Current advisor: David G. DeNardo, PhD
Undergraduate university: University of Washington
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal malignancies. While checkpoint immunotherapies are effective therapies in many solid malignancies, these same regimens have not been effective in PDAC. Furthermore, clinical trials combining checkpoint immunotherapies with standard of care chemotherapy or radiation therapy (RT), which should be able to prime anti-tumor immunity and unlock immunotherapies, have not been successful. Thus, understanding why the combinations of RT and immunotherapy fail in PDAC is critical.
To better understand why RT and checkpoint immunotherapies fail, we studied the impact of stereotactic body radiotherapy (SBRT), an RT regimen which delivers precise and intense doses of radiation into tumor cells, on antigen specific T cell responses in both human PDAC tissues and genetically engineered mouse models of PDAC. In human PDAC tumors, we found no increase in the number of CD8 tumor infiltrating T cells in the tumor stroma compared to a control group, which gives us no evidence of T cell priming following SBRT. Using the p48-Cre/LSL-KrasG12D/p53Flox/Flox/OVA-GFP+ (KPC-OG) mice, RT alone, despite inducing temporary tumor control did not prime new antigen specific T cell responses, similar to what we found in the human PDAC tissues. We postulated that the unique PDAC tumor microenvironment (TME), which is characterized by a fibrotic desmoplastic stroma, might play a role in limiting immune priming by SBRT. To study the role of PDAC’s TME to RT response, we developed a 3D organoid in vitro co-culture system. We found that fibroblasts and collagen work synergistically to cause RT resistance, which is mediated in part through the hyperactivation of Focal Adhesion Kinase (FAK). In KPC mice, FAK inhibitor (FAKi) rescues RT resistance leading to significant tumor regression and enhances long-term survival. Associated with this regression, we found enhanced anti-tumor immunity in the form of increased conventional dendritic cells and tumor specific CD8 T cells. Single cell RNA sequencing data revealed that this treatment combination enhances antigen processing and presentation and T cell activation in the immune myeloid compartment and alters the composition of cancer associated fibroblasts in the PDAC stroma. Based on these data, we initiated a phase Ib study in which FAKi (VS-6063) will be given in combination with SBRT to patients with locally advanced PDAC (NCT04331041). This trial is currently underway.
With this human trial underway, we next hypothesized the combination of RT and FAKi would render immunotherapy effective. Pre-clinical studies in mouse PDAC models showed that while RT and checkpoint blockade was ineffective at tumor control, the triple combination of FAKi, RT, and checkpoint blockade led to extended long-term survival. Overall, these data suggest that stromal modulation can be used to allow RT to prime anti-tumor immunity in PDAC and unlock checkpoint immunotherapy efficacy.
Somani VK, Zhang D, Dodhiawala PB, Lander VE, Liu X, Kang LI, Chen HP, Knolhoff BL, Li L, Grierson PM, Ruzinova MB, DeNardo DG, Lim KH. 2022 IRAK4 Signaling Drives Resistance to Checkpoint Immunotherapy in Pancreatic Ductal Adenocarcinoma. Gastroenterology, 162(7):2047-2062.
Lander VE, Belle JI, Kingston NL, Herndon JM, Hogg GD, Liu X, Kang LI, Knolhoff BL, Bogner SJ, Baer JM, Zuo C, Borcherding NC, Lander DP, Mpoy C, Scott J, Zahner M, Rogers BE, Schwarz JK, Kim H, DeNardo DG. 2022 Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade. Cancer Discov, 12(12):2774-99.
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.