Publications by authors named "Otto Hemminki"

32 Publications

Oncolytic Adenovirus Type 3 Coding for CD40L Facilitates Dendritic Cell Therapy of Prostate Cancer in Humanized Mice and Patient Samples.

Hum Gene Ther 2021 Feb 22;32(3-4):192-202. Epub 2021 Jan 22.

Cancer Gene Therapy Group, Translational Immunology Research Program and Department of Oncology, University of Helsinki, Helsinki, Finland.

Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment by expressing CD40L. Activated DCs would then activate cytotoxic T cells against the tumor, resulting in therapeutic immune responses. Oncolytic cell killing due to cancer cell-specific virus replication adds to antitumor effects but also enhances the immunological effect by releasing tumor epitopes for sampling by DC, in the presence of danger signals. In this study, we evaluated the companion effect of Ad3-hTERT-CMV-hCD40L and DC-therapy in a humanized mouse model and PC histocultures. Treatment with Ad3-hTERT-CMV-hCD40L and DC resulted in enhanced antitumor responses . Treatment of established histocultures with Ad3-hTERT-CMV-hCD40L induced DC maturation and notable increase in proinflammatory cytokines. In conclusion, Ad3-hTERT-CMV-hCD40L is able to modulate an immunosuppressive prostate tumor microenvironment and improve the effectiveness of DC vaccination in PC models and patient histocultures, setting the stage for clinical translation.
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http://dx.doi.org/10.1089/hum.2020.222DOI Listing
February 2021

Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition.

Oncoimmunology 2020 05 22;9(1):1761229. Epub 2020 May 22.

Cancer Gene Therapy Group, Translational Immunology Research Program and Department of Oncology, University of Helsinki, Helsinki, Finland.

Checkpoint inhibitors have revolutionized cancer therapy and validated immunotherapy as an approach. Unfortunately, responses are seen in a minority of patients. Our objective is to use engineered adenoviruses designed to increase lymphocyte trafficking and cytokine production at the tumor, to assess if they increase the response rate to checkpoint inhibition, as these features have been regarded as predictive for the responses. When Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (an oncolytic adenovirus coding for TNFa and IL-2, also known as TILT-123) and checkpoint inhibitors were used together in fresh urological tumor histocultures, a significant shift toward immune activity (not only tumor necrosis alpha and interleukin-2 but also interferon gamma and granzyme B) and increased T-cell trafficking signals (CXCL10) was observed. , our viruses enabled an anti-PD-L1 (a checkpoint inhibitor) delivering complete responses in all the treated animals (hazard ratios versus anti-PD-L1 alone 0.057 [0.007; 0.451] or virotherapy alone 0.067 [0.011; 0.415]). To conclude, when an engineered oncolytic adenovirus was utilized to modify the tumor microenvironment towards what meta-analyses have pointed as predictive markers for checkpoint inhibitory therapy, the response to them increased synergistically. Of note, key findings were confirmed in fresh patient-derived tumor explants.
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http://dx.doi.org/10.1080/2162402X.2020.1761229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458667PMC
May 2020

Oncolytic viruses for cancer immunotherapy.

J Hematol Oncol 2020 06 29;13(1):84. Epub 2020 Jun 29.

Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.

In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains.As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors.Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.
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http://dx.doi.org/10.1186/s13045-020-00922-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325106PMC
June 2020

Impact noise of prostate biopsy devices.

Scand J Urol 2020 Apr 5;54(2):175-178. Epub 2020 Feb 5.

Department, of Otorhinolaryngology, Helsinki University Hospital, Helsinki, Finland.

To analyse the impact noise generated by prostate biopsy devices. In a laboratory setting, repeated impact noise was recorded at distances of 50 cm and 100 cm using five brands of device on chicken meat, an apple and an empty target. In a clinical setting, the impact noise levels of prostate biopsy devices were recorded in 40 real patient cases using three brands of device. In the laboratory setting, the average SPL (sound pressure level) peak level ranged from 104.3 to 121.3 dB. The highest impact noise levels were measured with the Monopty device, ranging from 114.8 to 122.4 dB. In the clinical setting, there were no statistical differences between repeated SPL values for each specific target. Also, the noise levels were equal when the same device brand was used at 50 cm and 100 cm. The highest SPLs were recorded with the Monopty device, which ranged from 110 to 127 dB. The corresponding values for the Max-Core and Multicore were from 106 to 122.5 dB and from 108 to 116.5 dB, respectively. Biopsy devices generate high peak levels of impact noise. Personnel performing biopsies are advised to consider using hearing protection, even though the impact noise may not induce permanent hearing loss.
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http://dx.doi.org/10.1080/21681805.2020.1716068DOI Listing
April 2020

Comparison of Familial Clustering of Anogenital and Skin Cancers Between In Situ and Invasive Types.

Sci Rep 2019 11 6;9(1):16151. Epub 2019 Nov 6.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany.

