PHOTODYNAMIC THERAPY (PDT) AND 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 小鼠癌症模型的治疗和预防环境。然而，光动力疗法的机制 增强肿瘤的免疫原性尚不清楚。肿瘤细胞的PDT治疗已被证明可以诱导 释放能够刺激抗肿瘤免疫的“危险”信号。通过识别危险信号 危险信号受体、Toll样受体(TLRs)和NLRs(NLRs)。我们和其他人已经展示了 经PDT处理的肿瘤细胞含有TLR配体。在一项新的发现中，我们现在表明，光动力疗法治疗的肿瘤细胞 刺激NLR危险受体家族。我们假设TLR和NLR的激活对 光动力疗法增强抗肿瘤免疫作用。此外，我们假设光动力疗法或光动力疗法的组合 带有增强危险信号通路诱导的疗法的疫苗将进一步增强对 抗肿瘤免疫，将导致增强对远端疾病的控制，更具侵略性，自发性强 转移性肿瘤模型。因此，我们建议将光动力疗法与增强免疫的药物相结合。 通过与PDT治疗的肿瘤细胞互补的信号通路进行反应，以便 增强PDT疫苗或PDT诱导的抗肿瘤免疫反应。最后，我们展示了 PDT治疗的肿瘤细胞可以在辅助环境中使用，以增强手术后的抗肿瘤免疫 黑色素瘤临床前模型的切除。我们现在建议通过以下方式将这些发现扩展到临床环境 晚期III期运输中自体PDT疫苗的安全性和免疫原性研究 肿瘤手术切除后的黑色素瘤。此次更新的总体目标是了解 PDT增强肿瘤细胞免疫原性的机制及其发展的长期目标 增强抗肿瘤免疫和抗击继发性疾病的临床PDT方案。我们目前的情况 目的：了解光动力疗法促进抗肿瘤免疫的机制，以促进 既能控制肿瘤长期生长又能促进抗肿瘤的临床光动力疗法的研究进展 豁免权。计划了三个具体目标，以使我们能够检验我们的假设并实现这一目标。这个 前两个目标是临床前和协同作用；特殊目标1研究光动力疗法的治疗机制。 肿瘤细胞激活NLR家族成员NALP3。特定目标2探索TLR激动剂的使用 增强PDT疫苗的抗肿瘤效果。该申请在特定目标3中达到顶峰， 它测试了PDT产生的疫苗的临床应用。光动力疗法是一种治疗青光眼的有效方法。 然而，PDT的优化由于治疗的复杂性而受到阻碍。 我们的研究将有助于PDT的优化，并允许开发其增强抗肿瘤的能力 豁免权。

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.