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

通过间质局部消融免疫疗法增强全身抗肿瘤反应，与转移性胰腺肿瘤的免疫检查点疗法协同作用

• 批准号: 10580071
• 负责人: Wei R. Chen
• 金额: $ 47.68万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580071
• 关键词: Ablation; Aftercare; Animals; Antitumor Response; Cells; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Development; Diagnosis; Diffusion; Disease; Disseminated Malignant Neoplasm; Distant Metastasis; Dose; Fiber Optics; Foundations; Future; Histology; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunologic Adjuvants; Immunologic Stimulation; Immunologics; Immunology procedure; Immunotherapy; Implant; Infiltration; Injections; Interferons; Intervention; Invaded; Investigation; Label; Lasers; Light; Magnetic Resonance; Malignant neoplasm of pancreas; Maps; Melanoma Cell; Minor; Modality; Modeling; Modification; Monitor; Mus; Operative Surgical Procedures; Organ; Pharmaceutical Preparations; Radiation therapy; Reporting; Resistance; Spleen; Stimulant; Stromal Cells; Surface; Surgical incisions; Survival Rate; T-Cell Proliferation; T-Lymphocyte; Temperature; Testing; Therapeutic Effect; Thermometry; Time; Tissues; Translating; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Unresectable; absorption; anti-CTLA4; anti-PD-1; anti-PD-L1; cancer statistics; cancer therapy; checkpoint therapy; chemotherapy; clinical application; clinically relevant; conventional therapy; design; draining lymph node; efficacy evaluation; fluorescence imaging; glycated chitosan; immune function; immunogenic cell death; improved; interstitial; lens; malignant breast neoplasm; melanoma; neoplastic cell; novel; novel therapeutic intervention; optical fiber; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; photothermal therapy; preclinical study; response; secondary lymphoid organ; single-cell RNA sequencing; spatiotemporal; success; synergism; treatment group; tumor; tumor ablation; tumor growth; tumor microenvironment; tumor-immune system interactions

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.

项目总结