Akseli Hemminki

University of Helsinki, Helsinki, Southern Finland Province, Finland

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Publications (227)1374.4 Total impact

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    ABSTRACT: For long it has been recognized that tumor necrosis factor alpha (TNFa) has anti-cancer characteristics and its use as a cancer therapeutic was proposed already in the 80´s. However, its systemic toxicity has limited its usability. Oncolytic viruses, selectively cancer-killing viruses, have shown great potency and one of their most useful aspects is their ability to produce high amounts of transgene products locally, resulting in high local versus systemic concentrations. Therefore the overall magnitude of tumor cell killing results from the combination of oncolysis, transgene mediated direct effect such as TNFa mediated apoptosis, and, perhaps most significantly, from activation of the host immune system against the tumor. We generated a novel chimeric oncolytic adenovirus expressing human TNFa, Ad5/3-D24-hTNFa, whose efficacy and immunogenicity were tested in vitro and in vivo. The hTNFa expressing adenovirus showed increased cancer-eradicating potency, which was shown to be due to elevated apoptosis and necrosis rates and induction of various immune responses. Interestingly, we saw increase in immunogenic cell death markers in Ad5/3-d24-hTNFa treated cells. Moreover, tumors treated with Ad5/3-D24-hTNFa displayed enhanced presence of OVA-specific cytotoxic T cells. We thus can conclude that tumor eradication and anti-tumor immune responses mediated by Ad5/3-d24-hTNFa offer a new potential drug candidate for cancer therapy.
    Human gene therapy. 01/2015;
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    ABSTRACT: Oncolytic adenoviruses (Onc.Ads) produce significant antitumor effects but as single agents they rarely eliminate tumors. Investigators have therefore incorporated sequences into these vectors that encode immunomodulatory molecules to enhance antitumor immunity. Successful implementation of this strategy requires multiple tumor immune inhibitory mechanisms to be overcome, and insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. HDAds, however, lack replicative capacity. Since HDAds encode the adenoviral packaging signal, we hypothesized that the coadministration of Onc.Ad with HDAd would allow to be amplified and packaged during replication of Onc.Ad in transduced cancer cells. This combination could provide immunostimulation without losing oncolytic activity. We now show that coinfection of Onc.Ad with HDAd subsequently replicates HDAd vector DNA in trans in human cancer cell lines in vitro and in vivo, amplifying the transgenes the HDAd encode. This combinatorial treatment significantly suppresses the tumor growth compared to treatment with a single agent in an immunocompetent mouse model. Hence, combinatorial treatment of Onc.Ad with HDAd should overcome the inherent limitations of each agent and provide a highly immunogenic oncolytic therapy.
    Molecular Therapy — Oncolytics. 12/2014;
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    ABSTRACT: Oncolytic immunotherapy with cytokine armed replication competent viruses is an emerging approach in cancer treatment. In a recent randomized trial an increase in response rate was seen but the effect on overall survival is not known with any virus. To facilitate randomized trials, we performed a case-control study assessing the survival of 270 patients treated in an Advanced Therapy Access Program (ATAP), in comparison to matched concurrent controls from the same hospital. The overall survival of all virus treated patients was not increased over controls. However, when analysis was restricted to GMCSF-sensitive tumor types treated with GMSCF-coding viruses, a significant improvement in median survival was present (From 170 to 208 days, P = 0.0012, N=148). An even larger difference was seen when analysis was restricted to good performance score patients (193 versus 292 days, P = 0.034, N=90). The survival of ovarian cancer patients was especially promising as median survival nearly quadrupled (P = 0.0003, N=37). These preliminary data lend support to initiation of randomized clinical trials with GMCSF-coding oncolytic adenoviruses.Molecular Therapy (2014); doi:10.1038/mt.2014.218.
