Standing variations modeling captures inter-individual heterogeneity in a deterministic model of prostate cancer response to combination therapy

Harsh Vardhan Jain, Inmaculada C. Sorribes, Samuel K. Handelman, Johnna Barnaby, Trachette L. Jackson

Research output: Contribution to journalArticlepeer-review

Abstract

Sipuleucel-T (Provenge) is the first live cell vaccine approved for advanced, hormonally refractive prostate cancer. However, survival benefit is modest and the optimal combination or schedule of sipuleucel-T with androgen depletion remains unknown. We employ a nonlinear dynamical systems approach to modeling the response of hormonally refractive prostate cancer to sipuleucel-T. Our mechanistic model incorporates the immune response to the cancer elicited by vaccination, and the effect of androgen depletion therapy. Because only a fraction of patients benefit from sipuleucel-T treatment, inter-individual heterogeneity is clearly crucial. Therefore, we introduce our novel approach, Standing Variations Modeling, which exploits inestimability of model parameters to capture heterogeneity in a deterministic model. We use data from mouse xenograft experiments to infer distributions on parameters critical to tumor growth and to the resultant immune response. Sampling model parameters from these distributions allows us to represent heterogeneity, both at the level of the tumor cells and the individual (mouse) being treated. Our model simulations explain the limited success of sipuleucel-T observed in practice, and predict an optimal combination regime that maximizes predicted efficacy. This approach will generalize to a range of emerging cancer immunotherapies.

Original languageEnglish (US)
Article number1872
JournalCancers
Volume13
Issue number8
DOIs
StatePublished - Apr 2 2021

Bibliographical note

Funding Information:
This work was partially supported by NIH/NCI U01CA243075 (TLJ). The authors thank Krishna Natarajan and Giray Okten for many helpful discussions.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • ADT
  • Immunotherapy
  • Mathematical model
  • Prostate cancer
  • Provenge
  • Standing variations

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