PHOTODYNAMIC THERAPY (PDT) AND TUMOR IMMUNITY

光动力疗法 (PDT) 和肿瘤免疫

• 批准号: 7742976
• 负责人: Sandra O. Gollnick
• 金额: $ 35.46万
• 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/7742976
• 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 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; public health relevance; randomized trial; receptor; response; tumor; tumor growth; vaccine development

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Patients with advanced lymphatic metastatic melanoma have a poor long-term prognosis. The primary treatment for melanoma remains surgical excision, which can be curative for early disease, but has minimal effects on metastatic disease. The overall prognosis for patients with melanoma has not improved over the last 30 years despite substantial effort. In recent years a number of melanoma vaccines have been studied; however in spite of promising Phase I-II studies, no durable responses have been observed in Phase III randomized trials. These disappointing results are likely a result of a number of factors including tumor- induced immune suppression and tolerance and continued tumor growth. Thus efforts have focused on the development of vaccines that augment anti-tumor immunity by overcoming the natural suppressive factors, in an adjuvant setting, such as in combination with surgery. Our pre-clinical studies suggest that PDT directly alters tumor cell immunogenicity, in part through induction of "danger" signals. Our proposal is aimed at 1) understanding the response of immune cells to danger signals generated by PDT treatment of tumor cells and 2) enhancement of anti-tumor immunity by PDT vaccines through the use of combination treatments. We will use the results of these studies as guidelines for a Phase I trial that investigates the use of PDT-generated vaccines as adjuvants to surgical removal of tumors in patients with Stage III in-transient melanoma.

描述（由申请人提供）： 在癌症的鼠模型中，光动力疗法（PDT）处理的肿瘤细胞已被证明是有效的抗肿瘤疫苗。但是，PDT增强肿瘤免疫原性的机制尚不清楚。 PDT治疗肿瘤细胞已显示出诱导能够刺激抗肿瘤免疫力的“危险”信号的释放。危险信号由危险信号受体，收费受体（TLR）和点头lie受体（NLR）认识到。我们和其他人已经表明，PDT处理的肿瘤细胞含有TLR配体。在一个小说中，我们现在表明，经PDT处理的肿瘤细胞刺激了NLR危险受体家族。我们假设TLR和NLR的激活对于通过PDT增强抗肿瘤免疫力至关重要。此外，我们假设PDT或PDT疫苗与疗法的结合，即增强危险信号途径的诱导将进一步增强抗肿瘤免疫的诱导，并将导致对更积极的自发转移肿瘤模型的远距离疾病的控制。因此，我们建议将PDT与通过与PDT处理的肿瘤细胞相称的信号通路相结合，从而增强免疫反应，以增强PDT疫苗或PDT诱导的抗肿瘤免疫反应。最后，我们已经表明，在黑色素瘤前临床模型中，经手术切除后，可以在佐剂环境中使用PDT处理的肿瘤细胞，以增强抗肿瘤免疫力。现在，我们建议通过研究肿瘤手术切除后自体PDT疫苗对晚期黑色素瘤晚期III的自体PDT疫苗的安全性和免疫原性扩展到临床环境。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，其长期目标是开发临床PDT方案，从而增强了抗肿瘤免疫力和战斗继发性疾病。我们目前的目的是了解PDT促进抗肿瘤免疫的机制，以促进控制长期肿瘤生长并促进抗肿瘤免疫的临床PDT方案的发展。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。前两个目标是临床前和协同作用。具体目标1检查了PDT处理的肿瘤细胞激活NLR家族成员NALP3的机制。具体目标2探讨了TLR激动剂的使用来增强PDT生成的疫苗的抗肿瘤作用。该应用最终导致特定的目标3，该AIM 3测试了PDT生成的疫苗的临床应用。 PDT是越来越多的恶性肿瘤的有效疗法，但是PDT的优化受到治疗的复杂性的阻碍。我们的研究都将有助于优化PDT，并允许利用其增强抗肿瘤免疫力的能力。 公共卫生相关性： 晚期淋巴转移性黑色素瘤的患者的长期预后较差。黑色素瘤的主要治疗方法仍然是手术切除，可以治愈早期疾病，但对转移性疾病的影响最小。尽管付出了巨大的努力，但在过去30年中，黑色素瘤患者的总体预后尚未得到改善。近年来，已经研究了许多黑色素瘤疫苗。然而，尽管有有希望的I-II研究，但在III期随机试验中仍未观察到持久的反应。这些令人失望的结果可能是许多因素的结果，包括肿瘤诱导的免疫抑制和耐受性以及持续的肿瘤生长。因此，努力集中在疫苗的开发上，这些疫苗通过在辅助环境中（例如与手术结合使用）来克服自然抑制因素来增强抗肿瘤免疫力。我们的临床前研究表明，PDT部分通过诱导“危险”信号来直接改变肿瘤细胞的免疫原性。我们的建议针对1）了解免疫细胞对PDT治疗肿瘤细胞产生的危险信号的反应； 2）通过使用组合处理，通过PDT疫苗增强了抗肿瘤免疫力。我们将将这些研究的结果用作I期试验的指南，该指南研究了PDT生成的疫苗作为辅助剂作为手术清除肿瘤的辅助因子，这是III期期内置良好性黑色素瘤患者的肿瘤。