    Molecular Therapy 11/2014; · 6.43 Impact Factor
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    ABSTRACT: Cancer is one of the most common reasons for death in dogs. One promising approach is oncolytic virotherapy. We assessed the oncolytic effect of genetically modified vaccinia viruses in canine cancer cells, in freshly excised tumour biopsies, and in mice harbouring canine tumour xenografts. Tumour transduction efficacy was assessed using virus expressing luciferase or fluorescent marker genes and oncolysis was quantified by a colorimetric cell viability assay. Oncolytic efficacy in vivo was evaluated in a nude mouse xenograft model. Vaccinia virus was shown to infect most tested canine cancer cell lines and primary surgical tumour tissues. Virus infection significantly reduced tumour growth in the xenograft model. Oncolytic vaccinia virus has antitumour effects against canine cancer cells and experimental tumours and is able to replicate in freshly excised patient tumour tissue. Our results suggest that oncolytic vaccinia virus may offer an effective treatment option for otherwise incurable canine tumours.
    Veterinary and Comparative Oncology 10/2014; · 1.45 Impact Factor
  • Kari Hemminki, Mahdi Fallah, Akseli Hemminki
    Journal of Clinical Oncology 08/2014; 32. · 17.88 Impact Factor
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    ABSTRACT: Objectives Population-based data on metastatic sites and survival in site-specific metastases are lacking for lung cancer and for any cancer because most cancer registries do not record metastases. This study uses a novel population-based approach to identify metastases from both death certificates and national inpatient data to describe metastatic pathways in lung cancer patients. Material and methods 17,431 deceased lung cancer patients diagnosed 2002-2010 were identified from the nationwide Swedish Cancer Registry, which is based on compulsory reports. The influence of age at diagnosis, sex, and histological subtype on metastatic spread was investigated. Survival in metastatic lung cancer was assessed by histology and metastatic site. Results The most frequent metastatic sites were the nervous system, bone, liver, respiratory system, and adrenal gland. Liver (35%) and nervous system (47%) metastases were common in patients with metastases from small cell lung cancer, and bone (39%) and respiratory system (22%) metastases in adenocarcinoma. Women (43% vs. 35%) and younger patients had more metastases to the nervous system. Median survival after diagnosis was 13 months for non-metastatic and five months for metastatic lung cancer. In this novel data, liver metastases conferred the worst prognosis (three months), especially for large cell histology. Bone metastases also featured poor survival, whereas survival in respiratory and nervous system metastases was better. Conclusion Metastatic sites and survival in metastatic lung cancer is influenced by sex, histological subtype, and age at diagnosis. Liver and bone metastases signal poor survival, compared with nervous system metastases.
    Lung Cancer 08/2014; · 3.74 Impact Factor
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    ABSTRACT: Oncolytic Western Reserve strain vaccinia virus selective for EGFR pathway mutations and tumor associated hypermetabolism was armed with human GMCSF and a tdTomato fluorophore. Since the assessment of immunological responses to human transgenes is challenging in the most commonly used animal models, we utilized immunocompetent Syrian golden hamsters, known to be sensitive to human GMCSF and semi-permissive to vaccinia virus. Efficacy was initially tested in vitro on various human and hamster cell lines and oncolytic potency of transgene carrying viruses was similar to unarmed virus. The hGMCSF encoding virus was able to completely eradicate subcutaneous pancreatic tumors in hamsters, and to fully protect the animals from subsequent rechallenge with the same tumor. Induction of specific anti-tumor immunity was also shown by ex vivo co-culture experiments with hamster splenocytes. In addition, histological examination revealed increased infiltration of neutrophils and macrophages in GMCSF-virus treated tumors. These findings help clarify the mechanism of action of GMCSF armed vaccinia viruses undergoing clinical trials. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 07/2014; · 6.20 Impact Factor
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    ABSTRACT: Cancer of unknown primary (CUP) is a fatal cancer, accounting for 3-5% of all diagnosed cancers. Finding the primary site is important for therapeutic choices and we believe that the organ which is designated as the cause of death may give clues about the primary site.