Literature on familial risk of carcinomas in situ (CISs) is limited because many cancer registries do not collect information on CIS. In Sweden CISs are collected, and we used these data to analyze familial relative risks (RRs) for concordant (CIS-CIS) types of anogenital (cervical, other female and male genital and anal) and skin squamous cell CIS; additionally RRs were assessed between CIS types and between CIS and invasive forms. RRs were calculated for the offspring generations when family members were diagnosed CIS. Case numbers for CIS ranged from 330 in anal to 177,285 in cervical CIS. Significant concordant CIS-CIS RRs were 2.74 for female genital, 1.77 for cervical and 2.29 for SCC skin CISs. The CIS forms associated also with each other, except for cervical and skin CIS types. RRs for concordant CIS-invasive cancer associations were lower than CIS-CIS associations. Cervical CIS associated with non-Hodgkin CIS which may suggest immune dysfunction as a contributing factors. The results for anogenital CIS types suggest that life style related human papilloma virus infections contributed to the observed familial associations. Lower risks for CIS-invasive cancer than CIS-CIS suggest that CIS and invasive cancers share only partially risk factors that underlie familial clustering.
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http://dx.doi.org/10.1038/s41598-019-51651-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834624PMC
November 2019

Familial Clustering, Second Primary Cancers and Causes of Death in Penile, Vulvar and Vaginal Cancers.

Sci Rep 2019 08 14;9(1):11804. Epub 2019 Aug 14.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany.

Data on familial risks in penile and vulvar/vaginal cancers and in second primary cancers (SPCs) following these cancers are limited. We used the Swedish Family-Cancer Database from years 1958 through 2015 to identify 3641 penile and 8856 vulvar/vaginal cancers and to calculate relative risks (RRs) and 95% confidence intervals (CIs) for these cancers according to site-specific cancer in family members; additionally risk for SPCs was calculated. The familial RR for concordant (same) penile cancer was 3.22 (1.34-7.74), and it was 2.72 (1.69-4.39) for vulvar/vaginal cancer; RRs were increased for vulvar/vaginal cancer in families of anal cancer patients. RR for second penile cancer after penile cancers was 11.68 (7.95-17.18), while that for concordant vulvar/vaginal cancer was 9.03 (7.31-11.15). SPCs were diagnosed in 16.8% of penile cancer patients and in them 45.9% of deaths were caused by SPC (other than penile cancer). In vulvar/vaginal cancer patients with SPC, 36.4% of deaths were due to SPC. The results showed that these genital cancers might run in families and as SPCs are associated with human papilloma virus and smoking related cancers. Risk for these genital and anal SPCs are high and a follow-up plan should be agreed at diagnosis of these cancers.
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http://dx.doi.org/10.1038/s41598-019-48399-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694134PMC
August 2019

Familial Urinary Bladder Cancer with Other Cancers.

Eur Urol Oncol 2018 12 30;1(6):461-466. Epub 2018 Jun 30.

Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany; Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Family risks for urinary tract cancers (excluding kidney cancers) are known, but less is known about whether rare urinary tract cancer subtypes are also familial and if urinary tract cancers share familial risk for other (discordant) cancers.

Objective: To investigate the impact of family history on urinary tract cancers (International Classification of Diseases version 7 code 181) and discordant cancers.

Design, Setting, And Participants: The Swedish Family-Cancer Database, the largest family data set in the world, was used to assess familial risks between 86 058 patients with urinary tract cancers and patients with other cancers between 1958 and 2015.

Outcome Measurements And Statistical Analysis: A Poisson regression model was used to generate relative risks (RRs).

Results And Limitations: Some 7.0% of patients with urinary tract cancers had a parent or sibling diagnosed with the same cancer, yielding an RR of 1.81 (95% confidence interval [CI] 1.68-1.94). As novel familial findings, we also found that ureter (RR 1.62, 95% CI 1.04-2.53) and transitional cell in situ tumors (RR 2.04, 95% CI 1.49-2.80) were associated with urinary tract cancers. The most consistent discordant familial associations of urinary tract cancers were with smoking-related sites of cancer: lung, stomach, and kidney. Internally consistent familial associations not related to smoking were found for endometrial and thyroid cancers. Familial associations with urinary tract cancers were also found for rare anal, female genital, and cervical cancers. The main limitation was a lack of data on smoking.

Conclusions: Smoking-related cancers were associated with urinary tract cancer. We speculate that familial clustering of endometrial and thyroid cancers with urinary tract cancers may be ascribed to obesity.

Patient Summary: Diagnosis of bladder cancer in a close family member may be a sign of higher risk among other family members. Patients and family members should be told that bladder cancer is smoking-related and they should be counseled to recognize blood in urine as a possible early sign.
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http://dx.doi.org/10.1016/j.euo.2018.06.002DOI Listing
December 2018

Second cancers and causes of death in patients with testicular cancer in Sweden.

