Investigating the impact of tumor heterogeneity on sustained low dosage immunotherapy via a peritumoral immunotheranostic hydrogel

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One of the most challenging aspects of cancer therapy is the uniqueness of each patient's disease, which can result in significant delays in effective diagnosis and treatment. This issue has become particularly critical for immunotherapy, which is therapy that uses therapeutics (drugs) to modify or enhance a patient's own immune system's ability to target and kill cancerous cells. Current immunotherapy methods use a series of high dose infusions, e.g., injections, of therapeutics into the blood circulation, which can severely disrupt the normal function of the immune system, resulting in harsh and often unpredictable side effects. For patients with melanoma (skin cancer) and other solid tumors, responses to treatment depend on both the unique variety of cells within the tumors and the therapeutics' ability to reach these cells and tissues. Thus, the research objective of this project is to engineer a customizable delivery system for investigating lower dose treatment strategies and for assessing the ability of different therapeutics to reach critical immune and cancer cells within tumors. The investigators will optimize and validate this system by measuring the accumulation of therapeutics within tumors and cells of two mouse models of melanoma, which are representative of two patient-specific disease differences due to different tumor structures. As opposed to a series of high dose infusions, these therapeutics will be administered in a controlled continuous fashion at low doses to investigate sustained and localized immunotherapy. This work may lead to a new immunotherapy treatment option with a lower number of unwanted side effects. The educational objective of this project is to expose undergraduate students and the public to the contributions of Biomedical Engineering in the field of cancer research. A Cancer Engineering course for undergraduates will be implemented to discuss fundamental engineering-based strategies to treat cancer. An accompanying website will be maintained by the students in the class that focuses on educating the public on how engineering concepts enhance strategies for cancer therapy.The goal of this project is to design and apply a novel system to investigate the impact of tumor heterogeneity on the pathophysiology of the tumor microenvironment during sustained low dosage immunomodulation. The project's first objective is to tailor filomicelle (FM)-hydrogels for the sustained peritumoral delivery of immunotheranostic (combined immunotherapy and diagnostics) micelles (MCs) and biologics. FM-hydrogels will be customized to function as a tool for 1) real time diagnostic assessment of tumor margin heterogeneity via magnetic resonance imaging ( MRI), enabled by a DyLight 650 and Gd (gadolinium) tagged FM-hydrogels; 2) the sustained low dosage delivery of an immunostimulant (IMQ (imiquimod)) to induce pro-inflammatory stimulation of myeloid-derived suppressor cells (MDSCs) and localized release of cytokine IL-12 from tumor resident dendritic cells (DCs) and 3) the sustained low dosage delivery of IL-12 directly by loading the IL-12 within polymersomes (PS ) that will be covalently retained within the FM-hydrogel. During in vitro studies, photo-oxidation will be used to trigger the cylinder-to-sphere, i.e., FM-to-MC, transition and release of PS payloads on demand. Studies were designed to test the hypothesis that both IMQ and Gd will transfer from the FM-hydrogels to released micelles during the cylinder-to-sphere transition and remain active. The project's second objective is to investigate the influence of in vivo localized and sustained delivery of immunotheranostic MCs and IL-12 to the microenvironment of clinically relevant heterogeneous solid tumors. Two melanoma mouse models (BRAF(V600E)/PTEN and B16F10) were strategically selected due to their significant differences in vascular development and presence of immunosuppressive cells within their microenvironments. The differences in lymphatic drainage will be mapped and compared to provide insight into how heterogeneity at the tumor margin can impact intratumoral targeting of therapeutics and the interactions between nanomaterials and immune cells critical to cancer immunotherapy will be examined. Studies were designed to test two hypotheses: 1) that differences in tumor heterogeneity between the models will impact lymphatic drainage and access of micelles to the tumor microenvironment and 2) that sustained low dosage delivery of immunomodulatory factors through the draining lymphatics of solid tumors will more efficiently inhibit tumor-induced immune suppression compared to high dosage intermittent injections. In addition to the potential to generate new approaches to treat and monitor changes within tumors, the platform developed may be useful for investigating sustained therapeutic dosing regimens, for assessing patient-specific vascular and lymphatic access to tumors for personalized cancer therapy and for investigating the impact of specific immunomodulatory factors on the progression and growth of solid tumors.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.