Enhancing dendritic cell migration to drive potent anti-tumor immune responses

增强树突状细胞迁移以驱动有效的抗肿瘤免疫反应

• 批准号: 8593967
• 负责人: Kristen Batich
• 金额: $ 4.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593967
• 关键词: Accounting; Action Research; Active Immunotherapy; Address; Adult; Affect; Antigens; Area; Benchmarking; Biological Markers; Brain; Cancer Etiology; Cancer Vaccines; Cell physiology; Cells; Cessation of life; Chemotaxis; Child; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Data; Dendritic Cell Vaccine; Dendritic Cells; Diagnosis; Diphtheria; Diphtheria Toxoid; Dose; FDA approved; Glioblastoma; Granulocyte-Macrophage Colony-Stimulating Factor; Hodgkin Disease; Homing; Human; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Inflammation Mediators; Injection of therapeutic agent; Kidney; Lead; Life; Macrophage Inflammatory Protein-1; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of urinary bladder; Measurement; Mediating; Mediator of activation protein; Memory; Methods; Modality; Modeling; Mus; Operative Surgical Procedures; Outcome; Patients; Phase III Clinical Trials; Play; Prostate; Protocols documentation; Radiation; Randomized Clinical Trials; Refractory; Research; Role; Safety; Serology; Serum; Site; Solutions; Specificity; T memory cell; T-Lymphocyte; Testing; Tetanus; Time; Tumor Antigens; Vaccine Adjuvant; Vaccine Therapy; Vaccines; base; brain tissue; cancer therapy; cell motility; chemokine; chemotherapy; cohort; conditioning; cytokine; improved; improved functioning; lymph nodes; meetings; melanoma; migration; mortality; neoplastic cell; novel; outcome forecast; pre-clinical; public health relevance; response; tumor; tumor growth; vaccine efficacy

DESCRIPTION (provided by applicant): Malignant brain tumors in adults account for more deaths than Hodgkin's disease, melanoma, and cancers of the bladder or kidney. Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival of 15 months. Despite aggressive surgery, high-dose radiation, and toxic chemotherapy, GBM is almost universally fatal. Moreover, current therapy is limited by collateral damage to surrounding healthy brain. Immunotherapy directed against tumor cells holds the potential to precisely target GBM while sparing healthy brain tissue. The use of dendritic cells (DCs) as cancer vaccine adjuvants is a promising strategy to induce anti- tumor immune responses, and we are currently evaluating the use of DCs to stimulate immunity and prolong survival in GBM patients. Clinical trials routinely focus on T cell function and persistence as predictive biomarkers of vaccine efficacy, but these measurements rarely correlate with clinical responses. In a recently completed randomized clinical trial, we found that migration of injected DCs to local lymph nodes strongly correlated with clinical outcomes in GBM patients and that DC migration to lymph nodes was significantly enhanced by conditioning the injection site with a recall antigen. Our preclinical data corroborate these effects of enhanced DC migration and additionally elucidate that conditioning with the recall antigen 1) provides a sustained elevation in tumor antigen-specific T cells over time and 2) significantly suppresses malignant tumor growth. Preliminary data reveals that the memory T cell compartment plays a critical role in mediating DC migration, which suggests a novel role for the recall response in governing DC homing to lymph nodes. In this proposal, we will identify the cellular subsets and cell-derived soluble mediators that drive DC migration. Furthermore, we intend to improve our DC vaccine therapies through identification of serologic biomarkers that can predict efficient DC migration and ultimately superior anti-tumor responses. Lastly, we will evaluate the quality of immune responses that follow enhanced DC migration and lead to increased survival in a preclinical GBM model. This proposal addresses several research aims presented in the 2012 NCI research action plan, specifically those related to developing more effective and efficient treatments for cancer while maintaining safety to the patient. Eliciting the mechanisms by which immunologic memory responses drive DC lymph node homing addresses a critical immunobiologic question and provides translatable modalities aimed at overcoming the inherent boundaries in peripherally administering DC vaccines. Methods derived from this research to enhance DC migration have a significant potential to enhance the efficacy of our ongoing efforts at Duke in treating patients with GBM and other aggressively fatal cancers.

描述（由申请人提供）：成人恶性脑肿瘤的死亡人数比霍奇金氏病，黑色素瘤和膀胱或肾脏的癌症更多。胶质母细胞瘤多形（GBM）是最常见的恶性脑肿瘤，中位生存期为15个月。尽管手术，高剂量辐射和有毒化疗，但GBM几乎是致命的。此外，当前的治疗受到周围健康大脑的附带损害的限制。针对肿瘤细胞的免疫疗法在保留健康的脑组织时具有精确靶向GBM的潜力。 使用树突状细胞（DC）作为癌症疫苗佐剂是诱导抗肿瘤免疫反应的有前途的策略，我们目前正在评估DC在GBM患者中使用DC刺激免疫力和延长生存率。临床试验通常集中于T细胞功能和持久性作为疫苗功效的预测生物标志物，但是这些测量很少与临床反应相关。在最近完成的随机临床试验中，我们发现注射DC的迁移到局部淋巴结与GBM患者的临床结局密切相关，并且DC迁移到淋巴结的迁移可以通过调节注射部位的召回抗原来显着增强。我们的临床前数据证实了增强的直流迁移的这些影响，并阐明了召回抗原的调节1）随着时间的推移，肿瘤抗原特异性T细胞的持续升高和2）显着抑制了恶性肿瘤的生长。初步数据表明，记忆T细胞室在介导DC迁移中起着至关重要的作用，这暗示了召回响应在管理DC归位淋巴结中的新作用。在此提案中，我们将确定驱动直流迁移的细胞子集和细胞来源的可溶性介质。此外，我们打算通过鉴定可以预测有效的直流迁移并最终有效的抗肿瘤反应来改善直流疫苗疗法。最后，我们将评估遵循增强的直流迁移并导致临床前GBM模型中生存率增加的免疫反应质量。 该提案涉及2012年NCI研究行动计划中提出的几项研究目标，特别是那些与为癌症开发更有效和有效治疗的同时维持对患者的安全性的研究。引发免疫记忆反应驱动DC淋巴结归巢的机制解决了一个关键的免疫生物学问题，并提供了可翻译的方式，旨在克服外围施用直流疫苗的固有边界。从这项研究中得出的增强直流迁移的方法具有增强我们在杜克大学治疗GBM和其他积极致命癌症患者中努力的效力的重要潜力。