PLoS One 2019 28;14(3):e0214410. Epub 2019 Mar 28.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

While treatment for testicular cancer (TC) has become standardized after the 1980s with an associated significant improvement in patient survival, this has been accompanied by an increased risk of second primary cancers (SPCs). Patients were identified from the Swedish Cancer Registry spanning the years from 1980 to 2015, including 8788 individuals with primary TC and their SPCs. Relative risks (RRs) for SPC were calculated using the generalized Poisson regression model. SPCs were diagnosed in 9.4% of patients with TC and half of them were late onset cancers not common in the population in their 40s. Overall RR of SPCs (excluding second TC) was 1.30 (95%CI: 1.20-1.40), including high risks for seven solid cancers, non-Hodgkin lymphoma and leukemia. Second TC was the most common SPC and the RR of 17.19 (95%CI: 14.89-19.85) was the highest recorded. Cancers known to be fatal as first primary cancers were also fatal as SPC in TC patients. Survival at 30 years of follow-up was approximately 80% for TC patients without SPC but it decreased to 40% for patients with SPC. The unexpected finding that half of the identified SPCs were typical late onset cancers in the middle-aged population raises concerns that therapy may facilitate premature aging. The risks of SPC are clinically important for the long-term management of TC patients and the high-mortality calls for a future management strategy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214410PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438485PMC
December 2019

Effect of Genetic Modifications on Physical and Functional Titers of Adenoviral Cancer Gene Therapy Constructs.

Hum Gene Ther 2019 06 28;30(6):740-752. Epub 2019 Feb 28.

1 Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.

After the discovery and characterization of the adenovirus in the 1950s, this prevalent cause of the common cold and other usually mild diseases has been modified and utilized in biomedicine in several ways. To date, adenoviruses are the most frequently used vectors and therapeutic (, oncolytic) agents with a number of beneficial features. They infect both dividing and nondividing cells, enable high-level, transient protein expression, and are easy to amplify to high concentrations. As an important and versatile research tool, it is of essence to understand the limits and advantages that genetic modification of adenovirus vectors may entail. Therefore, a retrospective analysis was performed of adenoviral gene therapy constructs produced in the same laboratory with similar methods. The aim was to assess the impact of various modifications on the physical and functional titer of the virus. It was found that genome size (designed within "the 105% golden rule") did not significantly affect the physical titer of the adenovirus preparations, regardless of the type of transgene (, immunostimulatory vs. other), number of engineered changes, and size of the mutated virus genome. One statistically significant exception was noted, however. Chimeric adenoviruses (5/3) had a slightly lower physical titer compared to Ad5-based viruses, although a trend for the opposite was true for functional titers. Thus, 5/3 chimeric viruses may in fact be appealing from a safety versus efficacy viewpoint. Armed viruses had lower functional and physical titers than unarmed viruses, while five genomic modifications started to decrease functional titer. Importantly, even highly modified armed viruses generally had good titers compatible with clinical testing. In summary, this paper shows the plasticity of adenovirus for various vector, oncolytic, and armed oncolytic uses. These results inform future generations of adenovirus-based drugs for human use. This information is directly transferable to academic laboratories and the biomedical industry involved in vector design and production optimization.
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http://dx.doi.org/10.1089/hum.2018.240DOI Listing
June 2019

CD40L coding oncolytic adenovirus allows long-term survival of humanized mice receiving dendritic cell therapy.

Oncoimmunology 2018;7(10):e1490856. Epub 2018 Aug 15.

Cancer Gene Therapy Group, University of Helsinki, Helsinki, Finland.

Dendritic cells (DCs) are crucial players in promoting immune responses. Logically, adoptive DC therapy is a promising approach in cancer immunotherapy. One of the major obstacles in cancer immunotherapy in general is the immunosuppressive tumor microenvironment, which hampers the maturation and activation of DCs. Therefore, human clinical outcomes with DC therapy alone have been disappointing. In this study, we use fully serotype 3 oncolytic adenovirus Ad3-hTERT-CMV-hCD40L, expressing human CD40L, to modulate the tumor microenvironment with subsequently improved function of DCs. We evaluated the synergistic effects of Ad3-hTERT-CMV-hCD40L and DCs in the presence of human peripheral blood mononuclear cells and . Tumors treated with Ad3-hTERT-CMV-hCD40L and DCs featured greater antitumor effect compared with unarmed virus or either treatment alone. 100% of humanized mice survived to the end of the experiment, while mice in all other groups died by day 88. Moreover, adenovirally-delivered CD40L induced activation of DCs, leading to induction of Th1 immune responses. These results support clinical trials with Ad3-hTERT-CMV-hCD40L in patients receiving DC therapy.
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http://dx.doi.org/10.1080/2162402X.2018.1490856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207416PMC
August 2018

Prostate cancer survivors: Risk and mortality in second primary cancers.

