CCL3 as a Developmental Therapeutic to Enhance Brain Tumor Therapy

CCL3 作为一种增强脑肿瘤治疗的发育疗法

基本信息

批准号：
9216208
负责人：
JOHN H. SAMPSON
金额：
$ 34.78万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9216208
关键词：
Adjuvant Affect Antigens Bilateral Brain Brain Neoplasms CCR1 gene CCR5 gene CD8-Positive T-Lymphocytes Cancer Etiology Cells Cervical Cessation of life Clinical Trials Cytotoxic T-Lymphocytes Data Dendritic Cell Vaccine Dendritic Cells Developmental Therapeutics Program Diphtheria Toxoid Dose Glioblastoma Glioma Goals Human Immune Immunity Immunotherapy Individual Inflammation Inflammatory Injectable Interferon Type II Intracranial Neoplasms Laboratories Ligands Malignant - descriptor Malignant neoplasm of brain Mediator of activation protein Memory Methods Modeling Mus Nature Newly Diagnosed Normal tissue morphology Patients Pharmaceutical Preparations Phase Primary Brain Neoplasms Production Progression-Free Survivals Publications Publishing Renal carcinoma Role Signal Transduction Site Small Inducible Cytokine A3 Source T cell response T-Lymphocyte TNF gene Tetanus Toxic effect Tumor Antigens Tumor Immunity Vaccination Vaccines Work cell motility chemokine childhood cancer mortality cytokine gamma-Chemokines immune function improved individual patient innovation lymph nodes melanoma migration mouse model novel pre-clinical preclinical study preconditioning receptor response targeted treatment trafficking tumor tumor growth vaccine development vaccine efficacy young adult

项目摘要

ABSTRACT: Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma (GBM) is uniformly lethal, and current therapy is non-specific and produces a median overall survival of <15 months. In contrast, immunotherapy promises an exquisitely precise approach, and substantial evidence suggests that T cells can eradicate large, well-established tumors in mice and humans even when tumors reside within the brain. Dendritic cells (DCs) bearing tumor antigen can be delivered as a vaccine and migrate to the draining lymph nodes (DLN) to trigger the formation of potent tumor-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor while leaving normal tissue unharmed. However, despite individual cases of remarkable patient responses to antitumor DC vaccination, overall objective responses in early phase clinical trials have remained under 15%. The migration of vaccine-delivered DCs is low (~5%), and preclinical studies have demonstrated that preconditioning the vaccine site with the inflammatory cytokines can increase DC migration to the DLN and proportionately increase the magnitude of the antigen-specific T cell response. We hypothesized that preconditioning the vaccine site with the recall antigens in Tetanus/diphtheria toxoid (Td) would induce inflammation, increase DC migration, and elicit more consistently efficacious antitumor immunity. In a recent study in patients with newly diagnosed GBM published in Nature, we demonstrated that unilaterally preconditioning one vaccine site with Td resulted in increased bilateral DC migration to the DLNs and a significant increase in progression free survival and OS - with three of the six Td treated patients living past 4.5 years. A recapitulative murine model corroborated these findings, demonstrating that Td preconditioning both enhanced systemic DC migration to the DLNs and suppressed tumor growth in an antigen-dependent manner. Examination of both patient and murine sera revealed that the chemokine (C-C motif) ligand 3 (CCL3) was the only cytokine or chemokine significantly upregulated after Td preconditioning. Furthermore, in mice we demonstrated that the systemic increase in DC migration after Td preconditioning is dependent upon CD4+ memory effector T cells (CD4Td−mem) and CCL3. However, recent pilot data from our laboratory indicate that the CD4Td−mem are actually responsible for the production of CCL3, suggesting CCL3 serves as the primary driver of the improved antigen-dependent immunity from Td preconditioning. We hypothesize that in addition to enhancing the migration of DCs to the DLN, that CCL3 directly increases antigen-specific T cell magnitude and functionality as well as immune cell trafficking to tumor. This proposal will mechanistically determine the specific role of CCL3 in DC migration, antigen-specific T cell responses, as well as immune cell trafficking, and will further assess if the antitumor efficacy of DC vaccination can be further enhanced by the use of exogenous CCL3 as a vaccine-enhancing drug.

摘要：恶性原发性脑肿瘤是儿童癌症死亡的最常见原因和年轻人，其死亡人数比肾癌或胶质母细胞瘤 (GBM) 还要多。一致致命，目前的治疗是非特异性的，中位总生存期<15个月。相比之下，免疫疗法有望提供一种极其精确的方法，并且大量证据表明 T 即使肿瘤存在于小鼠和人类体内，细胞也可以根除巨大的、已形成的肿瘤。携带肿瘤抗原的树突状细胞（DC）可以作为疫苗输送并迁移至引流管。淋巴结（DLN）触发有效的肿瘤特异性细胞毒性T淋巴细胞（CTL）的形成，能够根除肿瘤同时保持正常组织不受伤害然而，尽管个别病例显着。患者对抗肿瘤 DC 疫苗接种的反应，早期临床试验中的总体客观反应疫苗递送的 DC 的迁移率仍低于 15%（约 5%），并且临床前研究表明。证明用炎症细胞因子预处理疫苗位点可以增加 DC 迁移 DLN 并按比例增加抗原特异性 T 细胞反应的强度。培育了用破伤风/白喉类毒素 (Td) 中的召回抗原预处理疫苗位点会诱发炎症，增加 DC 迁移，并引发更一致有效的抗肿瘤免疫。在最近发表在《自然》杂志上的一项针对新诊断 GBM 患者的研究中，我们证明单方面用 Td 预处理一个疫苗位点导致双侧 DC 向 DLN 迁移增加，并且无进展生存期和 OS 显着增加 - 6 名 Td 治疗患者中的 3 名活过 4.5 一个概括性的小鼠模型证实了这些发现，表明 Td 预处理了这两种情况。增强全身 DC 向 DLN 的迁移，并以抗原依赖性方式抑制肿瘤生长。对患者和小鼠血清的检查表明，趋化因子（C-C 基序）配体 3 (CCL3) 是此外，在小鼠中，只有细胞因子或趋化因子在 Td 预处理后显着上调。 Td 预处理后 DC 迁移的系统性增加取决于 CD4+ 然而，我们实验室最近的试验数据表明，记忆效应 T 细胞 (CD4Td−mem) 和 CCL3。 CD4Td−mem 实际上负责 CCL3 的产生，表明 CCL3 是主要驱动力 Td 预处理改善的抗原依赖性免疫。增强 DC 向 DLN 的迁移，CCL3 直接增加抗原特异性 T 细胞的数量，该提案将机械地确定功能以及免疫细胞向肿瘤的运输。 CCL3 在 DC 迁移、抗原特异性 T 细胞反应以及免疫细胞运输中的特定作用，以及将进一步评估DC疫苗接种的抗肿瘤功效是否可以通过使用外源性进一步增强 CCL3 作为疫苗增强药物。