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  • 1
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    A phase I/IIa clinical trial investigating the therapeutic cancer vaccine UV1 in combination with ipilimumab in patients with malignant melanoma: Four-year survival update.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 5_suppl ( 2020-02-10), p. 62-62
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 5_suppl ( 2020-02-10), p. 62-62
    Abstract: 62 Background: Combining checkpoint blockade with a cancer vaccine may induce broader immune responses, leading to better clinical outcomes. UV1 targets the enzyme telomerase (hTERT) which is expressed in almost all cancer types and is essential for the immortality of cancer cells and a hallmark of cancer. UV1 consists of three synthetic long peptides and vaccination induces Th1 responses in most patients irrespective of HLA type. This trial explores the synergistic effect of CTLA-4 blockade and hTERT vaccination, allowing unchecked expansion of hTERT-specific T cell clones. Increased number of tumor-specific T cells is associated with a favorable clinical outcome in patients with metastatic melanoma. We investigated the safety, immunological and clinical responses of UV1 vaccine and ipilimumab in this group of patients. Methods: In a phase I/IIa, single-center trial (NCT02275416) patients with metastatic melanoma received treatment with UV1 (300 µg) + GM-CSF (75 µg) as an adjuvant, combined with ipilimumab (3 mg/kg). Safety was assessed according to CTCAE v. 4.0, and tumor responses according to RECIST v.1.1. Immune responses against UV1 peptides were monitored in peripheral mononuclear blood cells by using 3 H-thymidine proliferation and IFN-γ ELISPOT assays. Tumor mutational burden (TMB) estimations were based on whole-exome sequencing. Results: 12 patients were treated from Feb to Nov 2015. Treatment was generally well tolerated. Adverse events mainly included injection site reactions and diarrhea. Immune responses occurred very early and 10/11 evaluable patients showed an immune response. Three patients obtained a partial response, and one patient a complete response. 3-year overall survival (OS) was 67%. 4-year survival outcome will be presented along with baseline characteristics and TMB estimations. Conclusions: Combining UV1 and ipilimumab is safe and induces clinical responses in melanoma. The high proportion of immunological responders and early induction of detectable immune responses suggest synergism. OS compares favorably to historical controls. Clinical trial information: NCT02275416.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.5_suppl.62
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Personalized HLA typing leads to the discovery of novel HLA alleles and tumor‐specific HLA variants
    Wiley ; 2022
    In:  HLA Vol. 99, No. 4 ( 2022-04), p. 313-327
    Details
    In: HLA, Wiley, Vol. 99, No. 4 ( 2022-04), p. 313-327
    Abstract: Accurate and full‐length typing of the HLA region is important in many clinical and research settings. With the advent of next generation sequencing (NGS), several HLA typing algorithms have been developed, including many that are applicable to whole exome sequencing (WES). However, most of these solutions operate by providing the closest‐matched HLA allele among the known alleles in IPD‐IMGT/HLA Database. These database‐matching approaches have demonstrated very high performance when typing well characterized HLA alleles. However, as they rely on the completeness of the HLA database, they are not optimal for detecting novel or less well characterized alleles. Furthermore, the database‐matching approaches are also not adequate in the context of cancer, where a comprehensive characterization of somatic HLA variation and expression patterns of a tumor's HLA locus may guide therapy and clinical outcome, because of the pivotal role HLA alleles play in tumor antigen recognition and immune escape. Here, we describe a personalized HLA typing approach applied to WES data that leverages the strengths of database‐matching approaches while simultaneously allowing for the discovery of novel HLA alleles and tumor‐specific HLA variants, through the systematic integration of germline and somatic variant calling. We applied this approach on WES from 10 metastatic melanoma patients and validated the HLA typing results using HLA targeted NGS sequencing from patients where at least one HLA germline candidate was detected on Class I HLA. Targeted NGS sequencing confirmed 100% performance for the 1st and 2nd fields. In total, five out of the six detected HLA germline variants were because of Class I ambiguities at the third or fourth fields, and their detection recovered the correct HLA allele genotype. The sixth germline variant let to the formal discovery of a novel Class I allele. Finally, we demonstrated a substantially improved somatic variant detection accuracy in HLA alleles with a 91% of success rate in simulated experiments. The approach described here may allow the field to genotype more accurately using WES data, leading to the discovery of novel HLA alleles and help characterize the relationship between somatic variation in the HLA region and immunosurveillance.