Cancer Med 2018 11 1;7(11):5752-5759. Epub 2018 Oct 1.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

To assess etiological and clinical consequences of second primary cancers (SPCs) in prostate cancer (PC) patients, we followed newly diagnosed patients to identify men who were diagnosed with a SPC and recorded their causes of death. We used the Swedish Family-Cancer Database to assess relative risks (RRs) and causes of death in SPCs until the year 2015 in patients with a PC diagnosis between 2001 and 2010. Among a total of 4.26 million men, 76 614 were diagnosed with PC at the median age of 71 years. Among them, 8659 (11.3%) received a subsequent diagnosis of SPC after a median follow-up of 4 years. The most common SPCs were colorectal, skin, bladder, and lung cancers, melanoma, and non-Hodgkin lymphoma. The ranking was almost identical with first cancers among elderly men in Sweden. The RR for SPCs in prostate-specific antigen-detected PC was approximately equal to RR in other PC. Mortality patterns of PC patients were distinct depending on the presence or absence of SPC. Among patients with SPC, 47.8% died as a result of the corresponding SPC, followed by other causes (22.2%) and PC (18.1%). For patients without SPC, PC and non-neoplastic causes almost matched each other as the main causes of death (48.5% and 47.8%). The results suggest that SPCs appear autonomous from primary PC and reflect incidence and mortality of first cancers in general. SPC was the most common cause of death in patients with SPC; close to half of the patients died due to SPC. For improved survival in PC patients, prevention and early detection of SPCs would be important, and the present results suggest that risk factors for SPC in PC are the same as those for first cancer in general.
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http://dx.doi.org/10.1002/cam4.1764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246949PMC
November 2018

Impact of family history of cancer on risk and mortality of second cancers in patients with prostate cancer.

Prostate Cancer Prostatic Dis 2019 03 5;22(1):143-149. Epub 2018 Sep 5.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany.

Background: Survival rates are increasing in patients with prostate cancer, and second primary cancers (SPCs) are becoming more common in these patients. However, the etiology and clinical consequences of SPCs are not well-known. We define the impact of family history on SPC and causes of mortality in these patients.

Patients And Methods: A nation-wide cohort study based on the Swedish Family-Cancer Database covering 4.4 million men and 80,449 prostate cancers diagnosed between 1990 and 2015. Relative risks (RRs) and cumulative incidence for SPCs and for familial SPC were calculated for prostate cancer patients.

Results: SPC was diagnosed in 6,396 men and more than a third of these patients had a first-degree family history of any cancer; the familial risk was 1.37 (95% CI: 1.27-1.40), compared to 1.10 (1.08-1.16), without a family history. Cumulative incidence by the age of 83 years reached 21% for prostate cancer alone, 28% in those with SPC, and 35% in patients with SPC and family history. Family history was associated with the risk of seven specific SPCs, including colorectal, lung, kidney, bladder and skin (both melanoma and squamous cell) cancers, and leukemia. Colorectal and lung cancers were common SPCs, and family history doubled the risk of these SPCs. In patients with SPC, half of all causes of death were due to SPC and only 12.77% were due to prostate cancer. Most deaths in SPC were caused by lung and colorectal cancers.

Conclusions: SPCs were an important cause of death in patients with prostate cancer and family history was an important risk factor for SPCs. Prevention of SPC should be essential when prostate cancer survival rates are being improved and this could start by conducting a thorough assessment of family history at the time of prostate cancer diagnosis.
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http://dx.doi.org/10.1038/s41391-018-0089-yDOI Listing
March 2019

Familial Associations in Testicular Cancer with Other Cancers.

Sci Rep 2018 Jul 18;8(1):10880. Epub 2018 Jul 18.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany.

Familial risks for testicular cancer (TC) are among the highest of all cancers. However, data are limited for histological types of TC and for possible familial associations of TC with other cancers. We used the nationwide Swedish Family-Cancer Database for years 1958 to 2015 to analyse familial relative risks (RR) for 11,138 TC patients when first-degree relatives were diagnosed with TC or other cancer in reference to those without a family history. A total of 191 familial TCs were found, which accounted for 2.0% of all TC. The RR was 5.06 when one family member was diagnosed with TC with no significant difference between seminoma and nonseminoma. However, the risk for nonseminoma was 33.59 when two family members were affected. Internally consistent familial associations of TC, particularly of seminoma, were found with breast and nervous system cancers and melanoma. Individual significant associations were found for a number of sites, including ovarian, endometrial and prostate cancers. Our results suggest that nonseminoma may have a stronger genetic background than seminoma but seminoma shares more familial associations with discordant cancers. Clustering of TC with hormone-dependent cancers of the breast, ovary, endometrium and prostate may suggest mechanistic links and possibly gene-environment interactions.
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http://dx.doi.org/10.1038/s41598-018-28819-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052159PMC
July 2018

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

Mol Ther Oncolytics 2018 Jun 22;9:41-50. Epub 2018 Apr 22.

Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

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-8], HMGB1, anti-viral 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.
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http://dx.doi.org/10.1016/j.omto.2018.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035494PMC
June 2018

Familial risks in and between stone diseases: sialolithiasis, urolithiasis and cholelithiasis in the population of Sweden.

BMC Nephrol 2018 07 3;19(1):158. Epub 2018 Jul 3.

Center for Primary Health Care Research, Lund University, 205 02, Malmö, Sweden.

Background: According to the literature the three stone diseases, sialolithiasis (SL), urolithiasis (UL) and cholelithiasis (CL) share comorbidities. We assess familial and spouse risks between these stone disease and compare them to familial risks for concordant (same) stone disease.

Methods: Study population including familiar relationships was obtained from the Swedish Multigeneration Register and stone disease patients were identified from nation-wide medical records. Standardized incidence ratios (SIRs) were calculated for 0-83 year old offspring when their first-degree relatives were diagnosed with stone disease and the rates were compared to individuals without a family history of stone disease. Numbers of offspring with SL were 7906, for UL they were 170,757 and for CL they were 204,369.

Results: SIRs for concordant familial risks were 2.06 for SL, 1.94 for UL and 1.82 for CL. SIRs for SL and UL were slightly higher for women than for men. Familial risks between stone diseases were modest. The highest risk of 1.17 was for UL when family members were diagnosed with CL, or vice versa. The SIR for UL was 1.15 when family members were diagnosed with SL. Familial risks among spouses were increased only for UL-CL pairs (1.10).

Conclusions: Familial risks for concordant SL were 2.06 and marginally lower for the other diseases. Familial risks between stone diseases were low but higher than risks between spouses. The data show that familial clustering is unique to each individual stone disease which would imply distinct disease mechanisms. The results cast doubt on the reported comorbidities between these diseases.
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http://dx.doi.org/10.1186/s12882-018-0945-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029375PMC
July 2018

RE: Familial Cancer Clustering of Urothelial Cancer: A Population-Based Case-Control Study.

J Natl Cancer Inst 2018 11;110(11):1277-1278

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

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http://dx.doi.org/10.1093/jnci/djy053DOI Listing
November 2018

Familial Risks Between Urolithiasis and Cancer.

Sci Rep 2018 02 15;8(1):3083. Epub 2018 Feb 15.

Center for Primary Health Care Research, Lund University, 205 02, Malmö, Sweden.

Urolithiasis (UL, urinary tract stone disease) has been reported to increase subsequent cancers in the urinary tract. Recently, we showed data that surveillance bias may be an important confounder in the reported associations. In the present approach we want to address the question of possible cancer risk posed by UL mechanistically. Both UL and cancer have strong genetic components and we hypothesize that familial association between UL and cancer may be plausible. We thus assess familial risks between UL and cancer, hoping to find an explanation why UL may pose a risk of cancer. UL patients were identified from hospital inpatient and outpatient records and they were organized in families based on the Multigeneration Register into which also national cancer data were linked. Standardized incidence ratios were calculated for cancer in the offspring generation when parents were diagnosed with UL, and conversely for UL when parents were diagnosed with cancer. Familial risks between UL and cancer were generally small and inconsistent providing no convincing support of genetic sharing between UL and cancer. However, bladder UL was associated weakly with prostate cancer, and ureter and bladder UL were associated with salivary gland cancer. Potential mechanisms for these findings are proposed.
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http://dx.doi.org/10.1038/s41598-018-21410-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814449PMC
February 2018

Familial risks for gallstones in the population of Sweden.

BMJ Open Gastroenterol 2017 29;4(1):e000188. Epub 2017 Dec 29.

Center for Primary Health Care Research, Lund University, Helsinki, Finland.

Objectives: Gallstone disease (cholelithiasis) has a familial component, but detailed data on the modification of familial risk are lacking. Using nationwide hospital and population records, we aimed to determine detailed familial risks for medically diagnosed gallstone disease.

Design: Subjects were obtained from the Multigeneration Register, which contains family data on the Swedish population, and patients with gallstone disease were identified from the Hospital Discharge Register (1964-2015) and the Outpatient Register (2001-2015). Standardised incidence ratios (SIRs) were calculated as the ratio of observed to expected number of cases.

Results: Gallstone disease was diagnosed in 660 732 patients, with an overall incidence of 131 per 100 000 person-years. Familial cases accounted for 36.0% of all patients with gallstone disease. Of these, 50.9% had a parental family history (SIR 1.62), 35.1% had a sibling history (SIR 1.75) and 14.0% had a parental+sibling history (SIR 2.58). Among a total of 54 630 affected siblings, 84.4% were sibling pairs (SIR 1.55). However, the remaining 15.6% of the affected siblings constituted the high-risk group of multiple affected siblings and an SIR >10; these persons accounted for 7.7% of all familial cases. The spousal risk was only slightly increased to 1.18.

