This is one of the presentations in our 2-hr symposium proposal (Engineered cytokines as turbochargers in cancer immunotherapy). Title of this specific talk is "A quantitative systems pharmacology model to characterize the PKPD relationship following treatment with IL-15R agonists" This specific presentation will talk about design of a novel PD1 targeted IL-15 Fc fusion, understanding its complex mechanism of action in vivo in preclinical species using a state of the art quantitative systems pharmacology model and will discuss how this model can be translated to humans for implementation to support clinical trial design aspects such as dose selection and dosing frequency.
Cytokines are one of the earliest immunotherapies that garnered interest in cancer treatment due to their unique ability to trigger and potentiate both innate and adaptive immune responses. Despite some early clinical success seen by cytokines such as IFNa and IL-2, the use of cytokines as anticancer agents has been limited due to their poor drug-like properties (including short half-life), pleiotropic nature and widespread systemic effects leading to poor safety and limited efficacy. However, emergence of other promising cancer immunotherapies in recent years (such as checkpoint blockers, T-cell bispecifics, CAR-T cell therapies) have reinvigorated interest in cytokine use in anticancer treatment. Cytokines that potentiate immune responses and boost anti-tumor immunity include IFN-a, IL-2, IL-15, IL-7 IL-12, IL-18, FTL3L, IL-21, IL-21. Other approaches include inhibition of immunosuppressive activity of cytokines such as TNF-a, TGF-b and CSF-1 and few others. More recently, a variety of engineering approaches are being utilized to improve tolerability and efficacy of cytokine-based therapies. Such approaches include targeted immunocytokines to redirect to tissue of interest using antibody-fusion constructs, cytokine mimetics to improve developability, masked cytokines with conditional activation at the site-of-interest, Fc-fusions and PEGylated moieties for half-life extension. Beyond engineering, optimizing PK/PD properties and improving safety is essential to realize the full potential of cytokines as therapeutics; this is required for improving therapeutic index by reshaping the biodistribution profile as well as target engagement characteristics. Moreover, strategies that include prolonging exposure (such as half-life extension) can improve developability and enable convenient dosing schedules. As cytokine engineering approaches become more complex, it becomes important to have mechanistic understanding of how each alteration can impact pharmacology, PK/PD properties and safety profile of these therapeutics. Such an understanding is critical to guide lead candidate selection, provide translational insights, define dosing strategies and suggest potential combination partners in the clinic. This symposium will focus on preclinical, translational and clinical PKPD efforts related to novel cytokine therapeutics including characterization of intricate PKPD relationships in preclinical/clinical setting and development of state-of-the-art in silico models to understand preclinical data or to inform design of clinical trials.
Learning Objectives:
Upon completion, participants will be able to describe translational PKPD aspects, challenges and considerations in preclinical and clinical development of novel engineered cytokines for cancer immunotherapy
Upon completion, participants will be able to learn and understand the factors that govern the pharmacokinetics, biodistribution, PKPD and safety of novel cytokine therapies
Upon completion, participants will be able to learn state of the art modeling and simulation techniques and their implementation in translational and clinical drug development of engineered cytokine therapies