An Integrated Image-Enabled Computational Model for Lung Cancer Intratumoral Therapy

About This Grant

PROJECT SUMMARY/ABSTRACT Platinum-based agents, such as cisplatin, are highly effective against non-small cell lung cancer (NSCLC) in vitro but fail to achieve the same efficacy when given intravenously (i.v.) due to low intratumoral concentrations and significant off-target systemic adverse events (AEs) that limit dosing. Direct intratumoral delivery of cisplatin is potentially less affected by these limitations and has the potential to prolong survival for the ~120,000 people in the US who die annually of Stage IV NSCLC, both due to improved local treatment of central airway obstruction, and the opportunity to increase tumor antigen presentation to drive immunotherapy response in non- treated lesions. However, the few prior trials that preceded our work used a simple fixed cisplatin dose, with no consideration of highly variant tumor volume or shape, effectively leaving much of the tumor untreated. To better inform intratumoral dosing, we developed a computational model, based on tumor volume and morphology. This image-enabled, computational dosing model is licensed by our industry partner, Quantitative Imaging Solutions (QIS) and was subsequently validated in a cohort of treated patients, correctly predicting tumor response in 72% of cases. However, our prior clinical trials have demonstrated variability in drug retention, ranging from 30-70%, that is present even when the same tumor is treated at multiple time points. Our strong preliminary data, and prior animal studies, indicated that dose retention is dependent on differences in regional microvascular perfusion. Here, we propose to use pre-operative dual-energy CT (DECT) to identify regions of low versus high perfusion and to evaluate retention of the computationally selected dose based on the different perfusion regions. We recently completed a Phase 1A study of a single dose of intratumoral cisplatin delivered via endobronchial ultrasound-guided transbronchial needle injection (EBUS-TBNI) for Stage IV NSCLC. In this application, we will evaluate the safety of the computationally selected dose, which is based on individual tumor volume and morphology, delivered into regions of low versus high perfusion in our FDA and IRB approved Phase 1B, 3+3, dose ranging trial of intratumoral cisplatin for Stage IV NSCLC. Aim 1 will evaluate for adverse events with dose limiting toxicity defined as Common Terminology Criteria for Adverse Events, CTCAE ≥ Grade 3, the primary outcome of Phase 1B. Aim 2 will determine cisplatin retention by high vs low perfusion region and its subsequent effect on cytotoxicity, CT response by RECIST (Response Evaluation Criteria in Solid Tumors) and quantitative regional image analytics, and the immunocellular infiltrate (by single cell RNA sequencing). Completion of these aims will provide the foundation for a computational, image-based, precision intratumoral dosing and delivery platform.