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 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 these treatments. Checkpoint pathways are active in both the tumor microenvironment and lymphoid tissues where they prevent T cell cytotoxic function and activation, respectively. While improving tumor and lymphoid delivery of these therapies offers a promising approach to advance the efficacy of ICB, clinical applications of ICB have so far only relied on systemic administrations, which often result in poor tumor and lymphoid accumulation. Additionally, administration of combination immunotherapies outside of ICB is challenging as many of these drugs are short-lived in vivo, are insoluble in aqueous solvents, and are not targeted to the cells of interest leading to off-target side effects. Given the current state of ICB therapy, the focus of this thesis work is to address the drug delivery barriers associated with conventional systemic administrations and non-targeted delivery of immune modulators. This work explored two unique delivery strategies: one which proposes drugging tumor draining lymph nodes with ICB therapies by way of lymphatics using local rather than systemic administrations to enhance anti-tumor efficacy; and the second which proposes a novel drug-eluting ICB platform by engineering an antibody-nanoparticle conjugate system for improved T cell targeting and sustained delivery of small molecule immunotherapies.