| 1. |
- Eriksson, Emma, et al.
(författare)
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Gemcitabine reduces MDSCs, tregs and TGF beta-1 while restoring the teff/treg ratio in patients with pancreatic cancer
- 2016
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cancer immunotherapy can be potentiated by conditioning regimens such as cyclophosphamide, which reduces the level of regulatory T cells (tregs). However, myeloid suppressive cells are still remaining. Accordingly to previous reports, gemcitabine improves immune status of cancer patients. In this study, the role of gemcitabine was further explored to map its immunological target cells and molecules in patients with pancreatic cancer.Methods: Patient blood was investigated by flow cytometry and cytokine arrays at different time points during gemcitabine treatment.Results: The patients had elevated myeloid-derived suppressor cells (MDSCs), and Tregs at diagnosis. Myeloid cells were in general decreased by gemcitabine. The granulocytic MDSCs were significantly reduced while monocytic MDSCs were not affected. In vitro, monocytes responding to IL-6 by STAT3 phosphorylation were prevented to respond in gemcitabine medium. However, gemcitabine could not prevent STAT3 phosphorylation in IL-6-treated tumor cell lines. TGF beta-1 was significantly reduced after only one treatment and continued to decrease. At the same time, the effector T cell:Treg ratio was increased and the effector T cells had full proliferative capacity during the gemcitabine cycle. However, after a resting period, the level of suppressor cells and TGF beta-1 had been restored showing the importance of continuous conditioning.Conclusions: Gemcitabine regulates the immune system in patients with pancreatic cancer including MDSCs, Tregs and molecules such as TGF beta-1 but does not hamper the ability of effector lymphocytes to expand to stimuli. Hence, it may be of high interest to use gemcitabine as a conditioning strategy together with immunotherapy.
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| 2. |
- Irenaeus, Sandra, et al.
(författare)
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First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies
- 2019
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Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 145:5, s. 1189-1199
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Tidskriftsartikel (refereegranskat)abstract
- Agonistic CD40 antibodies activate dendritic cells and can expand and activate tumor-specific T cells. Our purpose was to assess the CD40 agonistic antibody ADC-1013 in the clinical setting including intratumoral administration since preclinical studies have indicated that intratumoral is better than intravenous administration. A Phase I, open label, multicenter study was conducted in patients with advanced solid tumors who had received established treatments. A modified 3 + 3 dose-escalation was applied (every other week dosing). Twenty-three patients were treated with ADC-1013 intratumorally (dosing from 22.5 mu g/kg up to 400 mu g/kg) or intravenously (dosing at 75 mu g/kg). The pharmacodynamic effects observed in the patients were further verified in an hCD40tg mouse model. Adverse events were mostly Common Terminology Criteria for Adverse Events (CTCAE) Grades 1 or 2 and transient. The serum concentration ADC-1013 and cytokine release (MCP-1, TNF alpha and IL-6) were more pronounced in patients receiving injections in deep metastases compared to patients receiving injections in superficial metastases. Treatment with ADC-1013 resulted in a marked decrease in B cell levels in peripheral blood after 24 h while remaining B cells significantly increased their expression of the cell surface activation marker CD86. Activation of antigen-presenting cells and subsequent activation of T cells were demonstrated in hCD40tg mice. Moreover, ADC-1013 treatment in this mouse model acted synergistically with a PD-1 inhibitor. The results from the first-in-human study of ADC-1013 indicate that intratumoral administration of ADC-1013 into superficial lesions is well tolerated at clinically relevant doses and associated with pharmacodynamic responses.
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| 3. |
- Irenaeus, Sandra, 1984-
(författare)
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Intratumoral CD40 stimulating therapy in patients with advanced cancer
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- CD40-CD40L interaction activates DCs to become highly efficient APCs and skews the adaptive immune response towards a Th I phenotype driving cytotoxic T cells, M1 macrophages and natural killer cells. Furthermore, engagement of CD40L to CD40 positive cancer cells can have direct anti-proliferative effects, induce apoptosis and increase expression of MHC and other co-stimulatory molecules, thereby enhancing cancer cell recognition. Hence, activating the CD40-CD40L pathway may lead to several potential anti-tumoral effects. In this thesis we evaluated activation of the CD40-CD40L pathway in patients with solid cancer by investigating three medicinal products administered mainly through intratumoral injection: ADC1013 - an agonistic CD40 antibody, AdCD40L - a replication deficient adenovirus carrying the gene for CD40L and LOAd703 - an oncolytic adenovirus carrying two immunostimulatory genes: TMZ-CD40L and 4-1BBL. In paper I, ADC-1013 was investigated in patients with metastatic cancer (n=23) in a phase I trial. ADC-1013 was injected intratumorally (n=18) or intravenously (n=5). AdCD40L was investigated in a phase I/II study reported in paper II and III, respectively. In one cohort (paper II), patients with metastatic malignant melanoma (n=9) were treated with four weekly intratumoral injections with AdCD40L preceded by radiotherapy (single fraction 8 Gy) of the metastasis to subsequently be injected. Concomitant low dose cyclophosphamide was administered before the first and fourth intratumoral injection. In another cohort (paper III), patients with metastatic non melanoma solid cancer (n=6) were treated with the same schedule except from radiotherapy. Paper III also reports the results of the first-ever patient treated with AdCD40L. In paper IV, the preliminary results of phase I of a phase I/II study investigating LOAd703 administered intratumorally at a two-week interval are presented. LOAd703 was given as an add-on to standard-of-care chemotherapy, or with gemcitabine conditioning in patients having received established treatments. Patients (n=9) had locally advanced or metastatic pancreatic cancer, metastatic ovarian cancer or colorectal cancer. We conclude that treatment with all three medicinal products was safe and tolerable. For ADC-1013, the therapeutic ratio seemed to be more favorable for intratumoral injections into superficial metastases compared to deep metastases. We demonstrated that AdCD40L can be combined with radiotherapy without increasing toxicity although radiotherapy did not enhance treatment efficacy. Further, LOAd703 was safe to combine with chemotherapy. Although the number of patients treated in each trial was limited, and almost all patients were considered refractory to standard treatment at inclusion, some patients seemed to benefit from treatment which is encouraging.
