The Clash of Territorialities.: Regional Dimensions of A New Neighbourhood with PostCommunist Russia

Der Aufsatz untersucht die sich überlagernden Territorialisierungsmuster in der Finnisch-Russischen Grenzregion. Dabei wird den Friktionen zwischen diesen verschiedenen Mustern im Rahmen von EU-Politiken vor dem Hintergrund sich wandelnder historischer Formen supranationaler, nationaler und regionaler Territorialisierung besondere Aufmerksamkeit gewidmet. Das Fallbeispiel Karelien stand als historische Region für mehr als tausend Jahre im Zentrum von Auseinandersetzungen rivalisierender Projekte der Staats- und Nationenbildung im europäischen Norden. Der Aufsatz untersucht u. a., welche Rolle dieses historische Erbe in der Regionalpolitik der Europäischen Union spielt und in welcher Form es in heutigen supra-nationalen, nationalen und regionalen Vorstellungen von grenzüberschreitender Regionalisierung präsent ist. Karelien kann als Paradebeispiel für das Aufeinandertreffen verschiedener Formen der Regionalisierung, der Staatsbildung wie auch der Definition der Ost-West-Konfrontation gelten. Seine Territorialisierungsmuster haben immer auch die Machtverschiebungen innerhalb des europäischen Staatensystems reflektiert. Das historische Erbe der Region umfasst seit seiner doppelten imperialen Vergangenheit bis nach dem Kalten Krieg verschiedene Formen der Bestimmung dieser räumlichen Einheit: als regionale Gemeinschaft mit eigenen ethnischen, sprachlichen und religiösen Besonderheiten; als Grenzland, das von rivalisierenden Staaten und sich überlagernden nationalisierenden Ansprüchen geteilt wird; und schließlich als Berührungspunkt und Trennlinie zwischen Ost und West. Das Ende des Kalten Krieges und die Effekte der EU-Regionalpolitik brachten neue Formen der marktorientierten Regionalisierung hervor, wobei die EU die verschiedenen territorialen Ebenen hierarchisch organisierte und in hohem Maße die wechselseitigen historischen Verbindungen, Brüche und Konflikte ignorierte. Nach dem Zusammenbruch der Sowjetunion, der Einführung der EU-Regionalpolitik, einschließlich der neuen Nachbarschaftspolitik, und der Einrichtung der Euroregion Karelien im Jahr 2000 entstanden neue Formen des Austauschs in der Grenzregion. Grenzüberschreitende Kooperation, maßgeblich geprägt durch die Verlagerung des Schwerpunkts weg von einer nationalstaatlich dominierten Außenpolitik hin zu Mehrebenenstrukturen und -netzwerken die von unabhängigen Akteuren gebildet werden, hat die Rolle der mittleren Ebene gestärkt. Die Ziele der impulsgebenden Akteure dieser grenzüberschreitenden Praktiken waren dabei nicht auf die Herausbildung eines regionalen Grenzregimes begrenzt, sondern berührten auch zentrale Fragen europäischer und nationaler Identitätspolitik. Der Aufsatz plädiert für die Anerkennung der historischen und politischen Wechselbeziehungen, Brüche und Konflikte zwischen unterschiedlichen Verständnissen der territorialen Bezüge und unterstreicht die Notwendigkeit komparativer Studien zur politischen Sprache der grenzüberschreitenden Kooperation