    BMC Cancer 06/2014; 14(1):439. · 3.32 Impact Factor
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    ABSTRACT: Despite originating from several different tissues, soft-tissue sarcomas (STS) are often grouped together as they share mesenchymal origin and treatment guidelines. Also, with some exceptions, a common denominator is that when the tumor cannot be cured with surgery, the efficacy of current therapies is poor and new treatment modalities are thus needed. We have studied the combination of a capsid-modified oncolytic adenovirus CGTG-102 (Ad5/3-D24-GMCSF) with doxorubicin, with or without ifosfamide, the preferred first-line chemotherapeutic options for most types of STS. We show that CGTG-102 and doxorubicin plus ifosfamide together are able to increase cell killing of Syrian hamster STS cells over single agents, as well as upregulate immunogenic cell death markers. When tested in vivo against established STS tumors in fully immunocompetent Syrian hamsters, the combination was highly effective. CGTG-102 and doxorubicin (without ifosfamide) resulted in synergistic antitumor efficacy against human STS xenografts in comparison with single agent treatments. Doxorubicin increased adenoviral replication in human and hamster STS cells, potentially contributing to the observed therapeutic synergy. In conclusion, the preclinical data generated here support clinical translation of the combination of CGTG-102 and doxorubicin, or doxorubicin plus ifosfamide, for the treatment of STS, and provide clues on the mechanisms of synergy. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 06/2014; 136(4). · 6.20 Impact Factor
  • International Journal of Cancer 05/2014; · 6.20 Impact Factor
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    Akseli Hemminki
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    ABSTRACT: Following a century of preclinical and clinical work, oncolytic viruses are now proving themselves in randomized phase 3 trials. Interestingly, human data indicates that these agents have potent immunostimulatory activity, raising the possibility that the key consequence of oncolysis might be induction of antitumor immunity, especially in the context of viruses harboring immunostimulatory transgenes. While safety and efficacy of many types of oncolytic viruses, including adenovirus, herpes, reo, and vaccinia seem promising, few mechanisms of action studies have been performed with human substrates. Thus, the relative contribution of "pure" oncolysis, the immune response resulting from oncolysis, and the added benefit of adding a transgene remain poorly understood. Here, the available clinical data on oncolytic viruses is reviewed, with emphasis on immunological aspects.
    Scientifica. 01/2014; 2014:862925.
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    ABSTRACT: Sarcomas are a relatively rare cancer, but often incurable at the late metastatic stage. Oncolytic immunotherapy has gained attention over the past years, and a wide range of oncolytic viruses have been delivered via intratumoral injection with positive safety and promising efficacy data. Here, we report preclinical and clinical results from treatment of sarcoma with oncolytic adenovirus Ad5/3-D24-GMCSF (CGTG-102). Ad5/3-D24-GMCSF is a serotype chimeric oncolytic adenovirus coding for human granulocyte-macrophage colony-stimulating factor (GM-CSF). The efficacy of Ad5/3-D24-GMCSF was evaluated on a panel of soft tissue sarcoma (STS) cell lines and in two animal models. Sarcoma specific human data were also collected from the Advanced Therapy Access Program (ATAP), in preparation for further clinical development. Efficacy was seen in both in vitro and in vivo STS models. 15 patients with treatment refractory STS (13/15) or primary bone sarcoma (2/15) were treated in ATAP, and treatments appeared safe and well-tolerated. A total of 12 radiological RECIST response evaluations were performed and two cases of minor response, six cases of stable disease and four cases of progressive disease were detected in patients progressing prior to virus treatment. Overall, the median survival time post treatment was 170 days. One patient is still alive at 1459 days post virus treatment. In summary, Ad5/3-D24-GMCSF appears promising for the treatment of advanced STS; a clinical trial for treatment of refractory injectable solid tumors including STS is ongoing. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 12/2013; · 6.20 Impact Factor
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    ABSTRACT: Oncolytic vaccinia virus is an attractive platform for immunotherapy. Oncolysis releases tumor antigens and provides co-stimulatory danger signals. However, arming the virus can improve efficacy further. CD40 ligand (CD40L, CD154) can induce apoptosis of tumor cells and it also triggers several immune mechanisms. One of these is a T-helper type 1 (Th1) response that leads to activation of cytotoxic T-cells and reduction of immune suppression. Therefore, we constructed an oncolytic vaccinia virus expressing hCD40L (vvdd-hCD40L-tdTomato), which in addition features a cDNA expressing the tdTomato fluorochrome for detection of virus, potentially important for biosafety evaluation. We show effective expression of functional CD40L both in vitro and in vivo. In a xenograft model of bladder carcinoma sensitive to CD40L treatment, we show that growth of tumors was significantly inhibited by the oncolysis and apoptosis following both intravenous and intratumoral administration. In a CD40-negative model, CD40L expression did not add potency to vaccinia oncolysis. Tumors treated with vvdd-mCD40L-tdtomato showed enhanced efficacy in a syngenic mouse model and induced recruitment of antigen-presenting cells and lymphocytes at the tumor site. In summary, oncolytic vaccinia virus coding for CD40L mediates multiple antitumor effects including oncolysis, apoptosis and induction of Th1 type T-cell responses.Gene Therapy advance online publication, 5 December 2013; doi:10.1038/gt.2013.73.
