Therapeutic Response Testing of Biomaterials in Metastasis: Development of Clinical and Pre-Clinical Models

Abstract

In-market therapeutics have failed in treating distant tumors in comparison to localized tumors. To determine if this disparity is caused by the unique personalized metastatic niches present in distant tumors, metastatic tissue needs to be closely evaluated. Existing patient tissue research is strongly dependent on large, primary surgical specimens while metastases consist of smaller lesions with limited amounts of tissue. A systemic response clearance of local and distant tumors too small or inaccessible for surgical excision is needed for eradication. This thesis reviews the current literature present in the field of intratumoral drug delivery of immunoadjuvants, their setbacks, and how it could be further improved for eliciting a potent immune response against local and distant tumors. This thesis will also incorporate the development and workflow of an in vivo metastatic mouse model, a biobanking repository, and in vitro testing of human patient derived needle core biopsy specimens with an intact tumor microenvironment (TME). In vitro testing was further validated through detection of enzymatic release, fluorescence imaging, and histology using a novel AI Cell Segmentation and Nucleation Analysis Tool (CSNAT) for phenotypic characterization. In-clinic results from patient’s therapeutic responses were also cross examined with ex vivo cultures. Thus, establishing a feasible workflow of testing small fragments of tissue samples with pre-clinical therapeutic interventions. This workflow can be further applied in clinical therapeutics such as injectable oncolytic interventions for personalized patient care approaches where pre-clinical mouse models predominately fail in capturing the unique metastatic profile exhibited in each human.