Local Phototherapy Synergizes with Immunoadjuvant for Treatment of Pancreatic Cancer through Induced Immunogenic Tumor Vaccine

Abstract

To develop a synergistic combination therapy for advanced pancreatic cancer, using local phototherapy and immunotherapy, and to determine the efficacy and mechanism of the novel combination therapy using a highly metastatic pancreatic tumor model in mice. Mice bearing Panc02-H7 pancreatic tumors (both subcutaneous and orthotopic) were treated with noninvasive or interventional photothermal therapy, followed by local application of an immunoadjuvant. Tumor growth and animal survival were assessed. Immune cell populations within spleen and tumors were evaluated by FACS and IHC, and cytokine levels were determined by ELISA. Up to 75% of mice bearing subcutaneous tumors treated with combination therapy had complete tumor regression. Local photothermal therapy exposed/released damage-associated molecular patterns, which initiated an immunogenic tumor cell death, resulting in infiltration of antigen-presenting cells and Th1 immunity. Concomitant application of immunoadjuvant amplified Th1 immunity, especially the tumor-specific cytotoxic T lymphocyte response, with increased quantity and quality of T cells. Combination therapy also induced tumor-specific immune memory, as demonstrated by resistance to tumor rechallenge and production of memory T cells. For the treatment of orthotopic tumor, the combination therapy significantly reduced the primary tumors and metastases, and prolonged the animal survival time. This study indicated that combination of local phototherapy and immunotherapy induced a systemic immunity against established tumors and metastases in an aggressive, preclinical pancreatic tumor model, leading to a potential clinical method for patients with advanced pancreatic cancer. .

Laser adjuvant for vaccination

“…Zhou et al showed that mice treated with photothermal therapy (PTT) alone had a significant smaller tumor burden than that of the control mice. A 10‐minutes treatment with 980 nm laser at a density of 0.85 W/cm 2 (510 J/cm 2 in total) increased the temperature of tumor tissue, which caused cell death in mouse models of pancreatic cancer and melanoma . In this approach, heat generation in tissues is considered to induce immunologic cell death with release of heat shock proteins (HSPs), calreticulin (CRT), high‐mobility group box 1 (HMGB1) protein, and adenosine triphosphate (ATP) .…”

“…A 10-minutes treatment with 980 nm laser at a density of 0.85 W/cm 2 (510 J/cm 2 in total) increased the temperature of tumor tissue, which caused cell death in mouse models of pancreatic cancer and melanoma. 33 In this approach, heat generation in tissues is considered to induce immunologic cell death with release of heat shock proteins (HSPs), calreticulin (CRT), high-mobility group box 1 (HMGB1) protein, and adenosine triphosphate (ATP). 34 In response to this, DCs are stimulated and produce IFN-γ and increase their expression of MHCII and CD80 and recruitment of DCs and T cells in tumor microenvironment.…”

Near Infrared Light Triggered Photo/Immuno-Therapy Toward Cancers

“…An interventional PTT using an optical fiber with a NIR light of 980 nm was inserted into tumor center and an immunoadjuvant agent of glycated chitosan (GC) was intratumor-injected immediately after PTT in mouse pancreatic tumor model. The complete regression was achieved and more importantly, it triggered tumor-specific immune memory and the production of memory T cells to inhibit tumor rechallenge (Zhou et al, 2018). Ma et al (2019) adopted a second NIR (NIR II at 1086 nm) light to carry out the PTT.…”

ScRNA-seq reveals tumor microenvironment remodeling induced by local intervention-based immunotherapy

“…Laser immunotherapy (LIT) was developed to achieve this objective. LIT has two components: 1) local photothermal therapy (PTT) for disrupting target tumor homeostasis and releasing tumor antigens (12,13), and 2) local administration of an immunostimulant, such as N-dihydrogalactochitosan (GC) (14,15). In preliminary clinical studies for patients with metastatic, treatment-recalcitrant breast cancer and melanoma, LIT successfully reduced and/or eliminated the treated primary tumors and untreated metastases in the lungs (16-18).…”