    Gene therapy 12/2013; · 4.75 Impact Factor
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    ABSTRACT: At present it is not possible to reliably identify patients that will benefit from oncolytic virus treatments. Conventional modalities such as computed tomography (CT), which measure tumor size, are unreliable due to inflammation-induced tumor swelling. We hypothesized that magnetic resonance imaging (MRI) and spectroscopy (MRS) might be useful in this regard. However, little previous data exists and neither oncolytic adenovirus nor immunocompetent models have been assessed by MRS. Here we provide evidence that in T2 weighted MRI a hypointense core area, consistent with coagulative necrosis, develops in immunocompetent Syrian hamsters carcinomas that respond to oncolytic adenovirus treatment. The same phenomenon was observed in a neuroblastoma patient while he responded to the treatment. With relapse at a later stage, however, the tumor of this patient became moderately hyperintense. We found that MRS of taurine, choline and unsaturated fatty acids can be useful early indicators of response and provide detailed information about tumor growth and degeneration. In hamsters, calprotectin positive inflammatory cells (heterophils, macrophages) were found in abundance particularly surrounding necrotic areas in carcinomas and T cells were significantly increased in sarcomas, when these had been treated with a GM-CSF producing virus, suggesting a possible link between oncolysis, necrosis (seen as a hypointense core in MRI) and/or immune response. Our study indicates that both MRI and MRS could be useful in the estimation of oncolytic adenovirus efficacy at early timepoints after treatment. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 11/2013; · 6.20 Impact Factor
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    ABSTRACT: Computed tomography (CT) is the most commonly used radiological response evaluation method in contemporary oncology. However, it may not be optimally suitable for assessment of oncolytic virus treatments due to paradoxical inflammatory tumor swellings, which result from virus treatments, particularly when viruses are armed with immunostimulatory molecules. Here we investigated the prognostic utility of CT and [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oncolytic virus treatments. We also investigated possible appearance of false positive FDG-signals in FDG-PET imaging of humans and hamsters treated with oncolytic adenoviruses. First, Immunocompetent Syrian hamsters were treated with intratumoral adenovirus injections, tumor growth was followed up and [18F]-FDG-uptake was quantitated with small animal PET/CT. Second, we describe a retrospective patient series, essentially 17 individual case reports, of advanced cancer patients, treated with oncolytic adenoviruses in the context of an Advanced Therapy Access Program (ATAP), who underwent radiological response evaluation with both contrast enhanced CT and FDG-PET. Third, we collected a retrospective case series of radiological response and survival data of 182 patients treated with oncolytic adenoviruses in ATAP to evaluate the prognostic reliability of CT and FDG-PET. Overall, responses in CT and FDG-PET correlated well with each other and are equally reliable as prognostic markers for long survival after oncolytic adenovirus treatment. Interestingly, we observed that new FDG-avid lymph nodes appearing in FDG-PET after virus treatments may represent inflammatory responses and therefore should not be interpreted as treatment failure in absence of other signs or verification of disease progression. We also observed indications that FDG-PET might be more sensitive in detection of responses than tumor size.
