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Ullenhag, Gustav
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Publications (10 of 33) Show all publications
Gremel, G., Djureinovic, D., Niinivirta, M., Laird, A., Ljungqvist, O., Johannesson, H., . . . Pontén, F. (2017). A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma. BMC Cancer, 17, Article ID 9.
Open this publication in new window or tab >>A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma
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2017 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, article id 9Article in journal (Refereed) Published
Abstract [en]

Background: There is an unmet clinical need for better prognostic and diagnostic tools for renal cell carcinoma (RCC). Methods: Human Protein Atlas data resources, including the transcriptomes and proteomes of normal and malignant human tissues, were searched for RCC-specific proteins and cubilin (CUBN) identified as a candidate. Patient tissue representing various cancer types was constructed into a tissue microarray (n = 940) and immunohistochemistry used to investigate the specificity of CUBN expression in RCC as compared to other cancers. Two independent RCC cohorts (n = 181; n = 114) were analyzed to further establish the sensitivity of CUBN as RCC-specific marker and to explore if the fraction of RCCs lacking CUBN expression could predict differences in patient survival. Results: CUBN was identified as highly RCC-specific protein with 58% of all primary RCCs staining positive for CUBN using immunohistochemistry. In venous tumor thrombi and metastatic lesions, the frequency of CUBN expression was increasingly lost. Clear cell RCC (ccRCC) patients with CUBN positive tumors had a significantly better prognosis compared to patients with CUBN negative tumors, independent of T-stage, Fuhrman grade and nodal status (HR 0.382, CI 0.203-0.719, P = 0.003). Conclusions: CUBN expression is highly specific to RCC and loss of the protein is significantly and independently associated with poor prognosis. CUBN expression in ccRCC provides a promising positive prognostic indicator for patients with ccRCC. The high specificity of CUBN expression in RCC also suggests a role as a new diagnostic marker in clinical cancer differential diagnostics to confirm or rule out RCC.

Keywords
Cubilin, Renal cell carcinoma, Independent prognostic biomarker, Immunohistochemistry
National Category
Cancer and Oncology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-315058 (URN)10.1186/s12885-016-3030-6 (DOI)000391341500003 ()28052770 (PubMedID)
Funder
Swedish Cancer SocietyKnut and Alice Wallenberg Foundation
Available from: 2017-03-03 Created: 2017-03-03 Last updated: 2017-11-29Bibliographically approved
Eriksson, E., Milenova, I., Wenthe, J., Moreno, R., Ullenhag, G., Dimberg, A., . . . Loskog, A. S. (2017). Activating CD40 While Inhibiting IL6R Induces Cytokine Production without PDL1 Upregulation in DCs. Paper presented at 20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 10-13, 2017, Washington, DC. Molecular Therapy, 25(5 S1), 54-54
Open this publication in new window or tab >>Activating CD40 While Inhibiting IL6R Induces Cytokine Production without PDL1 Upregulation in DCs
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2017 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 25, no 5 S1, p. 54-54Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-331371 (URN)000401083600113 ()
Conference
20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 10-13, 2017, Washington, DC
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Eriksson, E., Moreno, R., Milenova, I. Y., Liljenfeldt, L., Dieterich, L. C., Christiansson, L., . . . Loskog, A. (2017). Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment. Gene Therapy, 24(2), 92-103
Open this publication in new window or tab >>Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment
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2017 (English)In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 24, no 2, p. 92-103Article in journal (Refereed) Published
Abstract [en]

CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.

