Akseli Hemminki

Mater Misericordiae University Hospital, Dublin, Leinster, Ireland

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Publications (356)

  • Tuuli Ranki · Sari Pesonen · Akseli Hemminki · [...] · Timo Joensuu
    [Show abstract] [Hide abstract] ABSTRACT: Background We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined. Methods The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT). Results No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients. Conclusions ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors. Trial registration NCT01598129. Registered 19/04/2012
    Article · Dec 2016
  • Matias Riihimäki · Akseli Hemminki · Kristina Sundquist · [...] · Kari Hemminki
    [Show abstract] [Hide abstract] ABSTRACT: The epidemiology of metastases in neuroendocrine tumors (=NET) is virtually unknown. The present novel approach took use of two nationwide Swedish registers to assess the distribution of metastatic sites in comparison to adenocarcinoma. 7,334 patients with NET were identified from the Swedish Cancer Registry. Metastatic sites were identified from the National Patient and Cause of Death Registries. Sites of metastasis were investigated depending on the primary site of NET. The metastatic potential of NET was assessed. The liver was the most common site of metastasis (82% of patients with metastases), and the small intestine was the most common source of NET metastases. Of all patients with metastatic lung NETs, 66% had liver metastases, whereas the corresponding number for adenocarcinoma of lung was only 20%. The risk of metastasis was highest if the primary was in the small intestine or pancreatohepatobiliary tract, whereas it was lower with appendiceal and rectal NET. Men had more bone metastases compared to women. Patients with metastatic NET had worse prognosis if the primary site was unknown (11 months, 9% of NET patients) compared to those whose primary was known (19 months). The metastatic potential of NETs varies profoundly depending on the primary site. NETs show a clear preference to metastasize to the liver. Surveillance of liver metastases may enable earlier diagnosis and treatment. In liver metastases from NET, the small intestine should be suspected as the primary site, whereas the lung should be suspected in nervous system metastases of NET origin. This article is protected by copyright. All rights reserved.
    Article · Aug 2016 · International Journal of Cancer
  • M. Riihimäki · A. Hemminki · K. Sundquist · [...] · K. Hemminki
    [Show abstract] [Hide abstract] ABSTRACT: Background: The epidemiology of metastatic gastric cancer is unexplored because cancer registries seldom cover metastatic involvement apart from "present or not". We used a novel approach by utilizing Swedish registers to assess metastatic spread in gastric cancer. To our knowledge, this is the first nationwide description of metastases in gastric cancer. Results: The most common sites of metastasis were liver (in 48% of metastatic cancer patients), peritoneum (32%), lung (15%), and bone (12%). Metastases to the lung, nervous system, and bone were more frequent in cardia cancer and men, whereas non-cardia cancer more frequently metastasized within the peritoneum. Signet ring adenocarcinomas more frequently metastasized within the peritoneum, bone and ovaries, and less frequently to the lungs and liver compared with generic adenocarcinoma. The liver and the peritoneum were commonly single metastases while lung metastases occurred frequently together with liver metastases. The median survival in metastatic gastric cancer was 3 months, worst among those with bone and liver metastases (2 months). Methods: A total of 7,559 patients with gastric cancer were identified. Metastatic patterns and survival depending on sex, age, stage, anatomical location (cardia and non-cardia), and histological type were assessed. Conclusions: The patterns of metastasis differ notably depending on histological type. Cardia cancer exhibits a completely different metastatic behavior than noncardia cancer. Awareness of the differing patterns may guide in tailored diagnosis of metastases. Survivors from cardia cancer would benefit from increased surveillance of extraperitoneal metastases. Bone metastases should be considered in patients with signet ring adenocarcinoma if symptoms emerge.
    Article · Aug 2016
  • Christoph Frank · Jan Sundquist · Akseli Hemminki · Kari Hemminki
    [Show abstract] [Hide abstract] ABSTRACT: Patient summary: It is known that prostate cancer runs in families, but it is not known whether other cancers are common in such families. We showed that at least breast, kidney, and nervous system tumors and myeloma occur more often than by chance.
    Article · Aug 2016 · European Urology
  • Ilkka Liikanen · S. Ta htinen · Kilian Guse · [...] · Akseli Hemminki
