PHOTODYNAMIC THERAPY (PDT) AND TUMOR IMMUNITY

光动力疗法 (PDT) 和肿瘤免疫

• 批准号: 8197158
• 负责人: Sandra O. Gollnick
• 金额: $ 34.28万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-14 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197158
• 关键词: Adjuvant; Agonist; Antigen-Presenting Cells; Autologous; Cancer Model; Cancer Vaccines; Caspase-1; Cells; Cellular Stress; Clinic; Clinical; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Distant; Excision; Family; Family member; Funding; Generations; Goals; Guidelines; Immune Tolerance; Immune response; Immunosuppression; In Situ; Infection; Inflammatory; Interleukin-12; Interleukins; Lead; Ligands; Lymphatic; Macrophage Activation; Malignant Neoplasms; Mediating; Melanoma Vaccine; Metastatic Melanoma; Modeling; Molecular; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Photochemotherapy; Pre-Clinical Model; Primary Neoplasm; Protocols documentation; Receptor Signaling; Regimen; Safety; Signal Pathway; Signal Transduction; Staging; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; Tumor Immunity; Vaccination; Vaccines; clinical application; combat; cytokine; effective therapy; immunogenicity; improved; macrophage; melanoma; member; neoplastic cell; novel; outcome forecast; pathogen; pre-clinical; preclinical study; randomized trial; receptor; response; tumor; tumor growth; vaccine development

Photodynamic therapy (PDT) treated tumor cells have proven to be efficacious anti-tumor vaccines in both therapeutic and preventative settings in murine models of cancer. However the mechanism by which PDT enhances tumor immunogenicity is unclear. PDT treatment of tumor cells has been shown to induce the release of "danger" signals capable to stimulating anti-tumor immunity. Danger signals are recognized by danger signal receptors, Toll-like receptors (TLRs) and NOD-lie receptors (NLRs). We and others have shown that PDT treated tumor cells contain TLR ligands. In a novel finding we now show that PDT-treated tumor cells stimulate the NLR family of danger receptors. We hypothesize that activation of TLR and NLR is critical to the enhancement of anti-tumor immunity by PDT. Furthermore we hypothesize the combination of PDT or PDT vaccines with therapies that augment induction of danger signal pathways will further enhance the induction of anti-tumor immunity and will lead to enhanced control of distant disease in more aggressive, spontaneously metastasizing tumor models. Therefore we propose to combine PDT with agents that enhance the immune response through signaling pathways complimentary to those induced by PDT-treated tumor cells, in order to augment the anti-tumor immune response induced by PDT vaccines or PDT. Finally we have shown that PDT-treated tumor cells can be used in an adjuvant setting to enhance anti-tumor immunity following surgical resection in a pre-clinical model of melanoma. We now propose to extend these findings to a clinical setting by investigating the safety and immunogenicity of an autologous PDT vaccine for advanced stage III in transit melanoma following surgical resection of tumors. The overall goal of this renewal is to understand the mechanisms by which PDT enhances tumor cell immunogenicity with the long-term goal of developing clinical PDT protocols that enhance anti-tumor immunity and combat secondary disease. Our current objective is to understanding the mechanisms by which PDT promotes anti-tumor immunity in order to facilitate the development of clinical PDT regimens that both control long-term tumor growth and promote anti-tumor immunity. Three specific aims are planned to enable us to test our hypotheses and achieve this objective. The first two aims are pre-clinical and synergistic; Specific Aim 1 examines the mechanism by which PDT-treated tumor cells activate the NLR family member, NALP3. Specific Aim 2 explores the use of TLR agonists to augment the anti-tumor effects of PDT-generated vaccines. The application culminates in Specific Aim 3, which tests the clinical application of PDT-generated vaccines. PDT is an effective therapy for a growing number of malignancies, however optimization of PDT has been hindered by the complexity of the therapy. Our studies will both aid in the optimization of PDT and permit exploitation of its ability to enhance anti-tumor immunity.

光动力疗法（PDT）治疗的肿瘤细胞已被证明是有效的抗肿瘤疫苗 在癌症的鼠模型中，治疗和预防性环境。但是PDT的机制 增强肿瘤免疫原性尚不清楚。 PDT治疗肿瘤细胞已显示出诱导 释放能够刺激抗肿瘤免疫力的“危险”信号。危险信号由 危险信号受体，收费受体（TLR）和点头lie受体（NLR）。我们和其他人已经表明 PDT处理的肿瘤细胞含有TLR配体。在一个小说发现中，我们现在表明PDT处理的肿瘤细胞 刺激NLR危险受体家族。我们假设TLR和NLR的激活对 PDT增强抗肿瘤免疫力。此外，我们假设PDT或PDT的组合 通过疗法增强危险信号途径的疫苗将进一步增强诱导 抗肿瘤免疫，并将在更具侵略性，自发的情况下增强对远处疾病的控制 转移肿瘤模型。因此，我们建议将PDT与增强免疫的剂相结合 通过信号通路的响应，与PDT处理的肿瘤细胞诱导的途径相称，以便为了 增强PDT疫苗或PDT诱导的抗肿瘤免疫反应。最后，我们证明了 PDT处理的肿瘤细胞可用于辅助设置，以增强手术后的抗肿瘤免疫力 在黑色素瘤临床前模型中切除。我们现在建议将这些发现扩展到临床环境 研究自体PDT疫苗的安全性和免疫原性用于运输中的晚期III 肿瘤手术切除后的黑色素瘤。这种更新的总体目标是了解 PDT增强肿瘤细胞免疫原性的机制，其长期目标的发展 临床PDT方案增强了抗肿瘤免疫力和战斗继发性疾病。我们的目前 目的是了解PDT促进抗肿瘤免疫以促进的机制 临床PDT方案的发展，既控制长期肿瘤生长又促进抗肿瘤 免疫。计划三个具体的目标，以使我们能够检验我们的假设并实现这一目标。这 前两个目标是临床前和协同作用。特定目标1检查了PDT处理的机制 肿瘤细胞激活NLR家族成员Nalp3。特定目的2探讨了TLR激动剂的使用 增强PDT生成的疫苗的抗肿瘤作用。该应用程序最终达到特定目标3， 测试PDT生成的疫苗的临床应用。 PDT是一种增长的有效疗法 疗法的复杂性阻碍了恶性肿瘤的数量，但是PDT的优化已受到阻碍。 我们的研究都将有助于优化PDT，并允许利用其增强抗肿瘤的能力 免疫。