National Category
Other Medical Biotechnology
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-318170 (URN)10.1038/gt.2016.80 (DOI)000394682800006 ()27906162 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2017-10-10Bibliographically approved
Schiza, A., Wenthe, J., Mangsbo, S., Svensson, E., Nilsson, A., Tötterman, T., . . . Ullenhag, G. (2017). Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients. Journal of Translational Medicine, 15(79)
Open this publication in new window or tab >>Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients
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2017 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 15, no 79Article in journal (Refereed) Published
Abstract [en]

Background and aims: Malignant melanoma is an aggressive tumor sensitive for immunotherapy such as checkpoint blockade antibodies. Still, most patients with late stage disease do not respond, and the side effects can be severe. Stimulation of the CD40 pathway to initiate anti-tumor immunity is a promising alternative. Herein, we demonstrate immune profiling data from melanoma patients treated with an adenovirus-based CD40 ligand gene therapy (AdCD40L). Methods: Peripheral blood mononuclear cells and plasma were collected from malignant melanoma patients (n = 15) enrolled in a phase I/IIa study investigating intratumoral delivery of AdCD40L with or without low dose cyclophosphamide. Cells were analyzed by flow cytometry while plasma samples were analyzed by a multi-array proteomics. Results: All patients had an increased Teffector/Tregulatory cell ratio post therapy. Simultaneously, the death receptors TNFR1 and TRAIL-R2 were significantly up-regulated post treatment. Stem cell factor (SCF), E-selectin, and CD6 correlated to enhanced overall survival while a high level of granulocytic myeloid-derived suppressor cells (gMDSCs), IL8, IL10, TGFb1, CCL4, PlGF and Fl3t ligand was highest in patients with short survival. Conclusions: AdCD40L intratumoral injection induced desirable systemic immune effects that correlated to prolonged survival. Further studies using CD40 stimulation in malignant melanoma are warranted.

Keywords
AdCD40L, Malignant melanoma, Immunotherapy, Proteomics, T regulatory cells, Myeloid-derived suppressor cells
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-322800 (URN)10.1186/s12967-017-1182-z (DOI)000399786900002 ()28427434 (PubMedID)
Available from: 2017-06-20 Created: 2017-06-20 Last updated: 2018-02-20Bibliographically approved
Schiza, A., Wenthe, J., Mangsbo, S., Eriksson, E., Nilsson, A., Tötterman, T., . . . Ullenhag, G. (2017). Adenovirus-mediated CD40L gene transfer increases teffector/tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 337-337
Open this publication in new window or tab >>Adenovirus-mediated CD40L gene transfer increases teffector/tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 337-337Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-346969 (URN)000411865200209 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-03-28Bibliographically approved
Ullenhag, G. J., Mozaffari, F., Broberg, M., Mellstedt, H. & Liljefors, M. (2017). Clinical and Immune Effects of Lenalidomide in Combination with Gemcitabine in Patients with Advanced Pancreatic Cancer. PLoS ONE, 12(1), Article ID e0169736.
Open this publication in new window or tab >>Clinical and Immune Effects of Lenalidomide in Combination with Gemcitabine in Patients with Advanced Pancreatic Cancer
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0169736Article in journal (Refereed) Published
Abstract [en]

Purpose To assess the immunomodulatory and clinical effects of lenalidomide with standard treatment of gemcitabine in patients with advanced pancreatic cancer. Patients and Methods Patients with advanced pancreatic cancer were treated in first line with lenalidomide orally for 21 days of a 28 days cycle and the standard regimen for gemcitabine. In Part I, which we previously have reported, the dose of lenalidomide was defined (n = 12). In Part II, every other consecutive patient was treated with either lenalidomide (Group A, n = 11) or gemcitabine (Group B, n = 10) during cycle 1. From cycle 2 on, all Part II patients received the combination. Results A significant decrease in the proliferative response of peripheral blood mononuclear cells and the frequency of DCs were noted in patients at baseline compared to healthy control donors while the frequencies of CD4+ and CD8+ T cells, NK-cells and MDSCs were significantly higher in patients compared to controls. In Group A, a significant increase in the absolute numbers of activated (HLA-DR+) CD4 and CD8 T cells and CD8 effector memory T cells (p<0.01) was noted during treatment. A statistical increment in the absolute numbers of Tregs were seen after cycle 1 (p<0.05). The addition of gemcitabine, reduced most lymphocyte subsets (p<0.05). In Group B, the proportion of lymphocytes remained unchanged during the study period. There was no difference in overall survival, progression free survival and survival rate at one year comparing the two groups. Discussion Patients with advanced pancreatic carcinoma had impaired immune functions. Lenalido-mide augmented T cell reactivities, which were abrogated by gemcitabine. However, addition of lenalidomide to gemcitabine seemed to have no therapeutic impact compared to gemcitabine alone in this non-randomized study.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-316028 (URN)10.1371/journal.pone.0169736 (DOI)000392380100031 ()28099502 (PubMedID)
Funder
Swedish Cancer Society, 110711The Karolinska Institutet's Research FoundationStockholm County Council
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2017-11-29Bibliographically approved
Valachis, A. & Ullenhag, G. (2017). Discrepancy in BRAF status among patients with metastatic malignant melanoma: A meta-analysis. European Journal of Cancer, 81, 106-115
Open this publication in new window or tab >>Discrepancy in BRAF status among patients with metastatic malignant melanoma: A meta-analysis
2017 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 81, p. 106-115Article, review/survey (Refereed) Published
Abstract [en]

