Senior Principal Scientist, Head of Biologics Modeling Certara UK (Simcyp Division) SHEFFIELD, England, United Kingdom
The aim of therapeutic modelling is to quantitatively describe the drug's absorption, distribution, and elimination, along with the relationships between dose, drug concentration, target engagement, and downstream pharmacology. The characteristic features of cell and gene therapy (CGT) are different from those of small- and large-molecule drugs • In CGT, the drug is either a living organism (e.g. CAR-T cell) or a virus (e.g. AAV), that can modify the genetic makeup of the target cell. These can be heterogeneous. • The target is typically a cell carrying a signature recognition molecule. • Absorption, distribution, metabolism, and elimination (ADME) properties of CGT modalities are very different from those of small molecules, with no diffusion across plasma membranes (like small molecules) or paracellular filtration (large molecules) • As living drugs, cellular drugs can proliferate during the therapeutic response, while genetic makeup modulation can be long-term. Cell and Gene Therapy modelling: • Physiologically-Based Pharmacokinetic (PBPK) modelling is desirable in principle, but difficult implement in practice, due to insufficient quantitative and mechanistic insight into the tissue distribution of cellular and viral therapeutics. Often, minimal PBPK modelling approaches are used instead. Tissue-specific distribution patterns (e.g., CAR-T cells trafficking to tumour sites and lymphoid organs) need to be evaluated in vivo. • The tracking of cell persistence, expansion, and contraction dynamics over time is often critical and relies upon Quantitative Systems Pharmacology (QSP) approaches that integrate multiple biological scales (cellular, tissue, organism) • Interpatient variability is very high due to CGT often involving one-time treatments with highly variable patient-dependent drug preparations and long-term responses. • Long-term efficacy extrapolations from short-term clinical trial data can be challenging and rely on complex survival analysis and disease progression modelling from clinical data. • For CAR-T therapies: the drug modelling also includes modelling of tumour burden dynamics, cytokine release, and the bidirectional relationship between tumour and CAR-T cells • For gene therapies: modelling of vector distribution, transduction efficiency, transgene expression kinetics, and durability • Incorporation of immune responses to the therapeutic product or vector
Examples to be discussed involve • Mechanistic Evaluation of Anti‐CD19 CAR‐T Cell Therapy Repurposed in Systemic Lupus Erythematosus Using a Quantitative Systems Pharmacology Model • Translational PK-PD model for in vivo CAR-T-cell therapy delivered using CAR mRNA-loaded polymeric nanoparticle vector
Learning Objectives:
To showcase cutting-edge developments in systems pharmacology models applied to novel biologics, cell and gene therapy.
Upon completion, the participants will have gained insight into the process of cell and gene therapy model construction.
To foster collaboration between computational biologists, pharmacologists, and clinical researchers.
Upon completion, the participants will have gained insight into the process of dose prediction and clinical data analysis for cell and gene therapies
Upon completion, the participants gain an appreciation that Cell and gene therapy (CGT) drugs are either living organisms (e.g., CAR-T cells) or viruses (e.g., AAV), which can permanently modify the genetic makeup of the target cell and are often available as single-dose therapies due to the immune response.
