Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Robert H. Vonderheide
Immune checkpoint blockade results in T cell antitumor responses but most patients fail to respond. This raises fundamental questions about mechanisms of tumor immune recognition and resistance. Here, I first report tumor regressions in a subset of patients with metastatic melanoma treated with anti-CTLA4 antibody and radiation (RT) and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common due to upregulation of PD-L1 on tumor cells and corresponding T cell exhaustion. Accordingly, optimal response in melanoma and other cancer types required RT, anti-CTLA4, and anti-PD-L1/PD1. When I investigated determinants of improved responses to combination therapy, I found that RT enhanced the antigenic diversity of intratumoral T cells, anti-CTLA4 predominantly inhibited regulatory T cells, and anti-PD-L1 reversed T cell exhaustion. I next extended my investigation of this combination therapy to pancreatic ductal adenocarcinoma (PDA), finding that optimal responses required addition of agonist CD40 monoclonal antibody.
Rech, Andrew J., "Determinants Of Adaptive Immunity In Cancer" (2017). Publicly Accessible Penn Dissertations. 2543.