Onkolyyttisen immunoterapian yhdistäminen perinteisiin syöpähoitoihin

Cancer remains a major cause of death and novel treatment modalities are needed. Oncolytic immunotherapy is a safe and promising approach, where cancer-selective viruses kill only cancer cells and mount an immune response against the tumor. We aimed to improve oncolytic adenoviral immunotherapy by combining it with chemotherapy and radiotherapy, and by identifying resistance mechanisms and biomarkers. We first showed that combining radiotherapy with adenoviral vector proteins E4orf3 and E4orf6, but not E1B55K, enhanced DNA damage accumulation and cancer cell killing, and inhibited prostate tumor growth in mice. This intrinsic ability of adenoviruses to radiosensitize cells could be harnessed against cancer cells by selective targeting, thus increasing efficacy while reducing the harmful side-effects of radiotherapy. In study two, we established two ovarian cancer mouse models, where tumors relapse despite the presence of functional oncolytic adenovirus, with tumor stroma maintaining the virus resistance. We identified upregulated interferon signaling in the resistant tumors by microarray, while pathway analyses suggested potential therapeutic targets, and myxovirus resistance protein A (MxA) was found a protein level indicator correlating with resistance to virus. Our results provide a putative biomarker and targets, which can help in detecting and overcoming resistance against oncolytic adenovirus. Antitumor T-cell activation appears to require autophagy and immunogenic cell death (ICD). In a translational study, we demonstrated preclinically that oncolytic adenovirus together with low-dose temozolomide and cyclophosphamide increased ICD and autophagy, resulting in tumor growth inhibition. Combination therapy was found safe in 41 treatments given to patients with refractory solid tumors in the context of an advanced therapy access program (ATAP). Increase of an ICD marker protein high-mobility group box 1 (HMGB1) and antitumor T-cell activity suggested activation of immune responses. Disease stabilization or better was observed in 67% of evaluable treatments, and as an estimated effect on survival, combination-treated patients trended for increased overall survival over non-randomized control patients. Biomarkers are urgently needed for identification of cancer patients likely to benefit from immunotherapy. Because HMGB1 protein is emerging a key player in immunomodulation, we addressed the biomarker value of HMGB1 serum level in an ATAP cohort of 202 cancer patients treated with oncolytic adenoviruses: Patients with low-baseline HMGB1 showed significantly improved overall survival and disease control rate in multivariate analyses as compared to high-baseline patients. Both patient groups showed good safety. HMGB1-low patients seemed to benefit from immunogenic virus constructs and antitumor T-cell activity. Thus, we have identified HMGB1 as a novel prognostic and predictive biomarker for oncolytic immunotherapy, which may distinguish between immunologically inert and responsive cancer patients. This thesis provides rationale for combining oncolytic adenoviruses with radiotherapy, low-dose temozolomide and cyclophosphamide. We report safety, possible signs of efficacy, and immunological effects in altogether 238 patient treatments, and introduce promising biomarkers for oncolytic immunotherapy. Our results can help in designing clinical trials and developing oncolytic adenovirus treatments.Syöpätaudit ovat maailman yleisin kuolinsyy, jonka vuoksi tehokkaampia hoitoja tarvitaan. Onkolyyttinen immunoterapia on turvallinen ja lupaava hoitomuoto, jossa vain syöpäsoluissa jakautuvat virukset tuhoavat kasvainkudosta säästäen terveet solut, samalla aktivoiden immuunijärjestelmää havaitsemaan syöpäkasvaimia. Tämä väitöskirjatutkimus tähtää onkolyyttisen adenoviraalisen immunoterapian kehittämiseen yhdistelmähoidoissa sädehoidon ja solunsalpaajien kanssa, sekä tutkimalla kasvainresistenssin syitä ja uusia biomarkkereita. Ensimmäisessä osajulkaisussa raportoimme kahden adenovirus-vektorin proteiinin, E4orf3:n ja E4orf6:n, herkistävän tehokkaasti eturauhassyöpää sädehoidolle estämällä DNA-korjausmekanismeja, sekä hidastavan tuumorikasvua yhdistelmähoidon hiirimallissa. Tämä adenovirusten luontainen kyky altistaa infektoitu solu sädehoidolle voidaan kohdentaa syöpäsoluja vastaan onkolyyttisesti, siten lisäten tehoa ja vähentäen säteilyn sivuvaikutuksia normaalikudoksiin. Toisessa osajulkaisussa tutkimme onkolyyttisiä adenoviruksia vastaan kehittyvää kasvainresistenssiä munasarjasyövän hiirimalleissa, joissa kasvaintukikudos näytti ylläpitävän vastustuskykyä. Havaitsimme interferoni-vasteen yliaktivoituneen ja löysimme mahdollisia lääkinnällisiä kohteita resistenssikasvaimista. Identifioimme potentiaalisesti hyödyllisen biomarkkerin, myxovirus-proteiini A:n (MxA), joka korreloi virus-resistenssin kanssa. Tuloksemme valottavat viruksia vastaan kehittyvän kasvainresistenssin mekanismeja ja voivat auttaa sen taltuttamisessa. Hyödyllisten T-soluvasteiden aikaansaamisessa autofagia ja immunogeeninen solukuolema (ICD) ovat keskeisiä. Kolmas, translationaalinen tutkimuksemme osoitti onkolyyttisen adenoviruksen yhdessä matala-annoksisen temotsolomidin ja syklofosfamidin kanssa lisäävän syöpäsolujen ICD:aa, autofagiaa ja parantavan tehoa eturauhassyövän hiirimallissa. 41 yhdistelmähoitoa annettuna kokeellisessa ATAP-hoito-ohjelmassa pitkälle-edenneiden syöpäpotilaiden kasvaimiin osoittautuivat hyvin siedetyiksi. ICD:ssa vapautuvan high-mobility group box 1 (HMGB1) proteiinin nousu ja anti-tumoraaliset T-soluvasteet viittasivat immuunijärjestelmän aktivoitumiseen. Raportoimme taudinetenemisen hidastuneen kuvantamisessa 67%:lla arvioitavista potilashoidoista, sekä havaitsimme suuntaa-antavasti viitteitä elossaoloajan pitkittymisestä verrattuna ei-randomoituihin kontrollipotilaisiin. Biomarkkereita kaivataan kohdentamaan immunoterapeuttisia hoitomuotoja niistä hyötyville potilaille. Neljännessä tutkimuksessa määritimme seerumin HMGB1 proteiinin ennustearvon 202 syöpäpotilaan ATAP-hoidetussa aineistossa: Monimuuttuja-malleissa onkolyyttisen adenovirushoidon mahdollinen hyöty kuvantamisvasteissa ja elossaoloajassa korostui merkittävästi sillä osalla potilaista joiden veren HMGB1-taso oli alkutilanteessa matala. Raportoimme hoitojen olevan turvallisia molemmissa potilasryhmissä. HMGB1-matalat potilaat näyttivät hyötyvän immunogeenisistä hoitoviruksista sekä antitumoraalisten T-solujen aktivaatiosta, viitaten biomarkkerin mekanismin olevan immuunivälitteinen. Päättelemme siten seerumin HMGB1 proteiinin olevan lupaava ennusteellinen biomarkkeri onkolyyttiselle immunoterapialle. Väitöskirjatutkimuksemme edistää onkolyyttisen immunoterapian tehon ja turvallisuuden kehitystä erityisesti syövän yhdistelmähoidoissa, tarjoten perusteet kliinisiin jatkotutkimuksiin, ja esittelee uusia biomarkkereita jotka voivat auttaa paremmin kohdentamaan immunoterapeuttiset hoitomuodot niistä hyötyville syöpäpotilaille