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| 4. |
- Irenaeus, Sandra, et al.
(författare)
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Intratumoral immunostimulatory AdCD40L gene therapy in patients with advanced solid tumors.
- 2021
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Ingår i: Cancer Gene Therapy. - : Springer Science and Business Media LLC. - 0929-1903 .- 1476-5500. ; 28:10-11, s. 1188-1197
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Tidskriftsartikel (refereegranskat)abstract
- AdCD40L is a replication-deficient virus carrying the gene for CD40 ligand which has previously been evaluated in patients with urothelial cancer and malignant melanoma. Herein, we present the results of repeated intratumoral injections of AdCD40L in seven patients with metastatic solid cancer. One patient who developed urothelial cancer derived from a renal transplant was treated with repeated injections of AdCD40L alone. The remaining patients suffered from cholangiocarcinoma, kidney, breast, rectal, or ovarian cancer and received AdCD40L repeatedly (4x) in combination with cyclophosphamide. The treatment was safe and generally well-tolerated. Two patients had clinical benefit of the treatment and one of them was accepted for re-treatment. Circulating proinflammatory cytokines were commonly increased after treatment, but save for TNFα, significances were not reached which could be due to the low number of patients. Similar to earlier findings in AdCD40L-treated melanoma patients, IL8 plasma levels were high in the present study. In conclusion, gene therapy by repeated intratumoral AdCD40L injections alone, or in combination with cyclophosphamide, is feasible and safe in patients with solid cancers. The potential of intratumoral CD40L gene transfer as treatment of cancer was illustrated by the clinical improvement in two out of seven patients.
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| 5. |
- Irenaeus, Sandra, et al.
(författare)
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Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:45, s. 78573-78587
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
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| 7. |
- Johansson, Anna L., V, et al.
(författare)
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Were cancer patients worse off than the general population during the COVID-19 pandemic? : A population-based study from Norway, Denmark and Iceland during the pre-vaccination era
- 2023
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 31
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Tidskriftsartikel (refereegranskat)abstract
- Background In a population-based setting, we investigated the risks of testing positive for SARS-CoV-2 and developing severe COVID-19 outcomes among cancer patients compared with the general population.Methods In nationwide cohorts, we identified all individuals in Norway, Denmark and Iceland who tested positive for SARS-CoV-2 or had a severe COVID-19 outcome (hospitalisation, intensive care, and death) from March until December 2020, using data from national health registries. We estimated standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) comparing cancer patients with the general population.Findings During the first wave of the pandemic, cancer patients in Norway and Denmark had higher risks of testing SARS-CoV-2 positive compared to the general population. Throughout 2020, recently treated cancer patients were more likely to test SARS-CoV-2 positive. In Iceland, cancer patients experienced no increased risk of testing positive. The risk of COVID-19-related hospitalisation was higher among cancer patients diagnosed within one year of hospitalisation (Norway: SIR = 2.43, 95% CI 1.89-3.09; Denmark: 2.23, 1.96-2.54) and within five years (Norway: 1.58, 1.35-1.83; Denmark: 1.54, 1.42-1.66). Risks were higher in recently treated cancer patients and in those diagnosed with haematologic malignancies, colorectal or lung cancer. Risks of COVID-19-related intensive care and death were higher among cancer patients. Interpretation Cancer patients were at increased risk of testing positive for SARS-CoV-2 during the first pandemic wave when testing availability was limited, while relative risks of severe COVID-19 outcomes remained increased in cancer patients throughout 2020. Recent cancer treatment and haematologic malignancy were the strongest risk factors.
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| 8. |
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| 9. |
- Schiza, Aglaia, et al.
(författare)
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Evaluation of Diffusion-Weighted MRI and FDG-PET/CT to Assess Response to AdCD40L treatment in Metastatic Melanoma Patients
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The purpose was to evaluate the potential of diffusion-weighted-magnetic resonance imaging (DW-MRI) and F-18-fludeoxy-glucose-positron emission tomography integrated with CT (FDG-PET/CT) for prediction of overall survival (OS) following AdCD40L-immunotherapy in patients with metastatic malignant melanoma (MMM). Twenty-four patients with refractory MMM were treated with immunostimulatory AdCD40L gene therapy in a phase I/IIa study. Pre-therapeutic DW-MRI and FDG-PET/CT were performed and then repeated at 5 and 9 weeks post-treatment. Evaluation was conducted according to RECIST 1.1 and EORTC criteria. Apparent diffusion coefficient (ADC), true diffusion coefficient (D), maximum standardized uptake value (SUVmax) were measured in the injected lesions. Fold changes (F) in ADC (F ADC), D (FD), SUVmax (FSUVmax) were statistically assessed. F D >= 1 and F ADC >= 1 were associated with better OS in scans at week 5 and 9 respectively. F SUVmax was not correlated to OS. F ADC >= 1 in both post-treatment scans and F D >= 1 at week 5 were related to a significant decrease of size of the injected lesions. These results suggest that in patients with MMM treated with AdCD401, functional parameters of DW-MRI are better early predictors of OS than the established metabolic and morphologic criteria for FDG-PET/CT and MRI, respectively.
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