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

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.

Grant Number: 5R01CA269897-05
NIH Institute/Center: NIH
Principal Investigator: Wei Chen