Browsing by Subject "Immune Checkpoint Inhibitors"
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Item The Efficacy of Immunotherapy in Preventing Liver Cancer and the Role of Metabolic Zonation in Its Development(August 2021) Chung, Andrew Seungjae; McFadden, David G.; DeBerardinis, Ralph J.; Mani, Ram; Zhu, HaoIn order to study the development and progression of liver cancer, as well as the efficacy of novel therapeutic strategies, accurate models of human disease are needed. In particular, in vivo mouse models capture critical characteristics that are relevant to human hepatocellular carcinoma (HCC). There is a diverse array of mouse HCC models available, falling into three major categories: transplantation-based models, chemically-induced models, and genetically-induced models. Within these categories, models differ in factors such as the source of the tumor cells and the chemicals or genetic drivers used to induce tumorigenesis. All of these models offer specific advantages over the others but also have some disadvantages as well. Thus, the utility of any model is dependent on the specific investigatory aims of the study. In our case, we used two types of models to try to address two questions about HCC. First, we asked if immune checkpoint inhibition could prevent tumorigenesis in a chemically-induced mouse model of HCC. We found that initiation of anti-PD-1 immunotherapy prior to tumorigenesis could prevent up to 46% of liver tumors. This reduction in tumor burden was accompanied by infiltration of CD4+ T helper and CD8+ cytotoxic T cells into the liver parenchyma. Importantly, anti-PD-1 therapy did not exacerbate liver dysfunction or worsen overall health in this model. Given the safety and preservation of quality of life observed with long-term immunotherapy use, an immunotherapy chemoprevention strategy is likely associated with a low risk-to-benefit ratio and high value care in select patients. Along the portal-to-central axis within the hepatic lobule, there are profound differences in gene expression, metabolic processes, oxygen tension, and ploidy. Whether or not these differences reflect any differences in neoplastic potential is unclear. To address this, we turned to genetically-induced HCC models. We used various hepatic zone-specific CreERT2 mouse lines to induce activating mutations in Ctnnb1 and to delete Arid2. We found that mutant clones arising from zone 1 gradually expanded and persisted, while mutant clones arising from Zone 3 rapidly disappeared over time. However, more tumors ultimately developed in the zone 3 livers than in the zone 1 livers, suggesting that expression of some zonated metabolic genes may influence the fate of mutant hepatocytes. This could have major implications for prevention and treatment of HCC, as these metabolic genes could represent actionable preventive or therapeutic targets.Item Radiographic Challenges and Considerations with Cancer Immunotherapy(2020-05-01T05:00:00.000Z) Popat, Vinita; Gerber, David E.; Ariizumi, Kiyoshi; Minna, John D.; Khan, Saad A.BACKGROUND: With immune checkpoint inhibitor therapy, we observe new and challenging radiographic patterns such as hyperprogression and pseudoprogression. This begs the question - are there radiographic parameters that can predict response to immune checkpoint inhibitors? Historically, tumor burden has been considered an impediment to efficacy of immunotherapeutic agents, such as vaccines and allogeneic stem cell transplant. However, the association between tumor burden and efficacy of immune checkpoint inhibitors is unknown. We sought to determine the association between radiographic tumor burden parameters and efficacy of immune checkpoint inhibitors in advanced lung cancer. MATERIALS AND METHODS: We performed a retrospective analysis of patients with advanced lung cancer treated with immune checkpoint inhibitor monotherapy. Demographic, disease, and treatment data were collected. Serial tumor dimensions were recorded according to Response Evaluation Criteria in Solid Tumors 1.1. Associations between radiographic tumor burden (baseline sum of longest diameters [BSLD], longest single diameter) and clinical outcomes (radiographic response, progression-free survival, and overall survival) were determined using log-rank tests, cox proportional-hazard regression, and logistic regression. RESULTS: Among 105 patients, median baseline sum of longest diameters was 6.4 cm; median longest single diameter was 3.6 cm. BSLD was not associated with radiographic response, progression-free survival, or overall survival. In univariate and multivariate analyses, no significant associations were observed for the other radiographic parameters and outcomes when considered as categorical or continuous variables. CONCLUSIONS: Although tumor burden has been considered a mediator of efficacy of earlier immunotherapies, in advanced lung cancer it does not appear to impact outcomes from immune checkpoint inhibitors.