Modeling and Modulating Antitumor Immunity with Precision Nanomedicines in 3D-Bioprinted Tumoroids

Many drugs show promising results in laboratory research but eventually fail to show clinical benefit. One main reason for this translational gap is that the cancer models used are inadequate. Most models lack the complex tumor-stromal-immune cell interactions with their tumor microenvironment (TME) that are required for progression. Conventional 2D models, where cells grow on rigid plastic plates mainly as mono-cultures, fail to recapitulate these complex interactions. Hence, we developed a vascularized, hydrogel-based 3D-bioprinted tumor model consisting of patient-derived tumor, PBMCs, and TME cells. Our 3D models are based on our library of hydrogels as scaffolds for different tumor types according to the mechanical properties of the tissue of origin, which dictates the proteo-genomic signature and, hence, the response to different therapies. Using these unique high-throughput 3D models, we are currently validating their ability to mimic patient-specific tumors and TME, in order to serve as a tool to predict patient response to different treatments. To decide which therapies to test on our 3D platforms, we consider cancer-specific standard-of-care, investigational therapies that we develop in our lab, as well as therapies proposed by an AI-based algorithm that utilizes H&E slides to generate individual drug response scores for targeted and immune therapies. To validate the ability of our models to predict patient responses, we are currently conducting an 80-patient clinical trial at Sheba Medical Center, testing different treatments on samples covering 7 distinct cancer types. These unique 3D models have the potential to facilitate target discovery and drug development, as well as to serve as a reliable system for precision medicine.