Early, precise, and safe clinical evaluation of the pharmacodynamic effects of novel agents in the intact human tumor microenvironment

• DOI: 10.3389/fphar.2024.1367581
• Publication Date: 2024-04-12T14:40:05Z
• Authors: Kenneth R. Gundle; Karthik Rajasekaran; Jeffrey Houlton; Gary B. Deutsch; Thomas J. Ow; Robert G. Maki; John Pang; Cherie-Ann O. Nathan; Daniel Clayburgh; Jason G. Newman; Elyse Brinkmann; Michael J. Wagner; Seth M. Pollack; Matthew J. Thompson; Ryan J. Li; Vikas Mehta; Bradley A. Schiff; Barry I. Wenig; Paul L. Swiecicki; Alice L. Tang; Jessica L. Davis; Annemieke van Zante; Jessica A. Bertout; Wendy Jenkins; Atticus Turner; Marc Grenley; Connor Burns; Jason P. Frazier; Angela Merrell; Kimberly H. W. So...; Jonathan M. J. Derry; Kate C. Gillespie; Bre Mills; Richard A. Klingh...
• Keywords: Drug Development; MicroDose; Preclinical testing; Pharmacodynamics

Introduction: Drug development is systemically inefficient. Research and costs for novel therapeutics average hundreds of millions to billions dollars, with the overall likelihood approval estimated be as low 6.7% oncology drugs. Over half these failures are due a lack drug efficacy. This pervasive repeated rate success exemplifies how preclinical models fail adequately replicate complexity heterogeneity human cancer. Therefore, new methods evaluation, early in trajectory, essential both rule-in rule-out agents more rigor speed, but also spare clinical trial patients from potentially toxic sequelae (high risk) testing investigational that have producing response (low benefit). Methods: The vivo (CIVO ® ) platform was designed change this paradigm. CIVO precisely delivers microdose quantities up 8 drugs or combinations directly into patient tumors 4–96 h prior planned surgical resection. Resected tissue then analyzed responses at each site intratumoral exposure. Results: To date, has been used safely 6 trials, including 68 subjects, 5 17 approved agents. tissues were initially using immunohistochemistry situ hybridization assays (115 biomarkers). As technology advanced, paired spatial biology analysis platforms, successfully track anti-neoplastic immune-modulating activity injected intact tumor microenvironment. Discussion: Herein we provide report use patients, depiction robust enabled by platform, description operational regulatory mechanisms deploy approach synergistic partnership pharmaceutical partners. We further detail clinically safe scientifically precise alternative complement efficacy modeling, outputs inform, streamline, de-risk development.