Investigator:  Stephen Kennedy, University of Rhode Island

Mentor:  Niall Howlett, University of Rhode Island

Scientific Theme:  Cancer

Abstract:  Tremendous progress has been made in biomaterials-based cancer immunotherapy, where implantation of a biomaterial can be used to reprogram a patient’s own body to mount an immunological attack against cancer cells. Here, a biomaterial is implanted into a host that is loaded with dendritic cell (DC) recruitment factors, danger signal, and cancer antigen. DCs are actively recruited to the implant where they are presented with danger signal and cancer antigen. This dual presentation results in DC activation, the homing of DCs to the lymph nodes, and an eventual anti-tumor response by the host. Despite excellent survival rates in cancer-challenged mice, there is a major limitation in this strategy in that the biomaterial may be depleted of antigen and danger signal (through diffusion) by the time a robust population of DCs has been recruited to the biomaterial. This project’s goals will be to develop a biomaterial system capable of recruiting and harboring DCs, and subsequently delivering cancer antigen and danger signal to recruited DCs when remotely stimulated using magnetic fields. This sequenced delivery will activate a larger population of DCs, resulting in the host mounting a stronger and more efficacious anti-tumor response. The specific aims will be to: (1) develop a biomaterial system and demonstrate its ability to sequentially release DC recruitment factors, followed by magnetically triggered delivery of danger signal and antigen, and (2) verify the ability of this system to recruit DCs and activate them. In aim 1, the biomaterial system will comprise a recruitment compartment and a reprograming delivery compartment. The recruitment compartment will be a porous RGD-modified (for cell adhesion) alginate hydrogel loaded with GM-CSF (DC recruitment factor) and the reprogramming compartment will be a porous, iron-oxide-laden poly(acrylic acid) gel (for magnetic responsivity and electrostatic molecular retention) loaded with PEI-CpG-ODN condensates (danger signal) and tumor lysates (antigen). Delivery profiles will be verified using common protein and DNA detection assays (SA1). Successful DC recruitment will be verified using by digesting the gel and using a cell counter and DC activation will be verified using primary antibody detection (MDCII+ and CCR7+) and FACS (SA2).

Human Health Relevance:  This research will lead to improved cancer survival rates andimmunity and may be successful in combatting a wide range of cancers—particularly those that do not present a specific tumoral site (e.g., leukemia). Finally, this research will provide a salient demonstration of a platform technology that enables sequenced recruitment and reprogramming of cellswhich transcends biomedical disciplines far beyond oncology.