BioE PhD Defense- Maggie Manspeaker
Advisor: Susan Thomas, PhD (Georgia Institute of Technology)
John Blazeck, PhD (Georgia Institute of Technology)
Julie Champion, PhD (Georgia Institute of Technology)
M.G. Finn, PhD (Georgia Institute of Technology)
Haydn Kissick, PhD (Emory University School of Medicine)
Engineered Nanotechnology for the Delivery of Cancer Immunotherapies to Lymph Nodes to Modulate Anti-Tumor T Cell Immunity
The advent of immunotherapies, particularly immune checkpoint blockade (ICB) monoclonal antibodies (mAbs), to treat advanced cancers has drastically improved outcomes for some patients. These ICB mAbs work by blocking inhibitory immune checkpoint pathways and more recently have been shown to cause a proliferative burst of effector T cells attributable to a subset of antigen-specific CD8 T cells with stem cell-like properties, which are thought to reside in lymphoid tissues and in particular tumor–draining lymph nodes (TdLNs). TdLNs are a critically important tissue that mediates the mounting of effective anti-tumor immunity and are central in the response to ICB immunotherapy both due to active immune checkpoints in TdLNs and their role in housing CD8 stem-like cells. However, despite the promising clinical advances ICB mAbs represent, some patients experience no clinical benefit from therapy, leading to an increase in clinical investigations into various combination therapies that enhance patient response, such as adjuvants and chemotherapies. Additionally, success of cancer therapeutics is often stymied by low accumulation in target tissues and off-target effects. Therefore, a better understanding of how these combination therapies interact with the TdLN and resulting immune response is needed, which can be enabled with the use of nanotechnologies that improve therapeutic efficacy while avoiding success-limiting off-target effects. As such, the overall objective of this project is to use nanotechnologies that enable drug accumulation in the TdLN to 1) investigate how nanotechnology alters the efficacy of combination chemo- and immunotherapy and characterize the involvement of the TdLN in anti-tumor immunity following treatment, and to 2) elucidate the dynamics of CD8 stem-like T cells in response to adjuvant and ICB combination therapy, and characterize the efficacy of engineered drug delivery nanotechnologies on these combinations. This work will provide insight into role of the TdLN, and dynamics of important cell populations within, in the efficacy of drug and ICB combination therapies with clinical relevance and inform promising future therapeutic strategies for cancer.