    Type of Medium: Online Resource
    ISSN: 2059-2302 , 2059-2310
    URL: Issue
    URL: Article
    DOI: 10.1111/tan.v99.4
    DOI: 10.1111/tan.14562
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2844321-4
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  • 3
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    Therapeutic cancer vaccination against telomerase: clinical developments in melanoma
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Current Opinion in Oncology Vol. 35, No. 2 ( 2023-03), p. 100-106
    Details
    In: Current Opinion in Oncology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. 2 ( 2023-03), p. 100-106
    Abstract: Checkpoint inhibitors (CPIs) have revolutionized treatment outcomes for patients with malignant melanoma. Long-term follow-up shows that a substantial subset of patients who exhibit clinical responses achieve extended overall survival. Nevertheless, most patients do not achieve durable benefit from CPIs, and improvements are urgently needed. The clinical efficacy of CPIs depends on highly variable preexisting spontaneous T-cell immune responses. Cancer vaccines represent an independent treatment modality uniquely capable of expanding the repertoire of tumor-specific T cells in cancer patients and thus have the capacity to compensate for the variability in spontaneous T-cell responses. Vaccines are, therefore, considered attractive components in a CPI-combination strategy. Recent findings Here we discuss recent results obtained through therapeutic vaccination against telomerase human telomerase reverse transcriptase (hTERT). Recent publications on translational research and clinical results from phase I trials indicate that vaccination against telomerase in combination with CPIs provides relevant immune responses, negligible added toxicity, and signals of clinical efficacy. Conclusion In the near future, randomized data from clinical trials involving therapeutic cancer vaccines and checkpoint inhibitors will be available. Positive readout may spark broad development and allow cancer vaccines to find their place in the clinic as an important component in multiple future CPI combinations.
    Type of Medium: Online Resource
    ISSN: 1040-8746 , 1531-703X
    URL: Article
    DOI: 10.1097/CCO.0000000000000922
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2026986-9
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  • 4
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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
    BMJ ; 2022
    In:  Journal for ImmunoTherapy of Cancer Vol. 10, No. 5 ( 2022-05), p. e004345-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 5 ( 2022-05), p. e004345-
    Abstract: 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-γ and tumor necrosis factor-α 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.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-004345
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2719863-7
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  • 5
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    Table_2.pdf
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-5-11)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-5-11)
    Abstract: Ipilimumab improves survival for patients with metastatic malignant melanoma. Combining a therapeutic cancer vaccine with ipilimumab may increase efficacy by providing enhanced anti-tumor immune responses. UV1 consists of three synthetic long peptides from human telomerase reverse transcriptase (hTERT). These peptides comprise epitopes recognized by T cells from cancer patients experiencing long-term survival following treatment with a first-generation hTERT vaccine, and generate long-lasting immune responses in cancer patients when used as monotherapy. The objective of this trial was to investigate the safety and efficacy of combining UV1 with ipilimumab in metastatic melanoma. Patients and Methods In this phase I/IIa, single center trial [NCT02275416], patients with metastatic melanoma received repeated UV1 vaccinations, with GM-CSF as an adjuvant, in combination with ipilimumab. Patients were evaluated for safety, efficacy and immune response. Immune responses against vaccine peptides were monitored in peripheral blood by measuring antigen-specific proliferation and IFN-γ production. Results Twelve patients were recruited. Adverse events were mainly diarrhea, injection site reaction, pruritus, rash, nausea and fatigue. Ten patients showed a Th1 immune response to UV1 peptides, occurring early and after few vaccinations. Three patients obtained a partial response and one patient a complete response. Overall survival was 50% at 5 years. Conclusion Treatment was well tolerated. The rapid expansion of UV1-specific Th1 cells in the majority of patients indicates synergy between UV1 vaccine and CTLA-4 blockade. This may have translated into clinical benefit, encouraging the combination of UV1 vaccination with standard of care treatment regimes containing ipilimumab/CTLA-4 blocking antibodies.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.663865
    DOI: 10.3389/fimmu.2021.663865.s001
    DOI: 10.3389/fimmu.2021.663865.s002
    DOI: 10.3389/fimmu.2021.663865.s003
    DOI: 10.3389/fimmu.2021.663865.s004
    DOI: 10.3389/fimmu.2021.663865.s005
    DOI: 10.3389/fimmu.2021.663865.s006
    DOI: 10.3389/fimmu.2021.663865.s007
    DOI: 10.3389/fimmu.2021.663865.s008
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 6
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    NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma
    Springer Science and Business Media LLC ; 2021
    In:  Journal of Translational Medicine Vol. 19, No. 1 ( 2021-12)
    Details
    In: Journal of Translational Medicine, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2021-12)
    Abstract: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients. Methods NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy. Discussion Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy. Trial registration : ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU & draw=2 & rank=1 .
