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.
Skewing of the NK cell repertoire by MHC class I via quantitatively controlled enrichment and contraction of specific Ly49 subsets.
Brodin P, Lakshmikanth T, Kärre K, Höglund P
J. Immunol. 2012 Mar;188(5):2218-26
A modified FCCS procedure applied to Ly49A-MHC class I cis-interaction studies in cell membranes.
Strömqvist J, Johansson S, Xu L, Ohsugi Y, Andersson K, Muto H, et al
Biophys. J. 2011 Sep;101(5):1257-69
Current perspectives of natural killer cell education by MHC class I molecules.
Höglund P, Brodin P
Nat. Rev. Immunol. 2010 Oct;10(10):724-34
NK cell education: not an on-off switch but a tunable rheostat.
Brodin P, Kärre K, Höglund P
Trends Immunol. 2009 Apr;30(4):143-9
The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells.
Brodin P, Lakshmikanth T, Johansson S, Kärre K, Höglund P
Blood 2009 Mar;113(11):2434-41
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.
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
Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity.
Norell H, Carlsten M, Ohlum T, Malmberg KJ, Masucci G, Schedvins K, et al
Cancer Res. 2006 Jun;66(12):6387-94
A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth.
Holmgren L, Ambrosino E, Birot O, Tullus C, Veitonmäki N, Levchenko T, et al
Proc. Natl. Acad. Sci. U.S.A. 2006 Jun;103(24):9208-13
Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines.
Choudhury A, Charo J, Parapuram SK, Hunt RC, Hunt DM, Seliger B, et al
Int. J. Cancer 2004 Jan;108(1):71-7
Decreased expression of the signal-transducing zeta chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma.
Nakagomi H, Petersson M, Magnusson I, Juhlin C, Matsuda M, Mellstedt H, et al
Cancer Res. 1993 Dec;53(23):5610-2
Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy.
Kärre K, Ljunggren HG, Piontek G, Kiessling R
Evidence for a similar or common mechanism for natural killer cell activity and resistance to hemopoietic grafts.
Kiessling R, Hochman PS, Haller O, Shearer GM, Wigzell H, Cudkowicz G
Eur. J. Immunol. 1977 Sep;7(9):655-63
"Natural" killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell.
Kiessling R, Klein E, Pross H, Wigzell H
Eur. J. Immunol. 1975 Feb;5(2):117-21
19349689NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo.
Lakshmikanth T, Burke S, Ali TH, Kimpfler S, Ursini F, Ruggeri L, et al
J. Clin. Invest. 2009 May;119(5):1251-63
Natural killer cell recognition of missing self.
Nat. Immunol. 2008 May;9(5):477-80
Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants.
van Hall T, Wolpert EZ, van Veelen P, Laban S, van der Veer M, Roseboom M, et al
Nat. Med. 2006 Apr;12(4):417-24
Natural killer cell education in mice with single or multiple major histocompatibility complex class I molecules.
Johansson S, Johansson M, Rosmaraki E, Vahlne G, Mehr R, Salmon-Divon M, et al
J. Exp. Med. 2005 Apr;201(7):1145-55
A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy.
Oliveira AL, Thams S, Lidman O, Piehl F, Hökfelt T, Kärre K, et al
Proc. Natl. Acad. Sci. U.S.A. 2004 Dec;101(51):17843-8
LIR-1 expression on lymphocytes, and cytomegalovirus disease in lung-transplant recipients.
Berg L, Riise GC, Cosman D, Bergström T, Olofsson S, Kärre K, et al
Lancet 2003 Mar;361(9363):1099-101
A structural basis for LCMV immune evasion: subversion of H-2D(b) and H-2K(b) presentation of gp33 revealed by comparative crystal structure.Analyses.
Achour A, Michaëlsson J, Harris RA, Odeberg J, Grufman P, Sandberg JK, et al
Immunity 2002 Dec;17(6):757-68
Pivotal role of KARAP/DAP12 adaptor molecule in the natural killer cell-mediated resistance to murine cytomegalovirus infection.
Sjölin H, Tomasello E, Mousavi-Jazi M, Bartolazzi A, Kärre K, Vivier E, et al
J. Exp. Med. 2002 Apr;195(7):825-34
Recruitment and activation of natural killer (NK) cells in vivo determined by the target cell phenotype. An adaptive component of NK cell-mediated responses.
