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- Ellingsen, Espen Basmo, et al.
(author)
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Durable and dynamic hTERT immune responses following vaccination with the long-peptide cancer vaccine UV1 : long-term follow-up of three phase I clinical trials
- 2022
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In: Journal for ImmunoTherapy of Cancer. - : BMJ Publishing Group Ltd. - 2051-1426. ; 10:5
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Journal article (peer-reviewed)abstract
- Background Therapeutic cancer vaccines represent a promising approach to improve clinical outcomes with immune checkpoint inhibition. UV1 is a second generation telomerase-targeting therapeutic cancer vaccine being investigated across multiple indications. Although telomerase is a near-universal tumor target, different treatment combinations applied across indications may affect the induced immune response. Three phase I/IIa clinical trials covering malignant melanoma, non-small cell lung cancer, and prostate cancer have been completed, with patients in follow-up for up to 8 years.Methods 52 patients were enrolled across the three trials. UV1 was given as monotherapy in the lung cancer trial and concurrent with combined androgen blockade in the prostate cancer trial. In the melanoma study, patients initiated ipilimumab treatment 1 week after the first vaccine dose. Patients were followed for UV1-specific immune responses at frequent intervals during vaccination, and every 6 months for up to 8 years in a follow-up period. Phenotypic and functional characterizations were performed on patient-derived vaccine-specific T cell responses.Results In total, 78.4% of treated patients mounted a measurable vaccine-induced T cell response in blood. The immune responses in the malignant melanoma trial, where UV1 was combined with ipilimumab, occurred more rapidly and frequently than in the lung and prostate cancer trials. In several patients, immune responses peaked years after their last vaccination. An in-depth characterization of the immune responses revealed polyfunctional CD4+ T cells producing interferon-gamma and tumor necrosis factor-alpha on interaction with their antigen.Conclusion Long-term immunomonitoring of patients showed highly dynamic and persistent telomerase peptide-specific immune responses lasting up to 7.5 years after the initial vaccination, suggesting a plausible functional role of these T cells in long-term survivors. The superior immune response kinetics observed in the melanoma study substantiate the rationale for future combinatorial treatment strategies with UV1 vaccination and checkpoint inhibition for rapid and frequent induction of anti-telomerase immune responses in patients with cancer.
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| 2. |
- Bouwhuis, Marna G, et al.
(author)
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Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon.
- 2009
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 101:12, s. 869-77
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Journal article (peer-reviewed)abstract
- BACKGROUND: Appearance of autoantibodies and clinical manifestations of autoimmunity in melanoma patients treated with adjuvant interferon (IFN)-alpha2b was reported to be associated with improved prognosis. We assessed the association of the appearance of autoantibodies after initiation of treatment with recurrence-free interval in two randomized trials that compared intermediate doses of IFN with observation for the treatment of melanoma patients. METHODS: Serum levels of anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined using enzyme-linked immunosorbent assays in 187 and 356 patients in the European Organization for Research and Treatment of Cancer (EORTC) 18952 and Nordic IFN trials, respectively, immediately before and up to 3 years after random assignment. The association of the presence of at least one of the three autoantibodies with risk of recurrence was assessed by three Cox models in patients negative for all three autoantibodies at baseline (125 from the EORTC 18952 trial and 230 from the Nordic IFN trial): 1) a model that considered appearance of autoantibodies as a time-independent variable, 2) one that considered a patient autoantibody positive once a positive test for an autoantibody was obtained, and 3) a model in which the status of the patient was defined by the most recent autoantibody test. All statistical tests were two-sided. RESULTS: When treated as a time-independent variable (model 1), appearance of autoantibodies was associated with improved relapse-free interval in both trials (EORTC 18952, hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.25 to 0.68, P < .001; and Nordic IFN, HR = 0.51, 95% CI = 0.34 to 0.76, P < .001). However, on correction for guarantee-time bias, the association was weaker and not statistically significant (model 2: EORTC 18952, HR = 0.81, 95% CI = 0.46 to 1.40, P = .44; and Nordic IFN, HR = 0.85, 95% CI = 0.55 to 1.30, P = .45; model 3: EORTC 18952, HR = 1.05, 95% CI = 0.59 to 1.87, P = .88; and Nordic IFN, HR = 0.78, 95% CI = 0.49 to 1.24, P = .30). CONCLUSIONS: In two randomized trials of IFN for the treatment of melanoma patients, appearance of autoantibodies was not strongly associated with improved relapse-free interval when correction was made for guarantee-time bias.
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| 3. |
- Brandberg, Yvonne, et al.
(author)
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Role functioning before start of adjuvant treatment was an independent prognostic factor for survival and time to failure. A report from the Nordic adjuvant interferon trial for patients with high-risk melanoma.
