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Document Type:Latin Dissertation
Language of Document:English
Record Number:53896
Doc. No:TL23850
Call number:‭3461776‬
Main Entry:Dina Preise
Title & Author:Vascular-targeted photodynamic therapy: In situ antitumor vaccinationDina Preise
College:The Weizmann Institute of Science (Israel)
Date:2008
Degree:Ph.D.
student score:2008
Page No:83
Abstract:This PhD thesis focused on the impact of vascular-targeted photodynamic therapy (VTP) of solid tumors on the host immune system and it's effect on treatment outcome with possible implications to tumor therapy in the clinical set up. Photodynamic therapy (PDT) involves the use of photochemical reactions mediated through the interaction of photosensitizing agents (PS, the drug), light and oxygen for the treatment of malignant or benign diseases. This is a two-step procedure comprising of photosensitization of the PS with light at a matched wavelength, directed toward the target tissue, in the presence of oxygen to locally produce cytotoxic reactive oxygen species (ROS). VTP takes advantage of intravascular excitation of the circulating photosensitizer. The induced ROS trigger a snow-balling cascade of vascular damage manifested by rapid local thrombus formation, vascular occlusion and tissue hypoxia culminating with tumor eradication due to oxygen and nutrients deprivation. VTP initiates massive tumor tissue death accompanied by acute local inflammation inside the illuminated area, creating a perfect milieu for stimulation of adaptive immune responses. Consequently, we addressed the possibility of protective antitumor immunity induction by the treatment. The specific goals of this study were: (i) to test the prerequisite of the functional immune system for successful tumor ablation by VTP; (ii) to examine the contribution of vascular compartment to VTP-induced immunity; (iii) to study the cellular and molecular mediators of VTP-mediated immune response. The necessity of a functional immune system for successful VTP was established using mouse strains with defects in adaptive immunity. BALB/Nude and NOD/Scid mice, which lack adaptive immune system, demonstrated a significant reduction in animal cure rates (18.8 and 11% survival respectively) compared to immunocompetent BALB/c mice (∼80% survival). We also found that intrinsic tumor cell immunogenicity affects the responsiveness of a particular tumor to VTP. This observation provides additional support to the working hypothesis stating that immune response is an important mechanism of VTP-mediated tumor ablation. VTP also induced long-lasting systemic protection against tumor re-challenge signifying formation of immune memory. This memory was non-tumor specific, namely protection was induced also against mismatched tumors. This finding stands in contrast to published data related to conventional PDT. We hypothesized that extensive photodamage inflicted by VTP to the vascular compartment (host-derived and thus shared by all tested tumors) may at least partly be responsible for contributing additional potential antigens. Unfortunately, approaches taken in the present study did not shed light into this question and further attempts should be dedicated to develop appropriate models for examining the role of the tumor vasculature in VTP-induced immunity. Adoptive transfer of different T cell populations and sera from VTP-cured or naïve mice revealed that antitumor immunity induced by VTP involves both cellular and humoral components. Additionally, using a specific transgenic mouse model we demonstrated that dendritic cells are essential during the acute phase of VTP as their absence significantly decreased treatment success. We also suggested several molecular mediators that might be responsible for VTP-induced immune response. It was found that photodynamic treatment of cultured tumor cells induces release of several stress proteins, such as Hsp72 and Hsp27 whose role in stimulating antitumor immunity is documented in the literature. Additionally, a number of oxidative modifications, namely protein nitrosilation and formation of lipid peroxidation product 4-hydroxy-nonenal were observed in tumor xenografts subjected to WST11-VTP. These modifications are capable of braking immune tolerance towards silent antigens as reported by several published studies. Finally, we found that tumor cells exposed to photodynamic action in vitro can be utilized as effect ve vaccines to induce protective immunity against subsequent tumor challenge in the vaccinated animals. Vaccination with PDT-lysates induced protection against mismatched tumors similarly to in vivo VTP. This suggests production of overlapping antigens upon the treatment. To conclude, this work provides convincing evidences about involvement of host immune system in VTP-mediated tumor ablation. Further studies of the molecular nature of VTP-induced antigens can contribute to our understanding of tumor immunogenicity basis and the mechanisms of enhancing immunogenicity. Based on these findings novel protocols could be suggested combining local VTP with other anticancer therapies (e.g. immunotherapy) to further enhance host antitumor immunity and increase treatment efficacy. This might also enable the conversion of this modality from treatment of local to disseminated disease.
Subject:Health and environmental sciences; Photodynamic therapy; Tumor therapy; Vascular-targeted photodynamic therapy; Immunology; Oncology; 0982:Immunology; 0992:Oncology
Added Entry:Y. Salomon
Added Entry:The Weizmann Institute of Science (Israel)