Conclusions: Overall, the results point to the underlying genetic causes for the observed familial clustering, which may involve polygenic gene-environmental interactions for most familial cases but high-risk genes in close to 10% of cases. Family histories should be taken into account in the medical setting and used for counselling of at-risk individuals.
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http://dx.doi.org/10.1136/bmjgast-2017-000188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759740PMC
December 2017

Familial risks in urolithiasis in the population of Sweden.

BJU Int 2018 03 14;121(3):479-485. Epub 2018 Jan 14.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Objective: To assess detailed familial risks for medically diagnosed urolithiasis (UL, urinary tract stone disease) based on nationwide hospital and population records.

Patients/subjects And Methods: Subjects were identified from the Swedish Multigeneration Register in which there were 211 718 patients with UL. Standardised incidence ratios (SIRs) were calculated by comparison to individuals without a family history of UL.

Results: The highest familial SIRs were invariably found for the same (concordant) type of UL: 2.18 for kidney, 2.20 for ureter, and 1.93 for bladder. SIRs increased from 1.84, when one parent was affected, to 3.54 when both parents were affected, which was a multiplicative interaction. The SIR was 1.79 when one sibling was affected but it increased to 24.91 when two siblings were affected. Such excessive risks (5.2% of familial cases) are probably explained by high-penetrant genes. A low SIR of 1.29 between spouses suggested a minor contribution by shared environmental factors on the familial risk.

Conclusions: The results point to underlying genetic causes for the observed familial clustering and establish the genetic landscape of UL. Family histories should be taken in UL diagnostics and prevention could follow guidelines recommended for recurrent UL.
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http://dx.doi.org/10.1111/bju.14096DOI Listing
March 2018

Surveillance Bias in Cancer Risk After Unrelated Medical Conditions: Example Urolithiasis.

Sci Rep 2017 08 14;7(1):8073. Epub 2017 Aug 14.

Center for Primary Health Care Research, Lund University, 205 02, Malmö, Sweden.

We analysed cancer risks in patients with urinary tract stones but some features of the generated results alarmed us about possible surveillance bias, which we describe in this report. We used nationwide Swedish hospital records to identify patients with urinary tract stones (N = 211,718) and cancer registration data for cancer patients for years 1987 to 2012. Standardized incidence ratios (SIRs) for cancer were calculated after the last medical contact for urinary tract stones. All cancers were increased after kidney (SIR 1.54, 95%CI: 1.50-1.58), ureter (1.44, 1.42-1.47), mixed (1.51, 1.44-1.58) and bladder stones (1.63, 1.57-1.70). The risk of kidney cancer was increased most of all cancers after kidney, ureter and mixed stones while bladder cancer was increased most after bladder stones. All SIRs decreased steeply in the course of follow-up time. Tumour sizes were smaller in kidney cancer and in situ colon cancers were more common in patients diagnosed after urinary tract stones compared to all patients. The results suggest that surveillance bias influenced the result which somewhat surprisingly appeared to extend past 10 years of follow-up and include cancers at distant anatomical sites. Surveillance bias may be difficult to avoid in the present type of observational studies in clinical settings.
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http://dx.doi.org/10.1038/s41598-017-08839-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556042PMC
August 2017

Cancer-Targeted Oncolytic Adenoviruses for Modulation of the Immune System.

Curr Cancer Drug Targets 2018 ;18(2):124-138

Cancer Gene Therapy Group, Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.

Adenovirus is one of the most commonly used vectors for gene therapy and it is the first approved virus-derived drug for treatment of cancer. As an oncolytic agent, it can induce lysis of infected cells, but it can also engage the immune system, promoting activation and maturation of antigen- presenting cells (APCs). In essence, oncolysis combined with the associated immunostimulatory actions result in a "personalized in situ vaccine" for each patient. In order to take full advantage of these features, we should try to understand how adenovirus interacts with the immune system, what are the receptors involved in triggering subsequent signals and which kind of responses they elicit. Tackling these questions will give us further insight in how to manipulate adenovirus-mediated immune responses for enhancement of anti-tumor efficacy. In this review, we first highlight how oncolytic adenovirus interacts with the innate immune system and its receptors such as Toll-like receptors, nucleotide-binding and oligomerization domain (NOD)- like receptors and other immune sensors. Then we describe the effect of these interactions on the adaptive immune system and its cells, especially B and T lymphocytes. Finally, we summarize the most significant preclinical and clinical results in the field of gene therapy where researchers have engineered adenovirus to manipulate the host immune system by expressing cytokines and signalingmediators.
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http://dx.doi.org/10.2174/1568009617666170502152352DOI Listing
May 2019

Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy.

Oncoimmunology 2017;6(2):e1265717. Epub 2016 Dec 7.

Cancer Gene Therapy Group, Department of Oncology, University of Helsinki, Helsinki, Finland; TILT Biotherapeutics Ltd, Helsinki, Finland; Helsinki University Comprehensive Cancer Center, Helsinki, Finland.