    [Show abstract] [Hide abstract] ABSTRACT: Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing tumors. Nevertheless, systemic antibody therapy is expensive, limited in efficacy due to physical tumor barriers, and carries the risk of severe side-effects such as cardiomyopathy. Oncolytic viruses mediate cancer-selective transgene expression, kill infected cancer cells while mounting antitumor immune responses, and have recently demonstrated promising efficacy in combination treatments. Here we armed an oncolytic adenovirus with full-length trastuzumab to achieve effective in situ antibody production coupled with progressive oncolytic cancer cell killing. We constructed an infectivity-enhanced serotype 5 oncolytic adenovirus Ad5/3-∆24-tras coding for human trastuzumab antibody heavy and light chain genes, connected by an internal ribosome entry site. Infected cancer cells were able to assemble full-length functional antibody, as confirmed by Western blot, ELISA, and antibody-dependent cell-mediated cytotoxicity assay. Importantly, oncolysis was required for release of the antibody into tumors, providing additional spatial selectivity. Ad5/3-∆24-tras showed potent in vitro cytotoxicity and enhanced anti-tumor efficacy over oncolytic control virus Ad5/3-∆24 or commercial trastuzumab in HER2-positive cancer models in vivo (both P<0.05). Furthermore, Ad5/3-∆24-tras resulted in significantly higher tumor-to-systemic antibody concentrations (P<0.001) over conventional delivery. Immunological analyses revealed dendritic cell activation and natural killer cell accumulation in tumor-draining lymph nodes. Thus, Ad5/3-∆24-tras is an attractive anticancer approach combining oncolytic immunotherapy with local trastuzumab production, resulting in improved in vivo efficacy and immune cell activation in HER2-positive cancer. Moreover, the finding that tumor cells can produce functional antibody as directed by oncolytic virus could lead to many valuable anti-tumor approaches.
    Article · Jul 2016 · Molecular Cancer Therapeutics
  • Matias Riihimäki · Akseli Hemminki · Jan Sundquist · Kari Hemminki
    [Show abstract] [Hide abstract] ABSTRACT: Investigating epidemiology of metastatic colon and rectal cancer is challenging, because cancer registries seldom record metastatic sites. We used a population based approach to assess metastatic spread in colon and rectal cancers. 49,096 patients with colorectal cancer were identified from the nationwide Swedish Cancer Registry. Metastatic sites were identified from the National Patient Register and Cause of Death Register. Rectal cancer more frequently metastasized into thoracic organs (OR = 2.4) and the nervous system (1.5) and less frequently within the peritoneum (0.3). Mucinous and signet ring adenocarcinomas more frequently metastasized within the peritoneum compared with generic adenocarcinoma (3.8 [colon]/3.2 [rectum]), and less frequently into the liver (0.5/0.6). Lung metastases occurred frequently together with nervous system metastases, whereas peritoneal metastases were often listed with ovarian and pleural metastases. Thoracic metastases are almost as common as liver metastases in rectal cancer patients with a low stage at diagnosis. In colorectal cancer patients with solitary metastases the survival differed between 5 and 19 months depending on T or N stage. Metastatic patterns differ notably between colon and rectal cancers. This knowledge should help clinicians to identify patients in need for extra surveillance and gives insight to further studies on the mechanisms of metastasis.
    Article · Jul 2016 · Scientific Reports
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    Matias Riihimäki · Akseli Hemminki · Jan Sundquist · Kari Hemminki
    Full-text Dataset · Jul 2016
  • Mikko Siurala · Riikka Havunen · Dipongkor Saha · [...] · Akseli Hemminki
    [Show abstract] [Hide abstract] ABSTRACT: Adoptive T-cell transfer is a promising treatment approach for metastatic cancer, but efficacy in solid tumors has only been achieved with toxic pre- and postconditioning regimens. Thus, adoptive T-cell therapies would benefit from complementary modalities that enable their full potential without excessive toxicity. We aimed to improve the efficacy and safety of adoptive T-cell transfer by using adenoviral vectors for direct delivery of immunomodulatory murine cytokines into B16.OVA melanoma tumors with concomitant T-cell receptor transgenic OT-I T-cell transfer. Armed adenoviruses expressed high local and low systemic levels of cytokine when injected into B16.OVA tumors, suggesting safety of virus-mediated cytokine delivery. Antitumor efficacy was significantly enhanced with adenoviruses coding for murine interleukin-2 (mIL-2) and tumor necrosis factor alpha (mTNFa) when compared with T-cell transfer alone or viruses alone. Further improvement in efficacy was achieved with a triple combination of mIL-2, mTNFa and OT-I T-cells. Mechanistic studies suggest that mIL-2 has an important role in activating T-cells at the tumor, while mTNFa induces chemokine expression. Furthermore, adenovirus treatments enhanced tumor-infiltration of OT-I T-cells as demonstrated by SPECT/CT imaging of (111)In-labelled cells. Our results suggest the utility of cytokine-coding adenoviruses for improving the efficacy of adoptive T-cell therapies.
