Browsing by Subject "NK CELLS"

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  • Havunen, Riikka; Santos, Joao M.; Sorsa, Suvi; Rantapero, Tommi; Lumen, Dave; Siurala, Mikko; Airaksinen, Anu J.; Cervera-Carrascon, Victor; Tähtinen, Siri; Kanerva, Anna; Hemminki, Akseli (2018)
    Cancer treatment with local administration of armed oncolytic viruses could potentially induce systemic antitumor effects, or the abscopal effect, as they self-amplify in tumors, induce danger signaling, and promote tumor-associated antigen presentation. In this study, oncolytic adenovirus coding for human tumor necrosis factor alpha (TNF-alpha) and interleukin-2 (IL-2) Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 (also known as [a.k.a.] TILT-123) provoked antitumor efficacy in tumors that were injected with Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 and those that were left non-injected in the same animal. Importantly, the virus was able to travel to distant tumors. To dissect the effects of oncolysis and cytokines, we studied replication-incompetent viruses in mice. Systemic antitumor effects were similar in both models, highlighting the importance of the arming device. The cytokines induced positive changes in immune cell infiltrates and induced the expression of several immune-reaction-related genes in tumors. In addition, Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 was able to increase homing of adoptively transferred tumor-infiltrating lymphocytes into both injected and non-injected tumors, possibly mediated through chemokine expression. In summary, local treatment with Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 resulted in systemic antitumor efficacy by inducing immune cell infiltration and trafficking into both treated and untreated tumors. Moreover, the oncolytic adenovirus platform had superior systemic effects over replication-deficient vector through spreading into distant tumors.
  • Dufva, Olli; Kankainen, Matti; Kelkka, Tiina; Sekiguchi, Nodoka; Awad, Shady Adnan; Eldfors, Samuli; Yadav, Bhagwan; Kuusanmäki, Heikki; Malani, Disha; Andersson, Emma I.; Pietarinen, Paavo; Saikko, Leena; Kovanen, Panu E.; Ojala, Teija; Lee, Dean A.; Loughran, Thomas P.; Nakazawa, Hideyuki; Suzumiya, Junji; Suzuki, Ritsuro; Ko, Young Hyeh; Kim, Won Seog; Chuang, Shih-Sung; Aittokallio, Tero; Chan, Wing C.; Ohshima, Koichi; Ishida, Fumihiro; Mustjoki, Satu (2018)
    Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.
  • Hosseini, Seyed Samad; Khalili, Saeed; Baradaran, Behzad; Bidar, Negar; Shahbazi, Mohammad-Ali; Mosafer, Jafar; Hashemzaei, Mahmoud; Mokhtarzadeh, Ahad; Hamblin, Michael R. (2021)
    Bispecific antibodie (BsAbs) combine two or more epitope-recognizing sequences into a single protein molecule. The first therapeutic applications of BsAbs were focused on cancer therapy. However, these antibodies have grown to cover a wider disease spectrum, including imaging, diagnosis, prophylaxis, and therapy of inflammatory and autoimmune diseases. BsAbs can be categorized into IgG-like formats and non-IgG-like formats. Different technologies have been used for the construction of BsAbs including "CrossMAb", "Quadroma", "knobs-into-holes" and molecular cloning. The mechanism of action for BsAbs includes the induction of CDC, ADCC, ADCP, apoptosis, and recruitment of cell surface receptors, as well as activation or inhibition of signaling pathways. The first clinical trials included mainly leukemia and lymphoma, but solid tumors are now being investigated. The BsAbs bind to a tumor-specific antigen using one epitope, while the second epitope binds to immune cell receptors such as CD3, CD16, CD64, and CD89, with the goal of stimulating the immune response against cancer cells. Currently, over 20 different commercial methods have been developed for the construction of BsAbs. Three BsAbs are currently clinically approved and marketed, and more than 85 clinical trials are in progress. In the present review, we discuss recent trends in the design, engineering, clinical applications, and clinical trials of BsAbs in solid tumors. (C) 2020 Elsevier B.V. All rights reserved.
  • Kreutzman, Anna; Rohon, Peter; Faber, Edgar; Indrak, Karel; Juvonen, Vesa; Kairisto, Veli; Voglova, Jaroslava; Sinisalo, Marjatta; Flochova, Emilia; Vakkila, Jukka; Arstila, Petteri; Porkka, Kimmo; Mustjoki, Satu (2011)
  • Brück, Oscar; Dufva, Olli; Hohtari, Helena; Blom, Sami; Turkki, Riku; Ilander, Mette; Kovanen, Panu; Pallaud, Celine; Ramos, Pedro Marques; Lähteenmäki, Hanna; Välimäki, Katja; El Missiry, Mohamed; Ribeiro, Antonio; Kallioniemi, Olli; Porkka, Kimmo; Pellinen, Teijo; Mustjoki, Satu (2020)
    The immunologic microenvironment in various solid tumors is aberrant and correlates with clinical survival. Here, we present a comprehensive analysis of the immune environment of acute myeloid leukemia (AML) bone marrow (BM) at diagnosis. We compared the immunologic landscape of formalin-fixed paraffin-embedded BM trephine samples from AML (n = 69), chronic myeloid leukemia (CML; n = 56), and B-cell acute lymphoblastic leukemia (B-ALL) patients (n 5 52) at diagnosis to controls (n = 12) with 30 immunophenotype markers using multiplex immunohistochemistry and computerized image analysis. We identified distinct immunologic profiles specific for leukemia subtypes and controls enabling accurate classification of AML (area under the curve [AUC] = 1.0), CML (AUC = 0.99), B-ALL (AUC = 0.96), and control subjects (AUC = 1.0). Interestingly, 2 major immunologic AML clusters differing in age, T-cell receptor clonality, and survival were discovered. A low proportion of regulatory T cells and pSTAT(+)cMAF(-) monocytes were identified as novel biomarkers of superior event-free survival in intensively treated AML patients. Moreover, we demonstrated that AML BM and peripheral blood samples are dissimilar in terms of immune cell phenotypes. To conclude, our study shows that the immunologic landscape considerably varies by leukemia subtype suggesting disease-specific immunoregulation. Furthermore, the association of the AML immune microenvironment with clinical parameters suggests a rationale for including immunologic parameters to improve disease classification or even patient risk stratification.