The incidence of malignant melanoma is growing rapidly. Approximately half of the cases are BRAF mutated, making treatment with kinase inhibitors a (MEK and BRAF inhibitors) preferred choice in the advanced setting. The vast majority of these patients will benefit from the treatment. It is therefore of vital importance that the BRAF analysis is reliable and reflects the true nature of the tumour. Intraindividual tumour BRAF heterogeneity may exist, and changes of BRAF status over time might occur. We reviewed the literature by searching the PubMed database and 630 potentially relevant studies were identified. Thereafter, studies that investigated intralesional heterogeneity only, studies with <= 10 patients and studies that did not include adequate data to calculate discrepancy rates were excluded. Twenty-two studies met our inclusion criteria and were included in the meta-analysis. The pooled discrepancy rate between primary and metastatic lesions was 13.4% (95% confidence interval [CI]: 9.2-18.2%) while it was 7.3% (95% CI: 3.3-12.6) between two metastatic lesions. The number of patients whose tumoural BRAF status was changed from mutation to wild type and from wild type to mutation, respectively, was comparable. We conclude that a clinically meaningful discrepancy rate in BRAF status both between primary-metastatic and metastatic-metastatic melanoma lesions exists. Our results support the polyclonal model of melanomas in which subclones with different BRAF status co-exist in the same melanoma lesion. In addition, the results indicate a need for biopsy of a metastatic lesion for subsequent BRAF analysis when treatment with kinase inhibitors is considered.

Keywords
Melanoma, Discrepancy, BRAF, Meta-analysis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-335806 (URN)10.1016/j.ejca.2017.05.015 (DOI)000404894700013 ()28623774 (PubMedID)
Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2018-01-22Bibliographically approved
Irenaeus, S., Schiza, A., Mangsbo, S. M., Wenthe, J., Svensson, E., Krause, J., . . . Ullenhag, G. (2017). Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients. OncoTarget, 8(45), 78573-78587
Open this publication in new window or tab >>Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 45, p. 78573-78587Article in journal (Refereed) Published
Abstract [en]

Background: AdCD40L is an immunostimulatory gene therapy under evaluation for advanced melanoma, including ocular melanoma. Herein, we present the final data of a Phase I/IIa trial using AdCD40L alone or in combination with low dose cyclophosphamide +/- radiation therapy.

Methods: AdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L). Twenty-four patients with advanced melanoma were enrolled and treated with AdCD40L monotherapy, or combined with cyclophosphamide +/- single fraction radiotherapy. The patients were monitored for 10 weeks using immunological and radiological evaluations and thereafter for survival.

Results: AdCD40L treatment was safe and well tolerated both alone and in combination with cyclophosphamide as well as local radiotherapy. Four out of twenty-four patients had >1 year survival. Addition of cyclophosphamide was beneficial but adding radiotherapy did not further extend survival. High initial plasma levels of IL12 and MIP3b correlated to overall survival, whereas IL8 responses post-treatment correlated negatively with survival. Interestingly, antibody reactions to the virus correlated negatively with post IL6 and pre IL1b levels in blood.