    Article · Jun 2016 · Molecular Therapy
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    [Show abstract] [Hide abstract] ABSTRACT: Classically, anti-cancer therapies have always been applied with the primary aim of tumor debulking achieved through widespread induction of cancer cell death. While the role of host immune system is frequently considered as host protective in various (antigen-bearing) pathologies or infections yet in case of cancer overtime it was proposed that the host immune system either plays no role in therapeutic efficacy or plays a limited role that is therapeutically unemployable. The concept that the immune system is dispensable for the efficacy of anticancer therapies lingered on for a substantial amount of time; not only because evidence supporting the claim that anti-cancer immunity played a role were mainly contradictory, but also largely because it was considered acceptable (and sometimes still is) to test anticancer therapies in immunodeficient mice (i.e. SCID/athymic mice lacking adaptive immune system). This latter practice played a detrimental role in appreciating the role of anticancer immunity in cancer therapy. This scenario is epitomized by the fact that for a long time the very existence of cancer-associated antigens or cancer-associated ‘danger signaling’ remained controversial. However, over last several years this dogmatic view has been considerably modified. The existence of cancer-associated antigens and ‘danger signaling’ has been proven to be incontrovertible. These developments have together paved way for the establishment of the attractive concept of “immunogenic cell death” (ICD). It has been established that a restricted class of chemotherapeutics/targeted therapeutics, radiotherapy, photodynamic therapy and certain oncolytic viruses can induce a form of cancer cell death called ICD which is accompanied by spatiotemporally defined emission of danger signals. These danger signals along with other factors help cancer cells undergoing ICD to activate host innate immune cells, which in turn activate T cell-based immunity that helps eradicate live (or residual) surviving cancer cells. The emergence of ICD has been marred by some controversy. ICD has been criticized to be either experimental model or setting-specific or mostly a concept based on rodent studies that may have very limited implications for clinical application. However, in recent times it has emerged (through mainly retrospective or prognostic studies) that ICD can work in various human clinical settings hinting towards clinical applicability of ICD. However a widespread consensus on this issue is still transitional. In the current Research Topic we aimed to organize and intensify a discussion that strives to bring together the academic and clinical research community in order to provide a background to the current state-of-the-art in ICD associated bench-side research and to initiate fruitful discussions on present and future prospects of ICD translating towards the clinical, bedside reality.
    Full-text Book · Apr 2016
  • K. Taipale · I. Liikanen · A. Koski · [...] · A. Hemminki
    [Show abstract] [Hide abstract] ABSTRACT: The development of oncolytic viruses has recently made great progress towards being available to cancer patients. With the breakthrough into clinics, it is crucial to analyze the existing clinical experience and use it as a basis for treatment improvements. Here we report clinical data from 290 patients treated with oncolytic adenovirus. Using clinical variables and treatment characteristics, we constructed statistical models with regard to treatment response and overall survival. Additionally, we investigated effects of neutralizing antibodies, tumor burden and peripheral blood leucocyte counts on these outcomes. We found the absence of liver metastases to correlate with an improved rate of disease control (p=0.021). In multivariate evaluation, patients treated with viruses coding for immunostimulatory granulocyte macrophage colony-stimulating factor were linked to better prognosis (HR 0.378, p<0.001), as well as women with any cancer type (HR 0.694, p=0.017). In multivariate analysis for imaging response, patients treated via intraperitoneal injection were more likely to achieve disease control (OR 3.246, p=0.027). Patients with low neutrophil-to-lymphocyte ratio before treatment, had significantly longer overall survival (p<0.001). These findings could explain some of the variation seen in treatment outcomes after virotherapy. Furthermore, the results offer hypotheses for treatment optimization and patient selection in oncolytic adenovirus immunotherapy.Molecular Therapy (2016); doi:10.1038/mt.2016.67.
    Article · Apr 2016 · Molecular Therapy
