Add like
Add dislike
Add to saved papers

Radiation and PD-(L)1 treatment combinations: immune response and dose optimization via a predictive systems model.

BACKGROUND: Numerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive of outcome are lacking. We here present a model-based analysis of tumor size dynamics and immune markers, which integrates experimental data from multiple studies and provides a validated simulation framework predictive of biomarkers and anti-tumor response rates, for untested dosing sequences and schedules of combined radiation (RT) and anti PD-(L)1 therapies.

METHODS: A quantitative systems pharmacology model, which includes key elements of the cancer immunity cycle and the tumor microenvironment, tumor growth, as well as dose-exposure-target modulation features, was developed to reproduce experimental data of CT26 tumor size dynamics upon administration of RT and/or a pharmacological IO treatment such as an anti-PD-L1 agent. Variability in individual tumor size dynamics was taken into account using a mixed-effects model at the level of tumor-infiltrating T cell influx.

RESULTS: The model allowed for a detailed quantitative understanding of the synergistic kinetic effects underlying immune cell interactions as linked to tumor size modulation, under these treatments. The model showed that the ability of T cells to infiltrate tumor tissue is a primary determinant of variability in individual tumor size dynamics and tumor response. The model was further used as an in silico evaluation tool to quantitatively predict, prospectively, untested treatment combination schedules and sequences. We demonstrate that anti-PD-L1 administration prior to, or concurrently with RT reveal further synergistic effects, which, according to the model, may materialize due to more favorable dynamics between RT-induced immuno-modulation and reduced immuno-suppression of T cells through anti-PD-L1.

CONCLUSIONS: This study provides quantitative mechanistic explanations of the links between RT and anti-tumor immune responses, and describes how optimized combinations and schedules of immunomodulation and radiation may tip the immune balance in favor of the host, sufficiently to lead to tumor shrinkage or rejection.

Full text links

We have located links that may give you full text access.
Can't access the paper?
Try logging in through your university/institutional subscription. For a smoother one-click institutional access experience, please use our mobile app.

For the best experience, use the Read mobile app

Mobile app image

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app

All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

By using this service, you agree to our terms of use and privacy policy.

Your Privacy Choices Toggle icon

You can now claim free CME credits for this literature searchClaim now

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app