Conclusions: AdCD40L was safely administered to patients and effect was improved by cyclophosphamide but not by radiotherapy. Immune activation profile at baseline may predict responders better than shortly after treatment.

Keywords
AdCD40L, gene therapy, immunotherapy, irradiation, malignant melanoma
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-333305 (URN)10.18632/oncotarget.19750 (DOI)000412111300034 ()29108250 (PubMedID)
Available from: 2017-11-10 Created: 2017-11-10 Last updated: 2018-01-26Bibliographically approved
Svensson, E., Milenova, I., Wenthe, J., Ståhle, M., Leja-Jarblad, J., Ullenhag, G., . . . Loskog, A. S. (2017). Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus.. Clinical Cancer Research, 23(19), 5846-5857
Open this publication in new window or tab >>Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus.
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2017 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 19, p. 5846-5857Article in journal (Refereed) Published
Abstract [en]

Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications, but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein, we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways, respectively. As many cells in the tumor stroma, including stellate cells and the infiltrating immune cells, express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma.Experimental Design: Tumor, stellate, endothelial, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics, and functional analyses.Results: LOAd703-infected pancreatic cell lines were killed by oncolysis, and the virus was more effective than standard-of-care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGFβ and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce costimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells.Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses. Clin Cancer Res; 1-12. ©2017 AACR.

National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-330158 (URN)10.1158/1078-0432.CCR-17-0285 (DOI)000412160500021 ()28536305 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-09-27 Created: 2017-09-27 Last updated: 2018-02-02Bibliographically approved
Niinivirta, M., Enblad, G., Edqvist, P.-H. D., Pontén, F., Dragomir, A. & Ullenhag, G. (2017). Tumoral ANXA1 Is a Predictive Marker for Sunitinib Treatment of Renal Cancer Patients. Journal of Cancer, 8(19), 3975-3983
Open this publication in new window or tab >>Tumoral ANXA1 Is a Predictive Marker for Sunitinib Treatment of Renal Cancer Patients
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2017 (English)In: Journal of Cancer, ISSN 1837-9664, E-ISSN 1837-9664, Vol. 8, no 19, p. 3975-3983Article in journal (Refereed) Published
Abstract [en]

Background and aims: There is no established predictive marker for the treatment of renal cancer. Metastatic renal cell carcinoma (mRCC) patients are often treated with sunitinib, a tyrosine kinase inhibitor. Sunitinibs anti-cancer effect is at least partly mediated through interfering with angiogenesis. Our aim with the current study was to assess annexin A1 (ANXA1), which stimulates angiogenesis, as a predictive marker for sunitinib therapy in mRCC patients. Since previous studies have indicated a predictive potential for cubilin, we also investigated the predictivity of ANXA1 combined with cubilin.

Methods: ANXA1 expression was analysed in tumor tissue from a cohort of patients with advanced RCC (n= 139) using immunohistochemistry. Ninety-nine of the patients were treated with sunitinib in the first or second-line setting. Twenty-two of these were censored because of toxicity leading to the termination of treatment and the remaining (n= 77) were selected for the present study.

Results: Twenty-five (32%) out of seventy-seven of the tumors lacked ANXA1 in the cytoplasm. On statistical analyses using Kaplan-Meier method, aNXA1 negative tumors were significantly associated with a longer treatment benefit in terms of progression free survival (PFS). Overall survival was also significantly better for patients with ANXA1 negative tumors. The combined ANXA1 positive and cubilin negative expression could more accurately than ANXA1 alone define the group not benefitting from treatment.

Conclusions: Our results indicate that cytoplasmic expression of ANXA1 is a negative predictive marker for sunitinib therapy in mRCC patients. A possible explanation for this finding is that sunitinibs anti-angiogenic effect cannot overcome the pro-angiogenic drive from many ANXA1 proteins.

Keywords
Renal cancer, sunitinib, tissue microarray, predictive marker, ANXA1
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-339521 (URN)10.7150/jca.20889 (DOI)000418498600007 ()29187872 (PubMedID)
Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2018-10-09Bibliographically approved
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