In our translational research projects, we are primarily using patient samples instead of animal models and cell lines, as we hope that in this way the results can be more readily incorporated into clinical patient care. Our main research interests are tumor immunology, autoimmunity and personalized medicine for various leukemia types.
We have several academic and company-sponsored clinical trials ongoing (both phase I and phase II) studying the effects of tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib) in combination with other drugs. Our laboratory and clinical study center currently employs 3 study nurses (2 full-time, 1 part-time), a scientific secretary (part-time) and 4 clinical investigators (1 full-time, 3 part-time). More information about the ongoing studies in CML can be found in the hematology.fi web page.
Correspondingly to other cancers, also leukemias use various immune evasion mechanisms to escape the attacks of the immune system.
We have studied the anti-leukemia immune effects in chronic myeloid leukemia (CML) widely. We have previously discovered that especially the 2nd generation tyrosine kinase inhibitor (TKI) dasatinib has immunomodulatory properties (Kreutzman et al., Blood 2010; Kreutzman et al., Leukemia 2011; Mustjoki et al., Leukemia 2013; Kreutzman et al., Oncoimmunology 2014). Interestingly, the immune-related adverse events of dasatinib have been associated with better treatment responses in advanced CML. Despite the success of TKIs, it is believed that these drugs do not eradicate CML stem cells, and relapses occur often after treatment discontinuation. However, our recent studies suggest that a proportion of CML patients can discontinue the treatment and that NK cells are important in this successful treatment cessation (Ilander et al, Leukemia 2017).
Presently, we are also working with other haematological malignancies to characterize their immulonologic landscapes. Together with our collaborators, we analyze gene expression patterns in large-scale genomic data sets and characterize the immune environment in the bone marrow and blood samples with multicolor flow cytometry and multiplexed immunohistochemistry to understand the immune checkpoint molecule expression. The ultimate goal is to identify the patient subsets which may benefit from immune-based therapies such as immune checkpoint blockade.
In addition to hematological malignancies, our group has recently also begun to investigate the immune system in solid tumors (Hekim&Ilander et al, Cancer Immunol Res 2017). We are currently uncovering the in vivo immunomodulatory effects of immune checkpoint inhibitory treatment (e.g. anti-PD1) in melanoma patients concentrating especially on NK cells and charactering the immunological environment in renal cell carcinoma tumors.
Our aim is to discover novel biomarkers, by which clinicians could identify those patients who are most likely to benefit from the treatments.
Accumulation of acquired genetic alterations (somatic mutations) has been considered as a hallmark of cancer progression. However, somatic mutations not only occur in cancer patients, but also in hematopoietic stem cells of healthy individuals, and their frequency increases with age. Mutations occur more frequently during DNA replication, and thus cancers originate more commonly from rapidly proliferating cell types.
We hypothesize that during normal immune responses when T cells undergo rapid clonal expansion, they may also acquire genetic changes, which may alter their behaviour. In our model disease, LGL leukaemia, chronic antigen stimulation is appreciated as a potential initiator for the disease. Interestingly, in LGL leukaemia, somatic mutations in STAT3 gene predispose the patients to autoimmune co-manifestations, such as rheumatoid arthritis (RA) and immune-mediated cytopenias (Koskela HLM&Eldfors S. et al., NEJM 2012; Rajala et al., Hematologica 2014). Therefore, LGL leukemia may be considered as an extreme example of autoimmune response.
Chronic inflammation has been accepted as a potential risk factor for cancer. Our hypothesis is that the pathogenesis of some autoimmune diseases may share similar mechanisms with LGL leukemia. Recently, we have shown that patients with untreated RA harbour somatic mutations in their clonally expanded cytotoxic lymphocytes (Savola P&Kelkka T et al, Nat Commun 2017). Thus, by using state-or-art technologies we have identified a novel connection between autoimmune inflammation and cancer. Our present focus is to understand the role of these mutations in the development and regulation of the chronic inflammation.
In close collaboration with the Institute for Molecular Medicine Finland (FIMM), we apply the cancer cell Drug Sensitivity and Resistance Testing (DSRT) platform to functionally characterize the ex vivo sensitivity to hundreds of compounds in different leukemias both using fresh patient-derived samples as well as using established and experimental cell lines. Our recent discoveries in T-cell prolymphocytic leukemia (Andersson et al. Leukemia 2017), chronic myeloid leukemia (CML) (Pietarinen et al. Blood Cancer J 2015, Pietarinen et al. Oncotarget 2017) and STAT3-driven lymphocytic malignancies (Kuusanmäki et al. Oncotarget 2017) highlight the importance of the method in disease characterization as well as in the discovery of novel therapy options for different leukemias. Currently, we are studying the selective sensitivities of the potentially resistant leukemic stem cells (LSCs) in myeloid leukemias. We have begun to apply high-throughput flow cytometry-based drug profiling to understand the single-cell heterogeneity of drug responses in myeloid leukemias and to develop novel assays to discover immunomodulatory effects of oncology drugs that could synergize with cancer immunotherapies.
We have set up a biomarker discovery program, which is performed concurrent to the clinical drug studies, both academic and company sponsored. In the frame of Nordic CML study group we have especially analysed the leukemic stem cell burden at the diagnosis and during TKI therapy and its importance for the therapy response. These analyses have been performed during NordCML006 study, NordCML007 study Enest1st study. In addition to stem cell analysis, we are performing various immunological measurements aiming to understand immunological determinants of successful treatment response. Recently, our laboratory has headed an immunology biomarker substudy in European wide Euro-Ski study, which evaluated the probability of successful treatment discontinuation in CML.
We have also recently established significant research collaborations with pharmaceutical companies in which our unit serves as the central immunological biomarker discovery laboratory in international Phase I/II clinical studies.