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Bridging responses ...
Bridging responses to a human telomerase reverse transcriptase-based peptide cancer vaccine candidate in a mechanism-based model
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- Ibrahim, Eman I. K. (författare)
- Uppsala universitet,Institutionen för farmaci
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- Ellingsen, Espen B. (författare)
- Oslo Univ Hosp, Inst Canc Res, Dept Tumor Biol, Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway.;Ultimovacs ASA, Oslo, Norway.
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- Mangsbo, Sara M., 1981- (författare)
- Uppsala universitet,Institutionen för farmaci,Ultimovacs AB, Uppsala, Sweden
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- Friberg, Lena (författare)
- Uppsala universitet,Institutionen för farmaci
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(creator_code:org_t)
- Elsevier, 2024
- 2024
- Engelska.
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Ingår i: International Immunopharmacology. - : Elsevier. - 1567-5769 .- 1878-1705. ; 126
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- Therapeutic cancer vaccine
- Immunotherapy
- Model -informed drug development
- Quantitative system pharmacology
- Tumor growth dynamics model
- Pharmacometric modelling framework
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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