Optimizing Immunotherapy Strategies to Eliminate Recurrences after Cancer Surgery

优化免疫治疗策略以消除癌症手术后的复发

• 批准号: 9190873
• 负责人: Jarrod D Predina
• 金额: $ 6.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-06 至 2018-07-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190873
• 关键词: Adenoviruses; Adjuvant; Antigen Presentation; Blood; CD8B1 gene; Cells; Clinical; Clinical Trials; Cross Presentation; Cytotoxic Chemotherapy; Data; Dinoprostone; Disease; Effector Cell; Excision; Future; Goals; Human; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Interferon Type I; Interferon-alpha; Interferons; Lead; Malignant Neoplasms; Malignant Pleural Mesothelioma; Mammalian Cell; Mediator of activation protein; Mentors; Modeling; Mus; Myelogenous; Myeloproliferative disease; Operative Surgical Procedures; PTGS2 gene; Pathway interactions; Patients; Postoperative Period; Proteins; Radiation; Recurrence; Recurrent tumor; Regimen; Regulatory T-Lymphocyte; Research; Research Personnel; Residual Tumors; Scientist; Series; Signal Transduction; Site; Solid Neoplasm; Staging; Suppressor-Effector T-Lymphocytes; Techniques; Testing; Therapeutic; Therapeutic immunosuppression; Training; Tumor Antigens; Tumor Debulking; Vaccines; Work; base; cancer cell; cancer recurrence; cancer surgery; career; chemotherapy; clinical efficacy; cytokine; experience; graduate student; improved; inhibitor/antagonist; killings; leukemia; lymph nodes; macrophage; meetings; melanoma; neoplastic cell; next generation; novel; pre-clinical; prevent; research study; response; standard of care; success; tumor; tumor growth; tumor immunology; tumor microenvironment

Immunotherapy is based on the premise that there are intrinsic differences in the protein composition of tumor cells that allow the immune system to recognize tumor cells as “foreign” and eradicate them. There is increasing evidence that tumors respond to immunotherapy [1], particularly in scenarios of minimal disease [2- 4]. Because immunotherapy is effective in treating small amounts of disease, it seems “obvious” that if one could reduce tumor size with surgery/chemotherapy, the addition of immunotherapy would eliminate the minimal amount of residual disease and lead to a cure (i.e. the concept of adjuvant immunotherapy). Unfortunately, dozens of clinical trials using immunotherapy (usually vaccines) after surgery for a variety of cancers have been conducted and virtually all have failed [5-7]. As a graduate student, I obtained data suggesting that debulking surgery fails to eliminate immunosuppressive networks consisting of cellular and soluble factors at the (i) resection site, (ii) draining lymph nodes and (iii) blood [2]. The overarching hypothesis of this proposal is that disruption of post-operative immunosuppressive networks is necessary to maximize efficacy of immunotherapy. Using Malignant Pleural Mesothelioma (MPM) as a model, our proposed research aims to (1) determine the potential efficacy and mechanisms of a series of clinically available agents hypothesized to decrease immunosuppressive effects and (2) analyze combinations of immunotherapy, surgery, and chemotherapy in order to identify the optimal regimen for future clinical trials. MPM is an excellent choice to study this approach as the disease remains essentially incurable despite multi-modal approaches (including surgery, chemotherapy, radiation) [8] and our group has greater than 15 years of experience in human immunotherapy clinical trials for MPM [9-14]. The research will also serve as a training platform for the applicant towards competency in tumor immunology, mammalian cell techniques, and murine experiments, as well as provide the applicant with mentoring towards the goal of becoming an independent investigator in translational tumor immunology. This work will set the stage for the next generation of clinical trials which combines multi-modal immunotherapy with surgical resection for patients with MPM. These findings will also be applicable to other malignancies that are treated with surgery, chemotherapy and radiation.

免疫疗法的前提是蛋白质之间存在内在差异。 一种肿瘤细胞的成分，使免疫系统能够识别肿瘤细胞是“外来的”和 铲除他们。越来越多的证据表明，肿瘤对免疫治疗有反应[1]，尤其是 在病情轻微的情况下[2-4]。因为免疫疗法对治疗小细胞肺癌很有效 疾病的数量，这似乎是“显而易见的”，如果一个人可以通过 手术/化疗，加上免疫疗法将消除最少量的残留 疾病并导致治愈(即辅助免疫疗法的概念)。不幸的是，数十名 各种癌症手术后使用免疫疗法(通常是疫苗)的临床试验 已经进行了，几乎所有的都失败了[5-7]。作为一名研究生，我获得了数据 这表明去茎手术不能消除免疫抑制网络，该网络包括 (I)切除部位、(Ii)引流淋巴结和(Iii)血液中的细胞和可溶性因子 [2]。这一建议最重要的假设是手术后的干扰 免疫抑制网络对于最大化免疫治疗的效果是必要的。 以恶性胸膜间皮瘤(MPM)为模型，我们的研究目的是：(1)确定 一系列临床可用药物的潜在疗效和机制假设 减少免疫抑制效应和(2)分析免疫治疗、手术和 化疗，以确定未来临床试验的最佳方案。MPM是一种 研究这种方法的绝佳选择，因为这种疾病基本上仍然无法治愈，尽管 多种模式的方法(包括手术、化疗、放射治疗)[8]我们组有更大的 在MPM的人体免疫疗法临床试验方面有超过15年的经验[9-14]。这项研究 也将作为申请者培养肿瘤免疫学能力的培训平台， 哺乳动物细胞技术和小鼠实验，以及为申请者提供指导 朝着成为翻译肿瘤免疫学的独立研究者的目标前进。 这项工作将为结合多种模式的下一代临床试验奠定基础 免疫治疗联合手术切除治疗多发性骨髓瘤这些发现也将适用于 到其他接受手术、化疗和放射治疗的恶性肿瘤。