Naiset ja kieltolakikulttuuri

Arvosteltu teos: Kansan raittiudeksi ja kotien onneksi: Naisten kieltolakimielipiteet ja toiminta kieltolain puolesta ja sitä vastaan 1919-1932 / Aija Kaartinen. Helsinki : Suomalaisen Kirjallisuuden Seura, 2011

Oncograms Visualize Factors Influencing Long-Term Survival of Cancer Patients Treated with Adenoviral Oncolytic Immunotherapy

The first US Food and Drug Administration (FDA)- and EMA-approved oncolytic virus has been available since 2015. However, there are no markers available that would predict benefit for the individual patient. During 2007-2012, we treated 290 patients with advanced chemotherapy-refractory cancers, using 10 different oncolytic adenoviruses. Treatments were given in a Finnish Medicines Agency (FIMEA)-regulated individualized patient treatment program (the Advanced Therapy Access Program [ATAP]), which required long-term follow-up of patients, which is presented here. Focusing on the longest surviving patients, some key clinical and biological features are presented as "oncograms." Some key attributes that could be captured in the oncogram are suggested to predict treatment response and survival after oncolytic adenovirus treatment. The oncogram includes immunological laboratory parameters assessed in peripheral blood (leukocytes, neutrophil-to-lymphocyte ratio, interleukin-8 [IL-81, HMGB1, antiviral neutralizing antibody status), features of the patient (gender, performance status), tumor features (histological tumor type, tumor load, region of metastases), and oncolytic virus-specific features (arming of the virus). The retrospective approach used here facilitates verification in a prospective controlled trial setting. To our knowledge, the oncogram is the first holistic attempt to identify the patients most likely to benefit from adenoviral oncolytic virotherapy.Peer reviewe

Case-Control Estimation of the Impact of Oncolytic Adenovirus on the Survival of Patients With Refractory Solid Tumors

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Interleukin 8 activity influences the efficacy of adenoviral oncolytic immunotherapy in cancer patients

After the landmark approval of T-VEC, oncolytic viruses are finding their way to the clinics. However, response rates have still room for improvement, and unfortunately there are currently no available markers to predict responses for oncolytic immunotherapy. Interleukin 8 (IL-8) production is upregulated in many cancers and it also connects to several pathways that have been shown to impair the efficacy of adenoviral immunotherapy. We studied the role of IL-8 in 103 cancer patients treated with oncolytic adenoviruses. We found high baseline serum IL-8 concentration to be independently associated with poor prognosis (p <0.001). Further, normal baseline IL-8 was associated with improved prognostic potential of calculation of the neutrophil-to-lymphocyte ratio (p <0.001). Interestingly, a decrease in IL-8 concentration after treatment with oncolytic adenovirus predicted better overall survival (p <0.001) and higher response rate, although this difference was not significant (p=0.066). We studied the combination of adenovirus and IL-8 neutralizing antibody ex vivo in single cell suspensions and in co-cultures of tumor-associated CD15+ neutrophils and CD3+ tumor-infiltrating lymphocytes derived from fresh patient tumor samples. These results indicate a role for IL-8 as a biomarker in oncolytic virotherapy, but additionally provide a rationale for targeting IL-8 to improve treatment efficacy. In conclusion, curtailing the activity of IL-8 systemically or locally in the tumor microenvironment could improve anti-tumor immune responses resulting in enhanced efficacy of adenoviral immunotherapy of cancer. © Taipale et al.Peer reviewe

Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer

Background Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy. Methods Modulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5/3 increment 24-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (ISRCTN10141600, April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging/marker responses were evaluated by log-rank and Fisher's test, while coinhibitory receptors/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays. Results Preclinically, TIM-3(+) tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3(+) TIL subset through recruitment of less-exhausted CD8(+) TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8(+) lymphocytes and higher influx of CD8(+) TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy. Conclusions Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients.Peer reviewe

Fc-gamma receptor polymorphisms as predictive and prognostic factors in patients receiving oncolytic adenovirus treatment

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