Immune Response Template for Quantitative Systems Pharmacology Modeling: Description of Co-inhibitory and Co-stimulatory Receptors Interaction
Antonina Nikitich (1), Oleg Demin Jr (1)
(1) InSysBio, Russia
Objectives: Immunotherapy is a new class of cancer treatment that works by activation of immune response of patient to fight with tumor. Antibodies targeting co-inhibitory and co-stimulatory receptors expressed on the surface of immune and cancer cells are one of the most promising and effective type of immunotherapies used to treat cancer. The main aim of this study is to develop a platform facilitating the development of checkpoint inhibitors (antibodies targeting co-inhibitory receptors) and agonists of co-stimulatory receptors.
Methods: Immune Response Template (IRT) platform was developed. IRT is ordinary differential equations based model describing immune system in humans. It includes various cell types (CD4 and CD8 T cells, different types of macrophages (M1, M2a, M2b, M2c), B cells, dendritic cells, natural killer (NK) cells, myeloid-derived suppressor cells (MDSC), etc.), processes (antigen presentation, specific lysis, activation, differentiation, proliferation, etc.), mediators (TGF beta, IFN gamma, TNF alpha, IL-2, IL-6, IL-10, IL-12, etc.), and co-inhibitory and co-stimulatory receptors (TCR, CD3, MHC-I, MHC-II CD28, CD86, CTLA-4, PD-1, PD-L1, LAG3, TIM-3, GITR, OX40, 4-1BB etc.) involved in tumor progression and treatment. The interaction of surface molecules were described in framework of immunological synapse between different types of immune cells (for example, interaction of CD4 T cells and dendritic cells) and between immune cells and cancer cells (for example, interaction of CD8 T cells and tumor cells). Part of the developed model including CD4 T cells, dendritic cells and immunological synapse between them, was used to describe in vitro data on effect of nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor) combination on IFN gamma production by CD4 T cells stimulated by autologous dendritic cells .
Results: Model was developed and calibrated. Parameters were identified on the basis of published in vitro and in vivo data. Description of co-inhibitory and co-stimulatory receptors in framework immunological synapse takes into account the conformation and valency of receptors (for example, CTLA-4 is bivalent homodimer, i.e., it exists as dimer and each monomer is able to bind with other receptors). Developed model allows to describe increase in IFN gamma production by CD4 T cells cultured with autologous dendritic cells in presence of different concentrations of nivolumab and ipilimumab . Model was able to describe variability in response to nivoloumab/ipilimumab combination by cells obtained from different subjects. The variability was described by changing value of one parameter.
Conclusions: Developed model takes into account the interaction of co-inhibitory and co-stimulatory receptors in framework of immunological synapse between immune cells or immune cells and cancer cells. Model is able to describe the data on checkpoint inhibitors effect on CD4 T cells activation by dendritic cells including the variability in response. Developed platform could be used as tool to investigate and optimize immunotherapies for cancer treatment including combination of checkpoint inhibitors.
 Selby et al. PLoS One. 2016 Sep 9;11(9):e0161779