Potentiating a systemic antitumor response by interstitial localized ablative immunotherapy to synergize with immune checkpoint therapy for metastatic pancreatic tumors

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Project Summary Pancreatic cancer (PC) is one of the deadliest diseases. Based on the 2021 U.S. cancer statistics, the majority of PC patients are diagnosed with advanced-stage disease, either with distant metastasis (50%) or local invasion (30%), resulting in a five-year survival rate of 3% and 13%, respectively. In most cases, particularly at the late stages, PC is unresectable, non-permeable to drugs, immunologically suppressive, and highly metastatic. Conventional therapies, such as surgery, radiation, and chemotherapy, are largely ineffective. Even the advanced immunotherapies, such as immune checkpoint therapy (ICT), can only achieve limited success, due to the lack of T cells in the immunosuppressive tumor microenvironment (TME). We developed a localized ablative immunotherapy (LAIT), which combines local photothermal therapy (PTT) and local administration of immunostimulants. In our pre-clinical studies and preliminary clinical trials, LAIT has been shown to be able to eliminate treated tumors and eradicate untreated distant metastases. Specifically, PTT destroys tumor cells due to light absorption by the target tissue, leading to immunogenic cell death and the release of tumor antigens. The locally administered immunostimulants, combined with released tumor antigens, induces tumor-specific immune responses, particularly the infiltration, activation, and proliferation of T cells within the TME. However, so far LAIT has been applied mostly in non-invasive mode for surface tumors, such as melanoma and breast cancer. In this project, we will use interstitial LAIT (iLAIT) to treat orthotopic murine pancreatic tumors, in combination with ICT. We hypothesize 1) iLAIT remodels the TME and induces antitumor immunity that synergizes with ICT to improve therapeutic efficacy for PC; and 2) the mechanism of the novel iLAIT-ICT combination involves a coordinated interplay between tumor cells and immune cells to overcome the immunosuppressive TME. To test these hypotheses, we plan to achieve the following aims using two pancreatic tumor models in mice: 1) to optimize iLAIT and to determine its efficacy in treating metastatic pancreatic tumors; 2) to determine the effects of iLAIT in reversing immunosuppressive TME and inducing systemic antitumor responses in secondary immune organs; and 3) to determine the synergistic effects of iLAIT and ICT, specifically the efficacy in treating pancreatic tumors and the induced tumor-specific, long-term immunity. This project has high clinical relevance. The successful completion of this project will demonstrate the therapeutic efficacy of iLAIT-ICT, paving the way for its clinical applications, with minor modifications (doses of ablation and immunostimulation), for late-stage, metastatic PC patients, who face severely limited options. Furthermore, the understanding of the iLAIT-ICT-regulated, spatiotemporally coordinated interplay between tumor cells and immune cells can be used to design new therapeutic approaches for a variety of metastatic cancers in the future.