Vaccination with dendritic cells (DCs), the most potent professional antigen-presenting cells in the body, is a promising approach in cancer immunotherapy. However, tumors induce immunosuppression in their microenvironment that suppresses and impairs the function of DCs. Therefore, human clinical trials with DC therapy have often been disappointing. To improve the therapeutic efficacy and to overcome the major obstacles of DC therapy, we generated a novel adenovirus, Ad3-hTERT-CMV-hCD40L, which is fully serotype 3 and expresses hCD40L for induction of antitumor immune response. The specific aim is to enhance DCs function. Data from a human cancer patient indicated that this capsid allows effective transduction of distant tumors through the intravenous route. Moreover, patient data suggested that virally produced hCD40L can activate DCs . The virus was efficient and had potent antitumor activity In a syngeneic model, tumors treated with Ad5/3-CMV-mCD40L virus plus DCs elicited greater antitumor effect as compared with either treatment alone. Moreover, virally coded CD40L induced activation of DCs, which in turn, lead to the induction of a Th1 immune response and increased tumor-specific T cells. In conclusion, Ad3-hTERT-CMV-hCD40L is promising for translation into human trials. In particular, this virus could enable successful dendritic cell therapy in cancer patients.
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http://dx.doi.org/10.1080/2162402X.2016.1265717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353943PMC
December 2016

The Incidence of Senile Cataract and Glaucoma is Increased in Patients with Plasma Cell Dyscrasias: Etiologic Implications.

Sci Rep 2016 06 22;6:28500. Epub 2016 Jun 22.

Center for Primary Health Care Research, Lund University, 205 02 Malmö, Sweden.

Plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenström macroglobulinemia (WM) and light chain AL amyloidosis, are characterized by clonal expansion of plasma cells which produce a vast amount of an immunoglobulin-derived M-protein. We noted that MGUS diagnosis often coincided with diagnoses of senile cataract and glaucoma and tested the associations of MGUS, MM, WM and AL amyloidosis with subsequent eye diseases identified from the Swedish patient registers between 1997 and 2012. Standardized incidence ratios (SIRs) for senile cataract was significantly increased to 1.80 after MGUS, 1.70 after MM, 1.85 after WM and 2.31 after AL amyloidosis. The SIR for glaucoma was 1.60 after MGUS, 1.76 after WM and 2.18 after AL amyloidosis. All SIRs decreased systematically from age below 60 years to over 79 years, but most risks were also significant in age group over 79 years. The M-protein and the related increase in blood viscosity could be a novel etiologic discovery for these common eye diseases. As MGUS prevalence is around 3% at 60 years and close to 10% at age over 80 years, its contribution to the eye disease burden is expected to be remarkably high.
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http://dx.doi.org/10.1038/srep28500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916420PMC
June 2016

Predictive and Prognostic Clinical Variables in Cancer Patients Treated With Adenoviral Oncolytic Immunotherapy.

Mol Ther 2016 08 4;24(7):1323-32. Epub 2016 Apr 4.

Cancer Gene Therapy Group, University of Helsinki, Faculty of Medicine, Helsinki, Finland.

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 (OS). 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 (hazard ratio (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 (odds ratio (OR) 3.246, P = 0.027). Patients with low neutrophil-to-lymphocyte ratio before treatment had significantly longer OS (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.
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http://dx.doi.org/10.1038/mt.2016.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088758PMC
August 2016

Serum HMGB1 is a predictive and prognostic biomarker for oncolytic immunotherapy.

Oncoimmunology 2015 Mar 2;4(3):e989771. Epub 2015 Apr 2.

Transplantation laboratory; Cancer Gene Therapy Group (CGTG); Haartman Institute; University of Helsinki ; Helsinki, Finland ; TILT Biotherapeutics Ltd. ; Helsinki, Finland.

With the emergence of effective immunotherapeutics, which nevertheless harbor the potential for toxicity and are expensive to use, biomarkers are urgently needed for identification of cancer patients who respond to treatment. In this clinical-epidemiological study of 202 cancer patients treated with oncolytic adenoviruses, we address the biomarker value of serum high-mobility group box 1 (HMGB1) protein. Overall survival and imaging responses were studied as primary endpoints and adjusted for confounding factors in two multivariate analyses (Cox and logistic regression). Mechanistic studies included assessment of circulating tumor-specific T-cells by ELISPOT, virus replication by quantitative PCR, and inflammatory cytokines by cytometric bead array. Patients with low HMGB1 baseline levels (below median concentration) showed significantly improved survival ( = 0.008, Log-Rank test) and radiological disease control rate (49.2% 30.0%, = 0.038, χ test) as compared to high-baseline patients. In multivariate analyses, the low HMGB1 baseline status was a strong prognostic (HR 0.638, 95% CI 0.462-0.881) and the best predictive factor for disease control (OR 2.618, 95% CI 1.004-6.827). Indicative of an immune-mediated mechanism, antitumor T-cell activity in blood and response to immunogenic-transgene coding viruses associated with improved outcome only in HMGB1-low patients. Our results suggest that serum HMGB1 baseline is a useful prognostic and predictive biomarker for oncolytic immunotherapy with adenoviruses, setting the stage for prospective clinical studies.
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http://dx.doi.org/10.4161/2162402X.2014.989771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404794PMC
March 2015

Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM-CSF: Results in vitro, in rodents and in humans.

