Presage’s CIVOTM uses intratumoral microdosing to investigate novel cancer drugs
Developing drugs for patients with cancer is a daunting challenge. Biological hypotheses that work well in mouse models of cancer often fail to replicate in the setting that matters most – patients with cancer. Biopharma companies often generate far more drug candidates than can be effectively evaluated in clinical trials. The costs for clinical trials are simply too prohibitive to assess all available drug candidates or drug combinations. All told, the barriers for evaluating novel cancer drugs in patients with traditional clinical trials are staggeringly high.
Phase 0 Studies
Presage is pioneering a new approach to addressing this challenge. By coupling the CIVO platform with the FDA’s guidance on exploratory investigational new drug applications (Exploratory-IND), Presage has identified a path to rapidly evaluate multiple drug candidates, but without the costs and time associated with a traditional phase 1 clinical trial.Such eIND studies—also known as phase zero trials—use minute amounts of drugs to assess their pharmacodynamics effects in patients. Unlike traditional phase 1 clinical trials that expose patients to far higher doses of investigational drugs, and therefore an increased risk of toxicity, intratumoral microdosing uses approximately 100-fold lower doses of drug candidates.
Phase 2 Studies
Presage also aims to apply CIVO to novel later stage master protocol trial designs of multiple agents. Presage expects that investigators may be able to assess pathological response to intratumorally microdosed drugs and drug combinations in order to assign patients to particular arms of study.
A New Application of Microdosing
Unlike systemic microdosing studies that were used by drug developers in the mid-2000s, Presage’s CIVO device may be used to deliver microdose levels of a drug, but in a highly localized portion of a patient’s tumor. This is designed to provide full therapeutic-level drug exposure to a portion of the tumor.
The patented CIVO platform is a device that comprises a microinjector and fluorescent tracking microspheres. This device is intended to enable intratumoral microdosing of cancer agents.View Publication
Understanding the CIVO Platform
CIVO works by microinjecting up to eight columns of drug solution into a tumor. Unlike any traditional clinical approach, data can be obtained from multiple drugs across multiple tumor locations from a single tumor.
Different drugs are mixed with fluorescent tracking microspheres and loaded into the device by a pharmacist.
Drugs are injected into the patient’s tumor forming columns upon device removal.
Drugs are left in place to interact with tumor cells for 24–96 hours.
Microinjected tumor tissue is surgically resected and histologically sectioned for subsequent analysis.
Tumor tissue is analyzed using immunohistochemistry-based pharmacodynamic biomarkers.
Presage also uses the device to assess drug combination activity. In preclinical models, single agents are typically injected both separately and in combined formulations into the same tumor. Biological activity above what would be expected from mere additivity is indicative of potentially synergistic mechanisms of action of the drug combination. In an alternative experimental design, a single drug has been dosed systemically and then potential combination partner drugs are microdosed using the CIVO device.
High-resolution scanning of the entire microscopy slide is used to capture images of every cell from each tissue section generated. These digitized images are then processed with Presage’s in-house, custom image analysis platform CIVO Analyzer.
CIVO Analyzer combines automated detection of the drug injection sites, characterization and analysis of cellular and tissue architecture, molecular marker-specific algorithms, and cross-section registration to quantify multiple measures of drug response from various tumor depths along each injection column. Such analysis creates a comprehensive portrait of drug response by looking at elements such as how the drug induces death of cancer and stromal cells, how the drug provokes a response by the immune system, and how drugs work together to enhance effects.
Intratumoral Microdosing Advantages
- Assess biology in a native tumor microenvironment
- Microdosing of agents typically toxic at systemic doses
- Investigate multiple agents in a single patient tumor
- Assess a range of pharmacologically relevant drug concentrations
- Enable assessment of drug candidates in patient tumors at pre-IND stage
Drug testing in the patient: Toward personalized cancer treatment
R. Charles CoombesView Publication