De-risking Clinical Trial Failure Through Mechanistic Simulation

Overview

Journal Immunother Adv

Publisher Oxford University Press

Specialty Allergy & Immunology

Date 2022 Sep 30

PMID 36176591

Authors

Liam V Brown

Jonathan Wagg

Rachel Darley

Andy van Hateren

Tim Elliott

Eamonn A Gaffney

Mark C Coles

Affiliations

Soon will be listed here.

Abstract

Drug development typically comprises a combination of pre-clinical experimentation, clinical trials, and statistical data-driven analyses. Therapeutic failure in late-stage clinical development costs the pharmaceutical industry billions of USD per year. Clinical trial simulation represents a key derisking strategy and combining them with mechanistic models allows one to test hypotheses for mechanisms of failure and to improve trial designs. This is illustrated with a T-cell activation model, used to simulate the clinical trials of IMA901, a short-peptide cancer vaccine. Simulation results were consistent with observed outcomes and predicted that responses are limited by peptide off-rates, peptide competition for dendritic cell (DC) binding, and DC migration times. These insights were used to hypothesise alternate trial designs predicted to improve efficacy outcomes. This framework illustrates how mechanistic models can complement clinical, experimental, and data-driven studies to understand, test, and improve trial designs, and how results may differ between humans and mice.

Citing Articles

A Mathematical Modelling Study of Chemotactic Dynamics in Cell Cultures: The Impact of Spatio-temporal Heterogeneity.

Ayensa-Jimenez J, Doweidar M, Doblare M, Gaffney E Bull Math Biol. 2023; 85(10):98.

PMID: 37684435 PMC: 10491576. DOI: 10.1007/s11538-023-01194-9.

References

Kumbhari A, Kim P, Lee P . Optimisation of anti-cancer peptide vaccines to preferentially elicit high-avidity T cells. J Theor Biol. 2019; 486:110067. DOI: 10.1016/j.jtbi.2019.110067. View

Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C . Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med. 2012; 18(8):1254-61. DOI: 10.1038/nm.2883. View

Martin-Fontecha A, Lanzavecchia A, Sallusto F . Dendritic cell migration to peripheral lymph nodes. Handb Exp Pharmacol. 2008; (188):31-49. DOI: 10.1007/978-3-540-71029-5_2. View

Garboczi D, Hung D, Wiley D . HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. Proc Natl Acad Sci U S A. 1992; 89(8):3429-33. PMC: 48881. DOI: 10.1073/pnas.89.8.3429. View

Parham P, Brodsky F . Partial purification and some properties of BB7.2. A cytotoxic monoclonal antibody with specificity for HLA-A2 and a variant of HLA-A28. Hum Immunol. 1981; 3(4):277-99. DOI: 10.1016/0198-8859(81)90065-3. View

Parker K, Bednarek M, Coligan J . Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol. 1994; 152(1):163-75. View

Li W, Joshi M, Singhania S, Ramsey K, Murthy A . Peptide Vaccine: Progress and Challenges. Vaccines (Basel). 2015; 2(3):515-36. PMC: 4494216. DOI: 10.3390/vaccines2030515. View

Cahalan M, Parker I . Choreography of cell motility and interaction dynamics imaged by two-photon microscopy in lymphoid organs. Annu Rev Immunol. 2008; 26:585-626. PMC: 2732400. DOI: 10.1146/annurev.immunol.24.021605.090620. View

Bousso P . T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nat Rev Immunol. 2009; 8(9):675-84. DOI: 10.1038/nri2379. View

10.

Cahalan M, Parker I . Close encounters of the first and second kind: T-DC and T-B interactions in the lymph node. Semin Immunol. 2005; 17(6):442-51. PMC: 2953541. DOI: 10.1016/j.smim.2005.09.001. View

11.

Kumbhari A, Egelston C, Lee P, Kim P . Mature Dendritic Cells May Promote High-Avidity Tuning of Vaccine T Cell Responses. Front Immunol. 2020; 11:584680. PMC: 7662095. DOI: 10.3389/fimmu.2020.584680. View

12.

Aarntzen E, Srinivas M, Bonetto F, Cruz L, Verdijk P, Schreibelt G . Targeting of 111In-labeled dendritic cell human vaccines improved by reducing number of cells. Clin Cancer Res. 2013; 19(6):1525-33. DOI: 10.1158/1078-0432.CCR-12-1879. View

13.

Garstka M, Fish A, Celie P, Joosten R, Janssen G, Berlin I . The first step of peptide selection in antigen presentation by MHC class I molecules. Proc Natl Acad Sci U S A. 2015; 112(5):1505-10. PMC: 4321303. DOI: 10.1073/pnas.1416543112. View

14.

Gutenkunst R, Waterfall J, Casey F, Brown K, Myers C, Sethna J . Universally sloppy parameter sensitivities in systems biology models. PLoS Comput Biol. 2007; 3(10):1871-78. PMC: 2000971. DOI: 10.1371/journal.pcbi.0030189. View

15.

Mempel T, Henrickson S, von Andrian U . T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature. 2004; 427(6970):154-9. DOI: 10.1038/nature02238. View

16.

Gu Y, Zhao W, Meng F, Qu B, Zhu X, Sun Y . Sunitinib impairs the proliferation and function of human peripheral T cell and prevents T-cell-mediated immune response in mice. Clin Immunol. 2009; 135(1):55-62. DOI: 10.1016/j.clim.2009.11.013. View

17.

Reits E, Griekspoor A, Neijssen J, Groothuis T, Jalink K, van Veelen P . Peptide diffusion, protection, and degradation in nuclear and cytoplasmic compartments before antigen presentation by MHC class I. Immunity. 2003; 18(1):97-108. DOI: 10.1016/s1074-7613(02)00511-3. View

18.

Cavanagh L, Weninger W . Dendritic cell behaviour in vivo: lessons learned from intravital two-photon microscopy. Immunol Cell Biol. 2008; 86(5):428-38. DOI: 10.1038/icb.2008.25. View

19.

Bogle G, Dunbar P . T cell responses in lymph nodes. Wiley Interdiscip Rev Syst Biol Med. 2010; 2(1):107-116. DOI: 10.1002/wsbm.47. View

20.

Nielsen M, Lundegaard C, Worning P, Lauemoller S, Lamberth K, Buus S . Reliable prediction of T-cell epitopes using neural networks with novel sequence representations. Protein Sci. 2003; 12(5):1007-17. PMC: 2323871. DOI: 10.1110/ps.0239403. View