Biology subjects

Murphy, J. D.

Publications and source records attributed to Murphy, J. D..

3 recordsLinked to original sources

bioRxiv2025

Improving SBRT by re-wiring immunosuppressive neutrophils in murine pancreatic ductal adenocarcinoma

Radiation is used to treat pancreatic ductal adenocarcinoma (PDAC) in the locally-advanced setting. Stereotactic body radiation therapy (SBRT), in particular, has shown improved outcomes against conventional RT in a number of clinical trials. One key cell type involved in the response to RT are neutrophils. These innate immune cells are the first responders to tissue damage and infiltrate irradiated tumors in high numbers to rectify injury. Neutrophils typically possess an immunosuppressive, wound healing phenotype in this scenario, which allows the tumor to recover and actively suppress immunological efforts to eradicate the disease. Here, we aimed to elucidate the role of neutrophils in a murine model of PDAC treated with SBRT. Mice harboring PDAC tumors were treated with targeted SBRT and neutrophils were determined to be significantly increased in the tissue when compared to unirradiated controls. Additionally, phenotypic analysis determined that these cells were largely immunosuppressive and depletion studies confirmed they played a key role in acquired radioresistance in our model. In order to establish whether these infiltrating cells could be re-wired to contribute to anti-tumor immunity, we utilized a novel combination therapy consisting of SBRT and microspheres containing recombinant IL-12 to attempt to repolarize these cells. Transcriptomic analysis confirmed intratumoral neutrophils underwent considerable changes indicative of an immunostimulatory, anti-tumor phenotype following treatment. Moreover, depleting these cells resulted in a loss of treatment efficacy, suggesting that neutrophil re-wiring was vital for the therapeutic outcome. This study highlights neutrophils as key players in SBRT and IL-12 treatment and confirms they can act as a double-edged sword depending on the treatment employed.

immunology↗

bioRxiv2023

Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer

The immunosuppressive milieu in pancreatic cancer (PC) is a significant hurdle to treatments, resulting in survival statistics that have barely changed in 5 decades. Here we present a combination treatment consisting of stereotactic body radiation therapy (SBRT) and IL-12 mRNA lipid nanoparticles delivered directly to pancreatic murine tumors. This treatment was effective against primary and metastatic models, achieving cures in both settings. IL-12 protein concentrations were transient and localized primarily to the tumor. Depleting CD4 and CD8 T cells abrogated treatment efficacy, confirming they were essential to treatment response. Single cell RNA sequencing from SBRT/IL-12 mRNA treated tumors demonstrated not only a complete loss of T cell exhaustion, but also an abundance of highly proliferative and effector T cell subtypes. SBRT elicited T cell receptor clonal expansion, whereas IL-12 licensed these cells with effector function. This is the first report demonstrating the utility of SBRT and IL-12 mRNA in PC. Statement of significanceThis study demonstrates the use of a novel combination treatment consisting of radiation and immunotherapy in murine pancreatic tumors. This treatment could effectively treat local and metastatic disease, suggesting it may have the potential to treat a cancer that has not seen a meaningful increase in survival in 5 decades.

cancer biology↗

bioRxiv2019

A Model-Based Cost-Effectiveness Analysis of an Exercise Program for Lung Cancer Survivors Following Curative-Intent Treatment

RationaleThe Institute of Medicine emphasizes care in the post-treatment phase of the cancer survivorship continuum. Physical exercise has been shown to be effective in improving physical function and quality of life in cancer survivors; however, its cost-effectiveness in lung cancer survivors is not well established. ObjectiveWe performed a model-based cost-effectiveness analysis of an exercise intervention in lung cancer survivors following curative-intent treatment. MethodsWe constructed a Markov model to simulate the impact of the Lifestyle Interventions and Independence for Elders (LIFE) exercise intervention compared to usual care for stage I-IIIA lung cancer survivors. Costs and utility benefit of exercise were extracted from the LIFE study. Baseline utilities, transition probabilities, and survival were modeled. We calculated and considered incremental cost-effectiveness ratios (ICERs) <$100,000/quality-adjusted life-year (QALY) as cost-effective, and assessed model uncertainty using one-way and probabilistic sensitivity analyses. ResultsOur base-case model found that the LIFE exercise program would increase overall cost by $4,740 and effectiveness by 0.06 QALYs compared to usual care, and have an ICER of $79,504/QALY. The model was most sensitive to the cost of the exercise program, probability of increasing exercise, and utility benefit related to exercise. At a willingness-to-pay threshold of $100,000/QALY, the LIFE exercise program had a 71% probability of being cost-effective compared to 27% for usual care. When we included opportunity costs, the LIFE exercise program had an ICER of $179,774/QALY, exceeding the cost-effectiveness threshold. ConclusionsA simulation of the LIFE exercise program in lung cancer survivors following curative-intent treatment demonstrates cost-effectiveness from an organization but not societal perspective. Strategies to effectively increase exercise remotely may be more cost-effective than in-facility strategies for these patients.

epidemiology↗