Regional melanoma chemotherapy: a novel way to augment systemic immunotherapy

区域黑色素瘤化疗：增强全身免疫治疗的新方法

• 批准号: 8925659
• 负责人: DOUGLAS S TYLER
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925659
• 关键词: Adjuvant; Animal Model; Antibodies; Area; Biopsy; C57BL/6 Mouse; Cell Death; Clinical Trials; Colon Carcinoma; Correlative Study; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Development; Disease; Dose; Effectiveness; Elements; Event; Gene Expression; Goals; Grant; Health; Human; Immune; Immune response; Immune system; Immunocompetent; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In complete remission; Incidence; Indium; Individual; Infiltration; Infusion procedures; Knowledge; Limb structure; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediator of activation protein; Melphalan; Metastatic Melanoma; Mus; Neoplasm Metastasis; Patients; Phase; Pre-Clinical Model; Property; Proteins; Regional Chemotherapy; Regulatory T-Lymphocyte; Research Priority; Role; Secondary to; Signal Transduction; Solid Neoplasm; Sun Exposure; Therapeutic; Therapy Clinical Trials; Time; Transforming Growth Factor beta; Translating; Veterans; Work; advanced disease; anticancer research; base; chemotherapy; cytotoxic; disorder control; immune activation; improved; individualized medicine; malignant breast neoplasm; melanoma; neoplastic cell; novel; predictive of treatment response; prevent; public health relevance; response; temozolomide; treatment strategy; tumor; tumor microenvironment; years of life lost; young adult

 DESCRIPTION (provided by applicant): Metastatic melanoma is a highly lethal cancer that is associated with the greatest number of productive years of life lost of any solid tumor. Recently significant progress has been made in treating metastatic melanoma by commandeering the immune system through targeting the checkpoint proteins CTLA-4 and PD- 1. Durable response rates of 20-30% in patients with metastatic disease receiving anti-CTLA-4 and anti-PD-1 therapies have generated tremendous promise for a group of individuals whose mean survival had historically been measured in months. However, a significant gap exists in our knowledge of how to improve the effectiveness of checkpoint blockade specifically focused on the question of whether adding a cytotoxic anti- tumor treatment to checkpoint blockade can significantly augment the number of patients who benefit from this form of immunologic treatment. Because systemic chemotherapy treatments are frequently immunosuppressive and have limited effectiveness against melanoma, they are not ideal to utilize in conjunction with immunotherapeutic strategies. Uniquely, melanoma has an array of regional therapeutic strategies that are currently employed for patients with locally advanced disease. The most commonly utilized of these treatments is isolated regional chemotherapy infusions which have complete response rates in the range of 30-50%. Surprisingly, little is know as to whether tumors treated regionally generate an immune response or if these treatments can be synergistic with checkpoint blockade therapy. Therefore, the overall goal of this project is to determine if various regional anti-tumor chemotherapeutic treatments currently utilized in melanoma can augment the immunologic effectiveness of systemic checkpoint blockade therapy and to define the optimal way to deliver this form of combinational therapy. Our group specializes in utilizing preclinical models of advanced extremity melanoma to optimize local disease control and develop unique treatment strategies that are rapidly translated into phase I and II clinical trials. This work has generated our centra hypothesis that regional chemotherapy can generate an immune-activating response which could augment the therapeutic potential of immune checkpoint blockade therapy in overcoming tumor-induced immunosuppression. Integral to this proposal is our use of immunocompetent mice to define how the immune system contributes to local and systemic responses to our optimized regional treatment of melanoma. The scientific rationale behind the proposed specific aims in this grant is to not only determine if regional chemotherapy can render melanoma "visible" to the immune system but also to allow us to rapidly translate our findings into human trials by defining proper dosing and timing relative to checkpoint blockade. The projects specific aims are: SA 1. Explore the immunologic properties of novel regional chemotherapeutics, determining the optimal dose of these agents to stimulate innate immune activation and generate an adaptive anti-tumor immune response and defining the mediators of this response. SA 2. Determine if targeting immunosuppressive elements of the tumor microenvironment increases the magnitude and duration of anti-tumor immune responses generated by regional chemotherapeutic treatment. SA 3. Establish whether regional therapy combined with adjuvant antibody treatments to minimize immunosuppressive elements in the microenvironment can augment the induction of anti-tumor responses induced by various checkpoint blockade thera-pies and define the optimal timing for this approach. The impact of the studies proposed in this grant will be to either limit further use of regional therapies or define a new role for them in melanoma as part of combinational trials using checkpoint blockade therapy that can be rapidly translated into our current portfolio of clinical trials.

 描述（由申请人提供）： 转移性黑色素瘤是一种高度致命的癌症，与任何实体瘤的生命年生命年数年最多有关。最近，通过靶向检查点蛋白CTLA-4和PD-1来治疗转移性黑色素瘤，在治疗转移性黑色素瘤方面取得了重大进展。接受抗CTLA-4和抗PD-1疗法的转移性疾病患者的持久缓解率为20-30％，抗PD-1疗法对某些人的有意义的人来说已经为个人带来了巨大的希望。然而，我们的知识中存在一个很大的差距，即如何提高检查点阻滞的有效性，专门针对添加细胞毒性抗肿瘤治疗的问题是否可以显着增加从这种免疫治疗形式中受益的患者数量。由于系统性化疗治疗通常是免疫抑制性的，并且针对黑色素瘤的有效性有限，因此与免疫治疗策略结合使用并不理想。独特的是，黑色素瘤具有一系列区域治疗策略，目前针对局部晚期疾病的患者使用。这些治疗方法最常用的是孤立的区域化疗输注，其完全缓解率在30-50％的范围内。令人惊讶的是，鲜为人知的肿瘤是否会产生免疫反应，或者这些治疗方法是否可以通过检查点阻断疗法协同作用。因此，该项目的总体目标是确定当前在黑色素瘤中使用的各种区域性抗肿瘤化疗治疗是否可以增强全身检查点封锁治疗的免疫学有效性，并定义提供这种组合疗法的最佳方法。我们的小组专门利用晚期黑色素瘤的临床前模型来优化局部疾病控制和发展独特的治疗策略，这些治疗策略迅速转化为I期和II期临床试验。这项工作产生了我们的CentRA假设，即区域化疗可以产生免疫激活反应，从而可以增强免疫切除点阻断疗法在克服肿瘤诱导的免疫抑制方面的治疗潜力。该提案不可或缺的是，我们使用免疫能力的小鼠来定义免疫系统如何对我们对黑色素瘤进行优化的区域治疗的局部和全身反应做出贡献。该赠款中提出的特定目的背后的科学原理不仅是确定区域化疗是否可以使黑色素瘤“可见”到免疫系统中，而且还可以使我们能够通过定义相对于检查点封锁的适当定义适当的剂量和时间来将我们的发现迅速转化为人类试验。该项目具体的目的是：SA 1。探索新型区域化疗的免疫学特性，确定这些药物的最佳剂量以刺激肿瘤微环境的先天免疫抑制元素，从而增加了由区域化学治疗治疗产生的抗肿瘤免疫源的大小和持续时间。 SA 3。确定区域治疗是否与可调抗体治疗相结合，以最大程度地减少微环境中的免疫抑制元素可以增加通过各种检查点阻滞疗法引起的抗肿瘤反应的诱导，并定义此方法的最佳时机。本赠款中提出的研究的影响是限制进一步使用区域疗法，或者是使用CheckPoint Blockade治疗的组合试验的一部分，在黑色素瘤中定义了新作用，可以快速转化为我们当前的临床试验组合。