My  research group, Brain Tumour Immunology and Therapy Group is an integral node of the larger, Kristian Gerhard Jebsen Brain Rumour Research Centre, focussed on biomedical research to study malignant brain tumours.  My particular focus is to elucidate the role of natural killer cells in brain tumour and human cytomegalovirus immunesurveillance. During the last decade we have elucidated the function and clinical impact of the glial progenitor proteoglycan NG2/CSPG4  in  glioblastoma (GBM) progression and response to therapy. We are developing novel therapeutic strategies combining NK cells with mAbs against NG2/CSPG4 and other salient targets that mediate treatment resistance and poor survival in GBM patients. We use multidisciplinary approaches such as annotated population and brain tumour biobanks, as well as physiologically relevant biopsy-based animal models. Diverse analytic tools include but not limited to proteomics, functional magnetic resonance imaging (employing physical properties of tissues to describe biological processes), flow cytometry, and standard molecular and cell biology methods. The long term vision of the group is to develop an immunotherapy trial for GBM patients based on NK cells applied in combination therapies, additional to the standard treatment.

Patients that are diagnosed with the most malignant brain tumour, glioblastoma (GBM), and that are strong enough to tolerate the aggressive standard treatment of surgery, concomitant radiotherapy and chemotherapy will survive on average only 14.6 months. Moreover, less than 10% are alive after 5 years. New effective treatments are urgently needed for this deadly disease. Our research is focussed on developing a novel immunotherapy involving infusion into the tumour of natural killer (NK) cell subsets that  validated for cytotoxic potency . NK cells are white blood cells that are specialised to distinguish tumour or virus infected cells from healthy cells. Interactions (or lack thereof) of NK cells´ killer receptors with stress-induced ligands expressed by the unhealthy cells, transmit death signals that kill the target cells. Greater than 40% of GBM patients express cytomegalovirus (CMV) gene products in their tumour, yet NK cells in the microenvironment that are evolved to eliminate virus infected tumours, remain non-responsive. We investigate whether there is a particular receptor-ligand combination associated with CMV infected GBMs that may render NK cells poorly responsive and allow the tumour to propagate. We are also studying T cell responses generated in parallel to CMV infection,to understand how they contribute to immune contexture of GBMs. The goal is to characterise the tumour infiltrating NK and T cells within GBM biopsies to identify mechanisms of GBM tolerance and immunological escape. We will also investigate NK cell biomarkers that enable selection of  patients/donors with the most effective cells against GBM in preclinical models. The focus will be to functionally validate the receptor-ligand interactions that may determine potent killing of GBM. Once the potent NK and GBM cell receptor-ligand interactions are determined, NK cells will be combined with humanised antibodies against tumour antigens such as NG2/CSPG4,EGFR, or combined with proteasome inhibitors to potentiate tumour killing. Good Manufacturing Practice (GMP) expansion methods will be employed to obtain high yield of highly potent cells in preparation for clinical translation.