Glas R, Franksson L, Une C, Eloranta ML, Ohlén C, Orn A, et al
J. Exp. Med. 2000 Jan;191(1):129-38
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.
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
Bortezomib Treatment to Potentiate the Anti-tumor Immunity of Ex-vivo Expanded Adoptively Infused Autologous Natural Killer Cells.
Lundqvist A, Berg M, Smith A, Childs RW
J Cancer 2011 ;2():383-5
Unlicensed natural born killers.
Lundqvist A, Childs R
Blood 2011 Jun;117(26):6974-5
Fetal and adult multipotent mesenchymal stromal cells are killed by different pathways.
Götherström C, Lundqvist A, Duprez IR, Childs R, Berg L, le Blanc K
Cytotherapy 2011 Mar;13(3):269-78
Toxic effects of sorafenib when given early after allogeneic hematopoietic stem cell transplantation.
Yokoyama H, Lundqvist A, Su S, Childs R
Blood 2010 Oct;116(15):2858-9
Major histocompatibility complex-I expression on embryonic stem cell-derived vascular progenitor cells is critical for syngeneic transplant survival.
Ma M, Ding S, Lundqvist A, San H, Fang F, Konoplyannikov M, et al
Stem Cells 2010 Sep;28(9):1465-75
Cutting edge: bortezomib-treated tumors sensitized to NK cell apoptosis paradoxically acquire resistance to antigen-specific T cells.
Lundqvist A, Su S, Rao S, Childs R
J. Immunol. 2010 Feb;184(3):1139-42
Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells.
Berg M, Lundqvist A, McCoy P, Samsel L, Fan Y, Tawab A, et al
Cytotherapy 2009 ;11(3):341-55
Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells.
Lundqvist A, Yokoyama H, Smith A, Berg M, Childs R
Blood 2009 Jun;113(24):6120-7
Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib.
Yong AS, Keyvanfar K, Hensel N, Eniafe R, Savani BN, Berg M, et al
Blood 2009 Jan;113(4):875-82
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.
Long-term idiotype vaccination combined with interleukin-12 (IL-12), or IL-12 and granulocyte macrophage colony-stimulating factor, in early-stage multiple myeloma patients.
Hansson L, Abdalla AO, Moshfegh A, Choudhury A, Rabbani H, Nilsson B, et al
Clin. Cancer Res. 2007 Mar;13(5):1503-10
Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy.
Daneshmanesh AH, Mikaelsson E, Jeddi-Tehrani M, Bayat AA, Ghods R, Ostadkarampour M, et al
Int. J. Cancer 2008 Sep;123(5):1190-5
Silencing of ROR1 and FMOD with siRNA results in apoptosis of CLL cells.
Choudhury A, Derkow K, Daneshmanesh AH, Mikaelsson E, Kiaii S, Kokhaei P, et al
Br. J. Haematol. 2010 Nov;151(4):327-35
FcγR polymorphisms and clinical outcome in colorectal cancer patients receiving passive or active antibody treatment.
Wang B, Kokhaei P, Mellstedt H, Liljefors M
Int. J. Oncol. 2010 Dec;37(6):1599-606
A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease.
Bagnara D, Kaufman MS, Calissano C, Marsilio S, Patten PE, Simone R, et al
Blood 2011 May;117(20):5463-72
Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells.
Daneshmanesh AH, Hojjat-Farsangi M, Khan AS, Jeddi-Tehrani M, Akhondi MM, Bayat AA, et al
Leukemia 2012 Jun;26(6):1348-55
Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria.
Palma M, Hansson L, Choudhury A, Näsman-Glaser B, Eriksson I, Adamson L, et al
Cancer Immunol. Immunother. 2012 Jun;61(6):865-79
Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia.
Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, et al
J. Clin. Oncol. 2010 Apr;28(10):1749-55
Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study.
Rieger M, Osterborg A, Pettengell R, White D, Gill D, Walewski J, et al
Ann. Oncol. 2011 Mar;22(3):664-70
Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study.
Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Osterborg A, et al
Blood 2011 Nov;118(19):5126-9