    Type of Medium: Online Resource
    ISSN: 1479-5876
    URL: Article
    DOI: 10.1186/s12967-021-02905-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2118570-0
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  • 7
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    Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Translational Medicine Vol. 20, No. 1 ( 2022-09-11)
    Details
    In: Journal of Translational Medicine, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2022-09-11)
    Abstract: This clinical trial evaluated a novel telomerase-targeting therapeutic cancer vaccine, UV1, in combination with ipilimumab, in patients with metastatic melanoma. Translational research was conducted on patient-derived blood and tissue samples with the goal of elucidating the effects of treatment on the T cell receptor repertoire and tumor microenvironment. Methods The trial was an open-label, single-center phase I/IIa study. Eligible patients had unresectable metastatic melanoma. Patients received up to 9 UV1 vaccinations and four ipilimumab infusions. Clinical responses were assessed according to RECIST 1.1. Patients were followed up for progression-free survival (PFS) and overall survival (OS). Whole-exome and RNA sequencing, and multiplex immunofluorescence were performed on the biopsies. T cell receptor (TCR) sequencing was performed on the peripheral blood and tumor tissues. Results Twelve patients were enrolled in the study. Vaccine-specific immune responses were detected in 91% of evaluable patients. Clinical responses were observed in four patients. The mPFS was 6.7 months, and the mOS was 66.3 months. There was no association between baseline tumor mutational burden, neoantigen load, IFN-γ gene signature, tumor-infiltrating lymphocytes, and response to therapy. Tumor telomerase expression was confirmed in all available biopsies. Vaccine-enriched TCR clones were detected in blood and biopsy, and an increase in the tumor IFN-γ gene signature was detected in clinically responding patients. Conclusion Clinical responses were observed irrespective of established predictive biomarkers for checkpoint inhibitor efficacy, indicating an added benefit of the vaccine-induced T cells. The clinical and immunological read-out warrants further investigation of UV1 in combination with checkpoint inhibitors. Trial registration Clinicaltrials.gov identifier: NCT02275416. Registered October 27, 2014. https://clinicaltrials.gov/ct2/show/NCT02275416?term=uv1 & draw=2 & rank=6
    Type of Medium: Online Resource
    ISSN: 1479-5876
    URL: Article
    DOI: 10.1186/s12967-022-03624-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2118570-0
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  • 8
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    Telomerase as a Target for Therapeutic Cancer Vaccines and Considerations for Optimizing Their Clinical Potential
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-7-5)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-7-5)
    Abstract: Telomerase-based therapeutic cancer vaccines (TCVs) have been under clinical investigation for the past two decades. Despite past failures, TCVs have gained renewed enthusiasm for their potential to improve the efficacy of checkpoint inhibition. Telomerase stands as an attractive target for TCVs due to its almost universal presence in cancer and its essential function promoting tumor growth. Herein, we review tumor telomerase biology that may affect the efficacy of therapeutic vaccination and provide insights on optimal vaccine design and treatment combinations. Tumor types possessing mechanisms of increased telomerase expression combined with an immune permissive tumor microenvironment are expected to increase the therapeutic potential of telomerase-targeting cancer vaccines. Regardless, rational treatment combinations, such as checkpoint inhibitors, are likely necessary to bring out the true clinical potential of TCVs.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2021.682492
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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