Int J Cancer 2015 Oct 11;137(7):1775-83. Epub 2015 Apr 11.

Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory and Haartman Institute, University of Helsinki, Finland.

Metastatic melanoma is refractory to irradiation and chemotherapy, but amenable to immunological approaches such as immune-checkpoint-inhibiting antibodies or adoptive cell therapies. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Therefore, oncolytic immuno-virotherapy of malignant melanoma is an appealing approach, which was recently validated by a positive phase 3 trial. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a panel of melanoma cell lines and animal models, and summarized the melanoma-specific human data from the Advanced Therapy Access Program (ATAP). The virus effectively eradicated human melanoma cells in vitro and subcutaneous SK-MEL-28 melanoma xenografts in nude mice when combined with low-dose cyclophosphamide. Furthermore, virally-expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated the differentiation of human monocytes into macrophages. In contrast to human cells, RPMI 1846 hamster melanoma cells exhibited no response to oncolytic viruses and the chimeric 5/3 fiber failed to increase the efficacy of transduction, suggesting limited utility of the hamster model in the context of viruses with this capsid. In ATAP, treatments appeared safe and well-tolerated. Four out of nine melanoma patients treated were evaluable for possible therapy benefit with modified RECIST criteria: one patient had minor response, two had stable disease, and one had progressive disease. Two patients were alive at 559 and 2,149 days after treatment. Ad5/3-D24-GMCSF showed promising efficacy in preclinical studies and possible antitumor activity in melanoma patients refractory to other forms of therapy. This data supports continuing the clinical development of oncolytic adenoviruses for treatment of malignant melanoma.
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http://dx.doi.org/10.1002/ijc.29536DOI Listing
October 2015

Immunological data from cancer patients treated with Ad5/3-E2F-Δ24-GMCSF suggests utility for tumor immunotherapy.

Oncotarget 2015 Feb;6(6):4467-81

Cancer Gene Therapy Group, Transplantation Laboratory & Haartman Institute, University of Helsinki, Helsinki, Finland.

Oncolytic viruses that selectively replicate in tumor cells can be used for treatment of cancer. Accumulating data suggests that virus induced oncolysis can enhance anti-tumor immunity and break immune tolerance. To capitalize on the immunogenic nature of oncolysis, we generated a quadruple modified oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor (GMCSF). Ad5/3-E2F-Δ24-GMCSF (CGTG-602) was engineered to contain a tumor specific E2F1 promoter driving an E1 gene deleted at the retinoblastoma protein binding site ("Δ24"). The fiber features a knob from serotype 3 for enhanced gene delivery to tumor cells. The virus was tested preclinically in vitro and in vivo and then 13 patients with solid tumors refractory to standard therapies were treated. Treatments were well tolerated and frequent tumor- and adenovirus-specific T-cell immune responses were seen. Overall, with regard to tumor marker or radiological responses, signs of antitumor efficacy were seen in 9/12 evaluable patients (75%). The radiological disease control rate with positron emission tomography was 83% while the response rate (including minor responses) was 50%. Tumor biopsies indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414204PMC
http://dx.doi.org/10.18632/oncotarget.2901DOI Listing
February 2015

Case-control estimation of the impact of oncolytic adenovirus on the survival of patients with refractory solid tumors.

Mol Ther 2015 Feb 10;23(2):321-9. Epub 2014 Nov 10.

1] Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, Helsinki, Finland [2] Docrates Hospital, Helsinki, Finland [3] TILT Biotherapeutics Ltd, Helsinki, Finland.

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.
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http://dx.doi.org/10.1038/mt.2014.218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445619PMC
February 2015

Serotype chimeric oncolytic adenovirus coding for GM-CSF for treatment of sarcoma in rodents and humans.

Int J Cancer 2014 Aug 10;135(3):720-30. Epub 2014 Jan 10.

Cancer Gene Therapy Group Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.

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. Fifteen 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 1,459 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.
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http://dx.doi.org/10.1002/ijc.28696DOI Listing
August 2014

Oncolytic adenovirus with temozolomide induces autophagy and antitumor immune responses in cancer patients.

Mol Ther 2013 Jun 2;21(6):1212-23. Epub 2013 Apr 2.

Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.

Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum--a possible indicator of immune response--increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy.
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http://dx.doi.org/10.1038/mt.2013.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681222PMC
June 2013