Advisor: Susan Thomas, Ph.D. (Georgia Institute of Technology)
Julie Champion, Ph.D. (Georgia Institute of Technology)
Mark Prausnitz, Ph.D. (Georgia Institute of Technology)
Krishnendu Roy, Ph.D. (Georgia Institute of Technology)
Edmund Waller, M.D., Ph.D. (Emory University)
Enhancing immune checkpoint blockade and cancer immunotherapy via tissue targeting and biomaterial nanoparticles
Immune checkpoint blockade (ICB) has emerged in recent years as one of the most promising classes of new cancer therapies. However, a significant majority of patients receiving these therapies 1) do not respond, 2) experience adverse side effects, or 3) respond initially but relapse. Overcoming these limitations is therefore a critical hurdle in improving cancer outcomes using ICB. To this end, immune checkpoints are active in both the tumor microenvironment and lymphoid tissues where they prevent T cell cytotoxic function and activation, respectively. To date, however, clinical applications of ICB have relied on systemic administration of free antibody drugs, which results in poor accumulation in tumors and lymphoid tissues and increases the risk of off target toxicities. Improving the selective delivery of ICB therapies to target tissues offers a promising approach to augment both the efficacy and safety of ICB. Moreover, upregulation of non-redundant immunosuppressive pathways is hypothesized to result in disease recurrence, motivating the use of combination immunotherapies to prevent relapse. However, many promising immunomodulatory agents that could work in synergy with ICB are small molecules and are thus short-lived in vivo, insoluble in aqueous solvents, and not targeted to the cells of interest. The objectives of this proposal, which will be demonstrated through impaired disease progression, diminution in treatment-associated toxicities, and protection against recurrence in multiple advanced preclinical mouse tumor models, are to 1) improve the effects of ICB within tumor and lymphoid tissues using various routes of administration and 2) develop a drug-eluting ICB platform that improves delivery of small molecule immunomodulators to T cells while simultaneously blocking immune checkpoint signaling.