Anatomy

Vitenskapelig artikkel

• Blakstad, Hanne Kristin; Brekke, Jorunn; Rahman, Mohummad Aminur et al. (2023). Survival in a consecutive series of 467 glioblastoma patients: Association with prognostic factors and treatment at recurrence at two independent institutions. (ekstern lenke)
• Hannisdal, Marianne Hjellvik; Goplen, Dorota; Alam, Saruar et al. (2023). Feasibility of deep learning-based tumor segmentation for target delineation and response assessment in grade-4 glioma using multi-parametric MRI. (ekstern lenke)
• Rahman, Mohummad Aminur; Engelsen, Agnete ; Sarowar, Shahin et al. (2022). Bortezomib abrogates temozolomide-induced autophagic flux through an ATG5 dependent pathway. (ekstern lenke)
• Schneider, Matthias; Vollmer, Lea; Potthoff, Anna-Laura et al. (2021). Meclofenamate causes loss of cellular tethering and decoupling of functional networks in glioblastoma. (ekstern lenke)
• Rahman, Mohummad Aminur; Brekke, Jorunn; Arnesen, Victoria Smith et al. (2020). Sequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B study. (ekstern lenke)
• Rahman, Mohummad Aminur; Gras Navarro, Andrea; Brekke, Jorunn et al. (2019). Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival. (ekstern lenke)
• Gras Navarro, Andrea; Espedal, Heidi; Vareecal Joseph, Justin et al. (2019). Pretreatment of glioblastoma with bortezomib potentiates natural killer cell cytotoxicity through TRAIL/DR5 mediated apoptosis and prolongs animal survival. (ekstern lenke)
• Haspels, Heleen Neeltje; Rahman, Mohummad Aminur; Vareecal Joseph, Justin et al. (2018). Glioblastoma Stem-Like Cells Are More Susceptible Than Differentiated Cells to Natural Killer Cell Lysis Mediated Through Killer Immunoglobulin-Like Receptors-Human Leukocyte Antigen Ligand Mismatch and Activation Receptor-Ligand Interactions. (ekstern lenke)
• Bahador, Marzieh; Gras Navarro, Andrea; Rahman, Mohummad Aminur et al. (2017). Increased infiltration and tolerised antigen-specific CD8+ TEM cells in tumor but not peripheral blood have no impact on survival of HCMV+ glioblastoma patients. (ekstern lenke)
• Dominguez Valentin, Mev; Gras Navarro, Andrea; Rahman, Mohummad Aminur et al. (2016). Identification of a natural killer cell receptor allele that prolongs survival of cytomegalovirus-positive glioblastoma patients. (ekstern lenke)
• Kmiecik, Justyna; Gras Navarro, Andrea; Poli, Aurélie et al. (2014). Combining NK cells and mAb9.2.27 to combat NG2-dependent and anti-inflammatory signals in glioblastoma. (ekstern lenke)
• Torsvik, Anja; Stieber, Daniel; Enger, Per Øyvind et al. (2014). U-251 revisited: genetic drift and phenotypic consequences of long-term cultures of glioblastoma cells . (ekstern lenke)
• Brekke, Cecilie; Wang, Jian; Thuen, Marte et al. (2014). Dynamic contrast enhanced MRI detects early response to adoptive NK cellular immunotherapy targeting the NG2 proteoglycan in a rat model of glioblastoma. (ekstern lenke)
• Gras Navarro, Andrea; Kmiecik, Justyna; Leiss, Lina Wik et al. (2014). NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. (ekstern lenke)
• Rygh, Cecilie Brekke; Wang, Jian; Thuen, Marte et al. (2014). Dynamic Contrast Enhanced MRI Detects Early Response to Adoptive NK Cellular Immunotherapy Targeting the NG2 Proteoglycan in a Rat Model of Glioblastoma. (ekstern lenke)
