MSTP in PhD Training
Current advisor: David G. DeNardo, PhD
Undergraduate university: Rice University, 2015
Enrollment year: 2016
Harnessing Dendritic Cells as a Novel Therapy in Pancreatic Cancer
Checkpoint therapies have delivered unprecedented responses in malignancies such as melanoma and non-small-cell lung cancer. Unfortunately, checkpoint therapies are ineffective in Pancreatic Ductal Adenocarcinoma (PDAC). PDAC remains a devastating disease, with a 5-year-survival rate of less than 10% and new therapies are urgently needed. One possible explanation for the lack of checkpoint efficacy is that the pancreas is nearly devoid of conventional dendritic cells (cDCs). cDCs are highly specialized antigen presenting cells that can efficiently process cancer antigens and prime naïve T cells. Mounting evidence implicates cDCs as critical for tumor immune recognition. To overcome this mechanism of immune-evasion, I am investigating a novel combination immunotherapy in which cDCs are expanded with the cytokine Flt3L and licensed with a CD40 agonist antibody. Unexpectedly, the dual therapy results in a log fold increase in both intra-tumoral cDCs and T cells when compared with single arm Flt3L or CD40 alone. Additionally, we observe disease stabilization in our genetic mouse model of PDAC, which like the human disease is highly resistant to therapy. The canonical mechanism-of-action of either drug alone does not adequately predict the sum of their effects. Thus, I aim to elucidate the mechanisms through which the combination of Flt3L and CD40 drive anti-tumor immunity and disease control.
Peng H, James CA, Cullinan DR, Hogg GD, Mudd JL, Zuo C, Takchi R, Caldwell KE, Liu J, David DG, Fields RC, Gillanders WE, Goedegebuure SP, Hawkins WG. 2021 Neoadjuvant FOLFIRINOX therapy is associated with increased effector T cells and reduced suppressor cells in pancreatic cancer patients. Clin Cancer Res, (Sep. 30):clincanres.0998.2021.
Liu X, Hogg GD, DeNardo DG. 2021 Rethinking immune checkpoint blockade: ‘Beyond the T cell’. J Immunother Cancer, 9(1):e001460.
Hegde S, Krisnawan VE, Herzog BH, Zuo C, Breden MA, Knolhoff BL, Hogg GD, Tang JP, Baer JM, Mpoy C, Lee KB, Alexander KA, Rogers BE, Murphy KM, Hawkins WG, Fields RC, DeSelm CJ, Schwarz JK, DeNardo DG. 2020 Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer. Cancer Cell, 37(3):289-307.e9.
Panni RZ, Herndon JM, Zuo C, Hegde S, Hogg GD, Knolhoff BL, Breden MA, Li X, Krisnawan VE, Khan SQ, Schwarz JK, Rogers BE, Fields RC, Hawkins WG, Gupta V, DeNardo DG. 2019 Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med, 11(499):eaau9240.