    Human gene therapy 10/2013; · 4.20 Impact Factor
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    ABSTRACT: The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specific viral expression and replication. To this aim, we introduced four copies of miR-199 target sites within the 3' UTR of E1A gene, essential for viral replication. As consequence, E1A expression from Ad-199T virus was tightly regulated both at RNA and protein levels in HCC derived cell lines, and replication controlled by the level of miR-199 expression. Various approaches were used to asses in vivo properties of Ad-199T. Ad-199T replication was inhibited in normal, miR-199 positive, liver parenchyma, thus resulting in reduced hepatotoxicity. Conversely, the intrahepatic delivery of Ad-199T in newborn mice led to virus replication and fast removal of implanted HepG2 liver cancer cells. The ability of Ad-199T to control tumor growth was also shown in a subcutaneous xenograft model in nude mice and in HCCs arising in immune-competent mice. In summary, we developed a novel oncolytic adenovirus, Ad-199T, which could demonstrate a therapeutic potential against liver cancer without causing significant hepatotoxicity.
    PLoS ONE 09/2013; 8(9):e73964. · 3.53 Impact Factor
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    ABSTRACT: Oncolytic viruses have shown potential as cancer therapeutics, but not all patients seem to benefit from therapy. Polymorphisms in Fc gamma receptors (FcgRs) lead to altered binding affinity of IgG between the receptor allotypes and therefore contribute to differences in immune defense mechanisms. Associations have been identified between FcgR polymorphisms and responsiveness to different immunotherapies. Taken together with the increasing understanding that immunological factors might determine the efficacy of oncolytic virotherapy we studied whether FcgR polymorphisms would have prognostic and/or predictive significance in the context of oncolytic adenovirus treatments. 235 patients with advanced solid tumors were genotyped for two FcgR polymorphisms, FcgRIIa-H131R (rs1801274) and FcgRIIIa-V158F (rs396991), using TaqMan based qPCR. The genotypes were correlated with patient survival and tumor imaging data. In patients treated with oncolytic adenoviruses, overall survival was significantly shorter if the patient had an FcgRIIIa-VV/ FcgRIIa-HR (VVHR) genotype combination (P = 0,032). In contrast, patients with FFHR and FFRR genotypes had significantly longer overall survival (P = 0,004 and P = 0,006, respectively) if they were treated with GM-CSF-armed adenovirus in comparison to other viruses. Treatment of these patients with unarmed virus correlated with shorter survival (P < 0,0005 and P = 0,016, respectively). Treating FFHH individuals with CD40L-armed virus resulted in longer survival than treatment with other viruses (P = 0,047). Our data are compatible with the hypothesis that individual differences in effector cell functions, such as NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and tumor antigen presentation by APCs caused by polymorphisms in FcgRs could play role in the effectiveness of oncolytic virotherapies. If confirmed in larger populations, FcgR polymorphisms could have potential as prognostic and predictive biomarkers for oncolytic adenovirus therapies to enable better selection of patients for clinical trials. Also, putative associations between genotypes, different viruses and survival implicate potentially important mechanistic issues.
    Journal of Translational Medicine 08/2013; 11(1):193. · 3.99 Impact Factor

Publication Stats

8k Citations
1,374.40 Total Impact Points


  • 1995–2014
    • University of Helsinki
      • • Department of Oncology
      • • Transplantation Laboratory
      • • Department of Medical Genetics
      Helsinki, Southern Finland Province, Finland
  • 2012
    • Lund University
      • Center for Primary Health Care Research
      Lund, Skåne, Sweden
    • German Cancer Research Center
      • Division of Molecular Genetic Epidemiology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2011–2012
    • Unit of Virus Host Cell Interactions
      Grenoble, Rhône-Alpes, France
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, TX, United States
  • 1999–2012
    • Helsinki University Central Hospital
      • Department of Oncology
      Helsinki, Southern Finland Province, Finland
  • 2009–2011
    • University of Washington Seattle
      • Division of Medical Genetics
      Seattle, WA, United States
  • 2001–2011
    • University of Alabama at Birmingham
      • • Division of Gynecologic Oncology
      • • Department of Medicine
      • • Department of Obstetrics and Gynecology
      Birmingham, Alabama, United States
  • 2007
    • University of Mississippi Medical Center
      • Department of Pathology
      Jackson, MS, United States
  • 2003
    • University of Kuopio
      Kuopio, Eastern Finland Province, Finland
  • 1995–1998
    • VTT Technical Research Centre of Finland
      Esbo, Southern Finland Province, Finland