• Skeie, Bente Sandvei; Wang, Jian; Dodoo, Ernest et al. (2013). Gamma knife surgery as monotherapy with clinically relevant doses prolongs survival in a Human GBM Xenograft Model. (ekstern lenke)
• Kmiecik, Justyna; Poli, Aurélie; Brons, Nicolas H.C. et al. (2013). Elevated CD3(+) and CD8(+) tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. (ekstern lenke)
• Poli, Aurélie; Wang, Jian; Domingues, Olivia et al. (2013). Targeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival. (ekstern lenke)
• Kocinski, Marek; Klepaczko, Artur; Materka, Andrzej et al. (2012). 3D image texture analysis of simulated and real-world vascular trees. (ekstern lenke)
• Moen, Ingrid; Jevne, Alison Charlotte; Wang, Jian et al. (2012). Gene expression in tumor cells and stroma in dsRed 4T1 tumors in eGFP-expressing mice with and without enhanced oxygenation. (ekstern lenke)
• Wang, Jian; Svendsen, Agnete; Kmiecik, Justyna et al. (2011). Targeting the NG2/CSPG4 Proteoglycan Retards Tumour Growth and Angiogenesis in Preclinical Models of GBM and Melanoma. (ekstern lenke)
• Svendsen, Agnete; Verhoeff, Joost JC; Immervoll, Heike et al. (2011). Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma. (ekstern lenke)
• Poli, Aurélie MF; Brons, Nicolaas HC; Ammerlaan, Wim et al. (2010). Novel method for isolating untouched rat natural killer cells with higher purity compared with positive selection and fluorescence-activated cell sorting. (ekstern lenke)
• Moen, Ingrid; Øyan, Anne Margrete; Kalland, Karl-Henning et al. (2009). Hyperoxic treatment induces mesenchymal to epithelial transition in a rat adenocarcinoma model. (ekstern lenke)
• Verhoeff, Joost JC; Stalpers, Lukas JA; Van Noorden, Cornelius JF et al. (2009). Angiogenesis inhibitor DC101 delays growth of intracerebral glioblastoma but induces morbidity when combined with irradiation. (ekstern lenke)
• Wang, Jian; Miletic, Hrvoje; Sakariassen, Per Øystein et al. (2009). A reproducible brain tumour model established from human glioblastoma biopsies. (ekstern lenke)
• Joo, Nam E.; Watanabe, Takehiro; Chen, Cindy et al. (2008). NG2, a novel proapoptotic receptor, opposes integrin alpha 4 to mediate anoikis through PKC alpha-dependent suppression of FAK phosphorylation. (ekstern lenke)
• Chekenya, Martha; Krakstad, Camilla; Svendsen, Agnete et al. (2008). The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling. (ekstern lenke)
• Sakariassen, Per Øystein; Prestegarden, Lars; Wang, Jian et al. (2006). Angiogenesis-independent tumor growth mediated by stem-like cancer cells. (ekstern lenke)
• Brekke, C; Brekke, Cecilie; Lundervold, Arvid et al. (2006). NG2 expression regulates vascular morphology and function in human brain tumours. (ekstern lenke)
• Brekke, Cecilie; Lundervold, Arvid; Enger, Per Øyvind et al. (2005). NG2 expression regulates vascular morphology and function in human brain tumours. (ekstern lenke)
• Chekenya, M; Chekenya, M; Hjelstuen, Mari H. et al. (2002). NG2 proteoglycan promotes angiogenesis-dependent tumor growth in the central nervous system by sequestering angiostatin. (ekstern lenke)

