دورية أكاديمية
Bridging responses to a human telomerase reverse transcriptase-based peptide cancer vaccine candidate in a mechanism-based model.
| العنوان: | Bridging responses to a human telomerase reverse transcriptase-based peptide cancer vaccine candidate in a mechanism-based model. |
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| المؤلفون: | Ibrahim EIK; Department of Pharmacy, Uppsala University, Uppsala, Sweden., Ellingsen EB; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; Ultimovacs ASA, Oslo, Norway., Mangsbo SM; Department of Pharmacy, Uppsala University, Uppsala, Sweden; Ultimovacs AB, Uppsala, Sweden., Friberg LE; Department of Pharmacy, Uppsala University, Uppsala, Sweden. Electronic address: lena.friberg@farmaci.uu.se. |
| المصدر: | International immunopharmacology [Int Immunopharmacol] 2024 Jan 05; Vol. 126, pp. 111225. Date of Electronic Publication: 2023 Nov 20. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 100965259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1705 (Electronic) Linking ISSN: 15675769 NLM ISO Abbreviation: Int Immunopharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Amsterdam ; New York : Elsevier Science, c2001- |
| مواضيع طبية MeSH: | Carcinoma, Non-Small-Cell Lung* , Cancer Vaccines*/therapeutic use , Telomerase*/therapeutic use , Lung Neoplasms*/pathology , Melanoma*, Humans ; Peptides/therapeutic use |
| مستخلص: | Therapeutic cancer vaccines are novel immuno-therapeutics, aiming to improve clinical outcomes with other immunotherapies. However, obstacles to their successful clinical development remain, which model-informed drug development approaches may address. UV1 is a telomerase based therapeutic cancer vaccine candidate being investigated in phase I clinical trials for multiple indications. We developed a mechanism-based model structure, using a nonlinear mixed-effects modeling techniques, based on longitudinal tumor sizes (sum of the longest diameters, SLD), UV1-specific immunological assessment (stimulation index, SI) and overall survival (OS) data obtained from a UV1 phase I trial including non-small cell lung cancer (NSCLC) patients and a phase I/IIa trial including malignant melanoma (MM) patients. The final structure comprised a mechanistic tumor growth dynamics (TGD) model, a model describing the probability of observing a UV1-specific immune response (SI ≥ 3) and a time-to-event model for OS. The mechanistic TGD model accounted for the interplay between the vaccine peptides, immune system and tumor. The model-predicted UV1-specific effector CD4+ T cells induced tumor shrinkage with half-lives of 103 and 154 days in NSCLC and MM patients, respectively. The probability of observing a UV1-specific immune response was mainly driven by the model-predicted UV1-specific effector and memory CD4+ T cells. A high baseline SLD and a high relative increase from nadir were identified as main predictors for a reduced OS in NSCLC and MM patients, respectively. Our model predictions highlighted that additional maintenance doses, i.e. UV1 administration for longer periods, may result in more sustained tumor size shrinkage. Competing Interests: Declaration of Competing Interest EIKI and LEF declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EBE and SMM are employees of Ultimovacs ASA or Ultimovacs AB. SMM controls shares in Ultimovacs ASA via a privately owned company. (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Immunotherapy; Model-informed drug development; Pharmacometric modelling framework; Quantitative system pharmacology; Therapeutic cancer vaccine; Tumor growth dynamics model |
| المشرفين على المادة: | 0 (Cancer Vaccines) EC 2.7.7.49 (Telomerase) 0 (Peptides) |
| تواريخ الأحداث: | Date Created: 20231121 Date Completed: 20231228 Latest Revision: 20240207 |
| رمز التحديث: | 20240207 |
| DOI: | 10.1016/j.intimp.2023.111225 |
| PMID: | 37988911 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1878-1705 |
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| DOI: | 10.1016/j.intimp.2023.111225 |