  • Heikkinen, Sanna; Miettinen, Joonas; Pukkala, Eero; Koskenvuo, Markku; Malila, Nea; Pitkaniemi, Janne (2017)
    Background: It has been suggested that long-term activation of the body's stress-response system and subsequent overexposure to stress hormones may be associated with increased morbidity. However, evidence on the impact of major life events on mortality from breast cancer (BC) remains inconclusive. The main aim of this study is to investigate whether major negatively or positively experienced life events before or after diagnosis have an effect on BC-specific mortality in women who have survived with BC for at least 2 years. Methods: We conducted a case fatality study with data on life events from a self-administered survey and data on BC from the Finnish Cancer Registry. Cox models were fitted to estimate BC mortality hazard ratios (MRs) between those who have undergone major life events and those who haven't. Results: None of the pre-diagnostic negative life events had any effect on BC-specific mortality. Regarding post-diagnostic events, the effect was greatest in women with moderate scores of events. As for event-specific scores, increased BC mortality was observed with spouse unemployment, relationship problems, and death of a close friend. By contrast, falling in love and positive developments in hobbies were shown to be associated with lower BC mortality (MRs 0.67, 95% CI: 0.49-0.92 and 0.74, 95% CI: 0.57-0.96, respectively). In an analysis restricted to recently diagnosed cases (2007), also death of a child and of a mother was associated with increased BC mortality. Conclusions: Some major life events regarding close personal relationships may play a role in BC-specific mortality, with certain negative life events increasing BC mortality and positive events decreasing it. The observed favorable associations between positive developments in romantic relationships and hobbies and BC mortality are likely to reflect the importance of social interaction and support. (C) 2017 Elsevier Ltd. All rights reserved.
  • Lopes, Alessandra; Feola, Sara; Ligot, Sophie; Fusciello, Manlio; Vandermeulen, Gaëlle; Préat, Véronique; Cerullo, Vincenzo (2019)
    Background: DNA vaccines against cancer held great promises due to the generation of a specific and long lasting immune response. However, when used as a single therapy, they are not able to drive the generated immune response into the tumor, because of the immunosuppressive microenvironment, thus limiting their use in humans. To enhance DNA vaccine efficacy, we combined a new poly-epitope DNA vaccine encoding melanoma tumor associated antigens and B16F1-specific neoantigens with an oncolytic virus administered intratumorally. Methods: Genomic analysis were performed to find specific mutations in B16F1 melanoma cells. The antigen gene sequences were designed according to these mutations prior to the insertion in the plasmid vector. Mice were injected with B16F1 tumor cells (n = 7-9) and therapeutically vaccinated 2, 9 and 16 days after the tumor injection. The virus was administered intratumorally at day 10, 12 and 14. Immune cell infiltration analysis and cytokine production were performed by flow cytometry, PCR and ELISPOT in the tumor site and in the spleen of animals, 17 days after the tumor injection. Results: The combination of DNA vaccine and oncolytic virus significantly increased the immune activity into the tumor. In particular, the local intratumoral viral therapy increased the NK infiltration, thus increasing the production of different cytokines, chemokines and enzymes involved in the adaptive immune system recruitment and cytotoxic activity. On the other side, the DNA vaccine generated antigen-specific T cells in the spleen, which migrated into the tumor when recalled by the local viral therapy. The complementarity between these strategies explains the dramatic tumor regression observed only in the combination group compared to all the other control groups. Conclusions: This study explores the immunological mechanism of the combination between an oncolytic adenovirus and a DNA vaccine against melanoma. It demonstrates that the use of a rational combination therapy involving DNA vaccination could overcome its poor immunogenicity. In this way, it will be possible to exploit the great potential of DNA vaccination, thus allowing a larger use in the clinic.
  • Rajala, Hanna L. M.; Olson, Thomas; Clemente, Michael J.; Lagstrom, Sonja; Ellonen, Pekka; Lundan, Tuija; Hamm, David E.; Zaman, Syed Arshi Uz; Marti, Jesus M. Lopez; Andersson, Emma I.; Jerez, Andres; Porkka, Kimmo; Maciejewski, Jaroslaw P.; Loughran, Thomas P.; Mustjoki, Satu (2015)