Metastasis causes treatment failure and 90% of cancer-related deaths. We have developed laser immunotherapy (LIT) for the treatment of metastatic cancers. LIT combines local laser photothermal therapy (PTT) and immunotherapy using glycated chitosan (GC), a novel immunoadjuvant, to induce systemic antitumor immune responses. LIT has shown success in clinical trials for late-stage, metastatic cancer patients who had failed conventional treatment modalities. Specifically, LIT has demonstrated its ability to eliminate treated primary tumors and eradicate untreated metastases at distant sites. However, the mechanism of LIT, particularly how it controls tumor metastases, has not been fully investigated. Based on our previous studies, we believe that PTT and GC each induces unique immunological reactions, which, when synergized, produce a systemic, long-term antitumor immunity. Specifically, we hypothesize that: 1) PTT induces immunogenic tumor cell death (ICD), providing antigen sources and damage-associated molecular patterns (DAMPs) to trigger host antitumor immune responses; 2) GC enhances uptake and presentation of antigens generated by PTT-induced ICD, amplifying antitumor T cell response; and 3) LIT synergizes and amplifies the immune responses induced by PTT and GC, particularly when combined with other immunotherapies, such as checkpoint inhibition, providing potent, systemic therapeutic effects, especially on tumor metastases. To test these hypotheses, we plan to achieve the following aims: (1) to determine the photothermal-immunological effects of PTT by determining temperature distribution in tumor tissue and by characterizing the ICD and DAMPs generated by PTT; (2) to determine the effects of GC on immune system during LIT, particularly on activation of T cell as well as enhancement of antigen uptake and presentation; and (3) to determine the effects of LIT, as well as the combination of LIT and checkpoint inhibition, on the enhancement of tumor immunogenicity and on controlling tumor metastasis. The successful completion of this project will achieve the following goals: (1) to obtain a comprehensive understanding of the immunological mechanism of LIT in eliminating and inhibiting metastases; (2) to lay the foundation necessary to advance LIT into an effective treatment modality for patients with a variety of metastatic cancers; (3) to facilitate the development of new, novel treatment strategies using synergistic immunological mechanisms similar to that of LIT, in combination with other complementary therapies, for patients with metastatic cancers.
Metastasis causes 90% of cancer-related deaths and remains one of the biggest challenges in cancer research. We have developed laser immunotherapy (LIT) for treatment of late-stage, metastatic cancers, which combines local photothermal therapy (PTT), through tumor irradiation by a near-infrared laser, with immunotherapy, through local administration of glycated chitosan (GC), a novel immunological stimulant. In our preclinical studies and preliminary clinical trials for melanoma and breast cancer, LIT demonstrated the ability to eliminate treated primary tumors and eradicate untreated metastases at distant sites. This project is to study the mechanism of LIT. We plan to determine the functions of PTT and GC, as well as the mechanism of LIT-induced systemic antitumor immunity. We also plan to combine checkpoint inhibitors with LIT to enhance the induced systemic antitumor immunity to eliminate and inhibit metastases. Successful completion of this project will provide a comprehensive understanding of the immunological mechanism of LIT, paving the way for further development of new, novel cancer treatment strategies. Our long-term goal is to provide effective treatment modalities for patients with late-stage, metastatic cancers, who are facing severely limited options.
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