Quantitative Mechanistic Modeling in Support of Pharmacological Therapeutics Development in Immuno-Oncology
- There has been significant growth in the development of immuno-modulating pharmacological treatments for various cancers following the approval of the first immune checkpoint inhibitor.
- Challenges in immuno-oncology (IO) drug development are complex and span from the discovery phase to late-stage clinical testing and regulatory approval.
- In the preclinical setting:
- Numerous potential drug targets around immune checkpoints.
- Expanding list of immuno-modulatory forces in the tumor microenvironment, presenting new IO drug targets.
- Emergence of exploratory biomarkers.
- Potential of combination therapies necessitating quantitative, mechanistic systems models.
- In the clinical setting:
- Qualification of surrogate biomarkers predictive of IO treatment efficacy or outcomes.
- Optimization of IO trial design.
- The mini-review highlights the evolution and current state of quantitative systems models that describe the interplay between the tumor and the immune system.
- It also discusses the integration of these models with quantitative pharmacology models of IO-modulating agents as tools to address the challenges in IO drug development.
Immunotherapy of cancer has had a long history of development, starting from pioneering efforts in using coley toxins to treat patients—a therapeutic approach named after Dr. William Coley. Even though these earlier efforts never turned into a standard treatment, further investigations on the relationships between tumor cells and the immune system led to discoveries which unveiled fundamental principles underlying cancer progression, such as immune surveillance, cancer dormancy, cancer immuno-editing, and the cancer immunity cycle.
These discoveries were foundational for clinical successes and corresponding regulatory approvals in recent years, of therapies targeting the CTLA-4, PD-1, and PD-L1 immune checkpoints. In the wake of these successes, there has been an explosion in the development of immuno-modulating, anti-cancer pharmacological modalities, leading to the initiation of, literally, thousands of clinical trials. However, from the discovery phase to late-stage clinical testing and regulatory approval, challenges in the development of immuno-oncology (IO) drugs are multi-fold and complex, with related complexities in the design of clinical trials; if unaddressed, these may lead to a decreased probability of success...
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