- 2013
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In: Acta oncologica (Stockholm, Sweden). - 1651-226X. ; 52:6, s. 1086-1093
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Journal article (peer-reviewed)abstract
- Purpose. To investigate the role of health-related quality of life (HRQoL) at randomization as independent prognostic factors for survival and time to failure, and to explore associations between HRQoL and treatment effects. Material and methods. In the Nordic adjuvant interferon trial, a randomized trial evaluating if adjuvant therapy with intermediate-dose IFN had the same beneficial effects on overall and disease-free survival in high-risk melanoma as high-dose IFN, 855 patients in Denmark, Finland, Norway, and Sweden were included. The EORTC QLQ-C30 questionnaire was used to assess HRQoL before randomization. Results. A total of 785 (92%) agreed to participate in the HRQoL-study and provided baseline HRQoL data. Prognostic variables included in the multivariate model were age, sex, performance status, tumor thickness, stage, and number of positive lymph nodes. Univariate analyses revealed an association between prolonged survival and age, stage/ number of metastatic lymph nodes and the HRQoL variable role functioning (p ≤ 0.01). After controlling for other prognostic factors, these variables remained independently statistically significant for survival. The univariate analyses of time to failure showed significant associations with the clinical variable stage/nodes and with the HRQoL variables physical functioning and role functioning. Adjusted multivariate analyses including the same clinical conditions as above showed statistically significant relationships between time to failure and global quality of life, physical functioning, role functioning, social functioning and fatigue (p ≤ 0.01). No interactions between HRQoL variables and treatment were found, with the exception for cognitive functioning. Conclusion. Role functioning was found to be an independent prognostic factor for time to failure and survival in patients with high-risk melanoma. Thus, also in this early stage of melanoma, HRQoL variables might be useful as important prognostic factors for time to failure and overall survival.
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| 4. |
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| 5. |
- Hernberg, Micaela, et al.
(author)
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The prognostic role of blood lymphocyte subset distribution in patients with resected high-risk primary or regionally metastatic melanoma.
- 2007
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In: Journal of immunotherapy (Hagerstown, Md. : 1997). - 1524-9557. ; 30:7, s. 773-9
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Journal article (peer-reviewed)abstract
- The aim of this study was to investigate whether the profile of peripheral blood lymphocyte subsets of patients with high-risk malignant melanoma is associated with prognosis. Blood samples were systematically obtained from 31 patients with high-risk melanoma eligible for the Nordic Melanoma Cooperative Group adjuvant interferon study. The frequencies of peripheral blood lymphocyte subsets were monitored by flow cytometry using CD3, CD4, CD8, CD56, and CD69 monoclonal antibodies. Patients with low proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells before treatment had an improved disease-free survival compared to those with high proportions [77.7 vs. 16.8 mo, hazard ratio (HR) 0.25, confidence interval (CI) 0.09-0.71, P=0.005 and 77.2 vs. 16.0 mo, HR: 0.25, CI 0.086-0.73, P=0.001, respectively]. Low pretreatment levels of these cell populations also correlated with a better overall survival (79.2 vs. 22.6 mo, HR: 0.17, CI 0.05-0.52, P=0.0005 and 78.2 vs. 21.4 mo, HR: 0.2, CI 0.07-0.59, P=0.001, respectively). In the multivariate analysis both the pretreatment proportion of CD3+CD4+CD69+ cells (P=0.01, HR: 0.21, CI 0.07-0.67) and CD3+CD56+ cells (P=0.01, HR: 0.22, CI 0.062-0.65) were independent prognostic factors for overall survival. Our data show that both the proportions of CD3+CD4+CD69+ cells and of CD3+CD56+ cells seem to have a prognostic potential in the natural course of melanoma. These results need to be confirmed in larger studies.
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| 6. |
- Vihinen, Pia, et al.
(author)
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Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels.
- 2014
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In: Cancer Immunology, Immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004.
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Journal article (peer-reviewed)abstract
- Matrix metalloproteinases (MMPs) are important enzymes in tissue turnover and various inflammatory processes. In this study, it was evaluated whether serum MMP-8 can predict the response to adjuvant interferon alfa-2b (IFN-α) therapy in patients with operated high-risk cutaneous melanoma. Pre-treatment sera from 460 patients with stage IIB-IIIC melanoma were analyzed for MMP-8. The patients were randomized after surgery to adjuvant IFN-α for 12 or 24 months (n = 313) or observation only (n = 147). The median serum MMP-8 level was used to classify the patients into a low MMP-8 (n = 232) and a high MMP-8 (n = 228) group. In the high MMP-8 subgroup, IFN-α therapy significantly improved relapse-free survival (RFS). RFS was 36.8 months in patients with high MMP-8 levels receiving IFN-α therapy, whereas RFS for those with high MMP-8 levels with observation only was 10.6 months (P = 0.027). Median overall survival for patients with high MMP-8 and observation only was 36.7 versus 71.7 months in those receiving IFN-α (P = 0.13). In a multivariate model, IFN-α therapy was a significant predictor of favorable RFS (HR 0.74; 95 % CI 0.55-0.99; P = 0.048), after adjustment for pre-treatment MMP-8 (HR 1.17; 95 % CI 0.88-1.55; P = 0.28), gender (HR 1.16; 95 % CI 0.86-1.56; P = 0.32), age (HR 1.00; 95 % CI 1.00-1.02; P = 0.12), ulceration (HR 1.09; 95 % CI 0.81-1.46; P = 0.58), and the presence of node metastases (HR 1.36; 95 % CI 1.17-1.58; P
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