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    [Show abstract] [Hide abstract] ABSTRACT: In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI) to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate—and eventually the long-lasting adaptive immunity against cancer.
    Full-text Article · Mar 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Cancer of unknown primary (CUP) is a fatal disease diagnosed through metastases. It shows intriguing familial clustering with certain defined primary cancers. Here we examine whether metastatic location in CUP patients is related to primary non-CUP cancers in relatives based on the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for CUP patients defined by metastatic location depending on cancer in their first degree relatives. SIRs for CUP were high in association with liver (3.94), ovarian (3.41), lung (2.43) and colorectal cancers (1.83) in relatives. The SIR was 1.63 for CUP with metastases in the abdomen when a relative was diagnosed with ovarian cancer. CUP with liver metastases associated with liver (1.44) cancer in relatives. CUP with head and neck region metastases associated with relatives’ esophageal (2.87) cancer. CUP metastases in the thorax associated with a relative’s cancers in the upper aerodigestive tract (2.14) and lung (1.74). The findings, matching metastatic location in CUP and primary cancer in relatives, could be reconciled if these cases of CUP constitute a phenotypically modified primary lacking tissue identification, resulting from epitope immunoediting. Alternatively, CUP metastases arise in a genetically favored tissue environment (soil) promoting growth of both primary cancers and metastases (seeds).
    Full-text Article · Mar 2016 · Scientific Reports
  • Mikko Siurala · Markus Vähä-Koskela · Riikka Havunen · [...] · Akseli Hemminki
    [Show abstract] [Hide abstract] ABSTRACT: Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown promising yet sometimes suboptimal results in clinical trials for advanced cancer, underscoring the need for approaches improving efficacy and safety. Six implantable syngeneic tumor cell lines of the Syrian hamster were used to initiate TIL cultures. TIL generated from tumor fragments cultured in human interleukin-2 (IL-2) for 10 days were adoptively transferred into tumor-bearing hamsters with concomitant intratumoral injections of oncolytic adenovirus (Ad5-D24) for the assessment of antitumor efficacy. Pancreatic cancer (HapT1) and melanoma (RPMI 1846) TIL exhibited potent and tumor-specific cytotoxicity in effector-to-target assays. MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, indicating cytotoxic CD8+ T-cell activity. When TIL were combined with Ad5-D24 in vitro, HapT1 tumor cell killing was significantly enhanced over single agents. In vivo, the intratumoral administration of HapT1 TIL and Ad5-D24 resulted in improved tumor growth control compared with either treatment alone. Additionally, splenocytes derived from animals treated with the combination of Ad5-D24 and TIL killed autologous tumor cells more efficiently than monotherapy-derived splenocytes, suggesting that systemic anti-tumor immunity was induced. For the first time, tumor-infiltrating lymphocytes of the Syrian hamster have been cultured, characterized and used therapeutically together with oncolytic adenovirus for enhancing the efficacy of TIL therapy. Our results support human translation of oncolytic adenovirus as an enabling technology for adoptive T-cell therapy of solid tumors.
    Article · Feb 2016 · OncoImmunology
  • Dataset · Jan 2016
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    Full-text Dataset · Jan 2016
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    Full-text Dataset · Jan 2016
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    [Show abstract] [Hide abstract] ABSTRACT: The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of so-called “damage/associated molecular patterns” (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical and clinical aspects of ICD, in an attempt to capture the essence of this clinically relevant phenomenon, and identify future challenges for this rapidly expanding field of investigation.
    Full-text Article · Nov 2015 · Frontiers in Immunology
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    Kristian Taipale · Ilkka Liikanen · Anniina Koski · [...] · Akseli Hemminki
    Full-text Article · Nov 2015
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    Siri Tähtinen · Susanna Grönberg-Vähä-Koskela · Dave Lumen · [...] · Akseli Hemminki
    Full-text Article · Nov 2015
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    Riikka Havunen · Mikko Siurala · Suvi Parviainen · [...] · Akseli Hemminki
    Full-text Article · Nov 2015

Publication Stats

12k Citations

Institutions

  • 2014
    • Mater Misericordiae University Hospital
      Dublin, Leinster, Ireland
  • 2007
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2003
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 1997-2001
    • University of Helsinki
      • Department of Medical Genetics
      Helsinki, Uusimaa, Finland