma unit at the Oncology clinic. The group has participated as principal investigator or co-investigator in several investigator initiated clinical trials, of which many originates from basic research projects in his lab. The investigator initiated trials includes tumor vaccine trials based on pDNA in prostate- or breast cancer patients, Dendritic cell based trial in patients with gastric cancer and malignant melanoma, anti-oxidant treatment of patients with colorectal cancer, peptide based tumor vaccine in patients with ovarian cancer and currently a trial involving treatment of advanced melanoma patients with a combination of TIL cells and a DC tumor vaccine. Several of his current trials are carried out in close collaboration with clinicians at the Oncology clinic at Karolinska hospital and with Jonas Mattsson and Markus Maeurer at the CAST unit, Huddinge.
Infusion of tumor-specific T cells or natural killer (NK) cells has emerged as a promising anti-cancer treatment. Yet, the number of patients cured with this regimen is low.
We study two aspects that may enhance the success rate of clinical adoptive cell therapy. We investigate how to augment death ligand-mediated killing of tumor cells. By uncovering molecular mechanisms of death ligand regulation in human NK and T cells provide an opportunity to design improved adoptive cell therapies that could lead to better clinical response.
We also study how to improve migration of human NK and T cells toward solid tumors. Lymphocyte migration is an often overlooked aspect in tumor immunology. Pre-clinical results from in vivo tumor models will provide a platform to develop this innovative approach in patients with cancer.
These projects represent a long-term commitment to incorporate basic and translational findings on how innate and adaptive immune responses can be harnessed to develop a new generation of therapies of adoptive cell infusion in patients with cancer.
Through cellular therapy and immunomodulation, completely new strategies are currently being developed for the treatment of hematological malignancies.
A significant interest has recently been raised regarding the involvement of natural killer (NK) cells in the clinical effects of stem cell transplantation (SCT) and experimental treatments for acute myeloid leukemia (AML). NK cells are known for their ability to kill tumor cells without the requirement for prior sensitization. Recent knowledge of the molecular specificity of NK cells can now be implemented in novel treatment strategies for human cancer (Ljunggren and Malmberg, Nature Rev. Immunology, May, 2007).
The translational NK cell immunotherapy program at the Center for Hematology and Center for Infectious Medicine is built around five specific aims:
- Identify principles for receptor acquisition and education of human NK cells
- Gain insights into the reconstitution of NK cell function and receptor repertoires following allogeneic stem cell transplantation
- Decode receptor-ligand interactions responsible for NK cell targeting of fresh hematopoietic tumors
- Study the receptor repertoire and functional integrity of NK cells in disease settings
- Develop clinical protocols for adoptive immunotherapy with allogeneic NK cells
A better understanding of the NK cell maturation and receptor acquisition following SCT may lead to refined algorithms for donor selection. Uncovering a role for NK cells in the recognition of hematopoietic tumors provides a molecular basis for the effectiveness of current treatment strategies and set the stage for future NK cell-based immunotherapy. In parallel efforts, we aim to develop clinical protocols for adoptive immunotherapy with allogeneic NK cells.
Håkan Mellstedt, Anders Österborg, Maria Liljefors
The main focus of the group is to explore principles underlying immunity to cancer and approaches to harness the immune system for anticancer therapy.
The disease indications being studied include malignancies of hematological origin such as chronic lymphocytic leukemia (CLL), multiple myeloma (MM) as well as solid tumors such as pancreatic and colorectal tumors (CRC).
The group consists of basic scientists and translational part-time clinicians, clinical fellows and doctoral students with the common interest of transforming discoveries in fundamental cancer immunology to advances in immunotherapy of cancers.
Basic research conducted by the group aims at exploring new targets for immunotherapy, among which CD52 (in CLL and T-cell lymphomas) and 17-1A (in CRC) represents earlier lines of development. Next, in a true translational setting, early clinical trials are being conducted. One of them is a MUC 1-based vaccine in multiple myeloma. This phase I/II Stimuvax trial is being conducted in collaboration with Merck Serono in Darmstadt, Germany. Another investigator-sponsored study (ISS) examines vaccination with autologous dendritic cells that have endocytosed apoptotic leukemic cells in combination with various adjuvants in a phase I approach to immunotherapy of CLL. Several ISS are conducted exploring new approaches to targeted CD52 therapy in CLL. The group also develops and initiates large-scale multicenter immunotherapy clinical trials in collaboration with various pharmaceutical companies studying the therapeutic efficacy of, in particular, monoclonal antibodies in CLL; ofatumumab is a recent example. With regard to solid tumors, a recently concluded clinical study examined the effect of a telomerase-derived peptide vaccine together with the chemotherapy agent gemcitabine potentially as combinatorial approach in advance pancreatic cancer patients. Other ongoing ISS trials explore CEA-DNA vaccination approaches against the carcinoembryonic antigen in CRC patients and immunomodulating drugs, such as lenalidomide, in pancreatic cancer. Each of these clinical trials encompasses a diverse array of laboratory-based immunomonitoring assays to examine the patients immune response to the immunizing antigen and potential correlation with clinical outcome.
Ongoing basic and translational studies in the laboratory are directed at elucidating the link between the immune system and etiology of various malignancies as well as defining new target structures and pathways for immunotherapy of cancer. Ror-1 is a tyrosine kinase receptor that appears to be ubiquitously expressed on CLL cells but not on nonmalignant counterparts. Ror-1 is being developed as a target for antibody-based and small molecule inhibitor-based therapy. Another element of investigation is the putative role of T cells in supporting the growth and survival of CLL cells. The KLF-6 molecule is the focus of investigation in this regard for a possible role in the growth and aberrant function of T cells in CLL.