Brev til redaktøren

• Hannisdal, Marianne Hjellvik; Goplen, Dorota Katarzyna Pazdyk; Lundervold, Arvid et al. (2023). Exploiting Deep Learning to Enhance Tumour-conformed Delineation and Reduced Isotropic Margin in Radiotherapy: Updated ESTRO-EANO Guidelines. (ekstern lenke)

Mastergradsoppgave

• Suntharalingam, Susina; Enger, Martha; Rahman, Mohummad Aminur et al. (2022). Two distinct biomarkers and their role in glioblastoma biological behavior. (ekstern lenke)
• Sarowar, Shahin; Enger, Martha Chekenya; Gras Navarro, Andrea et al. (2016). Treatment with Bortezomib Sensitizes Glioblastoma Cells to Temozolomide. (ekstern lenke)
• Gras Navarro, Andrea; Enger, Martha Chekenya; Kmiecik, Justyna (2013). Activated NK cells are potent effectors against glioblastoma cells due to activating KIR2DS2 and KIR2DS4 - HLA ligand interactions – In vitro study. (ekstern lenke)

Vitenskapelig oversiktsartikkel/review

• Arnesen, Victoria Smith; Gras Navarro, Andrea; Enger, Martha (2021). Challenges and Prospects for Designer T and NK Cells in Glioblastoma Immunotherapy. (ekstern lenke)
• Gras Navarro, Andrea; Björklund, Andreas T.; Chekenya, Martha (2015). Therapeutic potential and challenges of natural killer cells in treatment of solid tumors. (ekstern lenke)
• Kmiecik, Justyna; Zimmer, Jacques; Chekenya, Martha (2014). Natural killer cells in intracranial neoplasms: presence and therapeutic efficacy against brain tumours. (ekstern lenke)
• Poli, Aurélie; Kmiecik, Justyna; Domingues, Olivia et al. (2013). NK cells in central nervous system disorders. (ekstern lenke)
• Krakstad, Camilla; Chekenya, Martha (2010). Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics. (ekstern lenke)
• Sakariassen, Per Øystein; Immervoll, Heike; Chekenya, Martha (2007). Cancer stem cells as mediators of treatment resistance in brain tumors: Status and controversies. (ekstern lenke)

Doktorgradsavhandling

• Gras Navarro, Andrea; Enger, Martha Chekenya; Kristoffersen, Einar Klæboe (2019). Towards Natural Killer cellular Immunotherapy for glioblastoma. KIR-HLA ligand interaction and proteasome inhibitors to potentiate efficacy. (ekstern lenke)
• Enger, Martha Chekenya (2006). The NG2 proteoglycan: Functional and therapeutic implications for human brain tumors. (ekstern lenke)

Sammendrag/abstract

• Brekke, Cecilie; Thuen, Marte; Poli, Aurélie et al. (2012). Early MRI findings of targeting the NG2 proteoglycan in GBM. (ekstern lenke)
• Chekenya, Martha; Wang, Jian; Poli, A et al. (2010). THERAPEUTIC TARGETING OF THE NG2 PROTEOGLYCAN WITH MAB 9.2.27 AND ADOPTIVELY TRANSFERRED NK CELLS LYSES HUMAN GLIOBLASTOMA MULTIFORME IN VIVO. (ekstern lenke)
• Chekenya, Martha; Netland, Inger Anne; Verhoeff, Joost JC et al. (2010). NG2 PROMOTES RESISTANCE TO IONIZING RADIATION BY ELEVATED PEROXIREDOXIN-1 AND DNA DAMAGE RESPONSE IN GLIOBLASTOMA MULTIFORME. (ekstern lenke)
• Wang, Jian; Miletic, Hrvoje; Sakariassen, Per Øystein et al. (2009). PHENOTYPIC MODULATION OF EXPERIMENTAL GLIOMAS: PROGRESSION FROM GLIOMATOSIS CEREBRI-LIKE LESIONS TO GLIOBLASTOMA. (ekstern lenke)
• Enger, Per Øyvind; Sakariassen, Per Øystein; Skaftnesmo, Kai Ove et al. (2004). Angiogenesis-independent growth by brain tumor cells exhibiting cancer stem cell properties. (ekstern lenke)

Poster

• Thuen, Marte; Wang, Jien; Enger, Per Øyvind et al. (2011). Therapeutic Targeting of NG2 Proteoglycan with MAb & Pre-Armed NK Cells in Human GMB Evaluated with Dynamic Enhanced & Diffusion Weighted MRI in Rats. (ekstern lenke)
• Moen, Ingrid; Øyan, Anne Margrete; Kalland, Karl-Henning et al. (2009). Hyperoxic Treatment induces Mesenchymal-to-Epithelial Transition in a Rat Adenocarcinoma Model. (ekstern lenke)
• Brekken, Christian; Brekke, Cecilie; Brekke, Cecilie et al. (2003). Phenotyping by MRI: NG2 Receptor Status Modifies Human Glioblastoma Development. (ekstern lenke)
• Brekken, Christian; Brekke, Cecilie; Brekke, Cecilie et al. (2003). NG2 receptor status modifies human glioblastoma development: Assessment by MRI. (ekstern lenke)

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ORCiD https://orcid.org/0000-0001-7241-3451